WikiVet English - User contributions [en]

Autoimmune Diseases

2009-08-15T11:04:22Z

Kwhittle: /* Cell mediated autoimmune diseases */

{{review}}

{{toplink
|linkpage =WikiClinical
|linktext =WikiClinical
|maplink = WikiClinical Content Map
|pagetype = Clinical
|sublink1 = Immunology - WikiBlood
|subtext1 = IMMUNOLOGY
}}
 
==Introduction==

'''Autoimmune disease''' is defined as ''a disease state characterised by a specific antibody or cell mediated response against the body's own tissues ('self' antigens).

The breakdown of [[Immune Tolerance - WikiBlood|tolerance]] to self antigens and the failure to regulate pathological immune responses are both responsible for autoimmune diseases. It has been shown in mice that thymectomy causes autoimmune disease, and plays a very important role in the recognition of 'self'.

Particular individuals may be more susceptible to autoimmune diseases due to:

===Genetic factors===

Many autoimmune diseases have a familiar component and the Human Leucocyte Antigen (HLA) haplotype is the predominant genetic factor, however having a particular HLA haplotype does not automatically result in the development of an autoimmune disease.

* HLA-DR3/DR4 (MHC Class II):
1. Diabetes Mellitus

2. Rheumatoid Arthritis

* HLA-B27 (MHC Class I):
1. Ankylosing spondylitis

* TNF alpha

* CTLA-4

===Hormonal factors===

Testosterone is protective against Systemic Lupus Erythematosus (SLE) and thus it is not seen in males.

===Environmental factors===

'''''Infection'''''

1. Molecular mimicry

* Some bacteria and viruses have antigens that resemble host-cell components and the body can then also initiate an immune response against itself.

2. Polyclonal activation

* T and B cells activation can occur as a result of an infection resulting in polyclonal activation. This can then cause autoreactive autoantibodies or mediate autoimmunity.

3. Inappropriate MHC expression

* Autoreactive T cells are activated because infection stimulates APC and upregulates MHC class II.

'''''Diet'''''

'''''Stress'''''

{| border="1" cellpadding="2"
!width="150"|
!width="150"|Antibody mediated
!width="50"|Antibody mediated
!width="200"|Cell mediated
|-
| '''Type of hypersensitivity''' || [[Type II Hypersensitivity - WikiBlood|Type II]] || [[Type III Hypersensitivity - WikiBlood|Type III]] || [[Type IV Hypersensitivity - WikiBlood|Type IV]]
|-
| '''Pathogenesis''' || Antibody to cell surface or matrix antigens || Antibody to soluble self antigens || T cell and macrophage activation to self antigens
|-
| '''Examples of diseases''' || Immune mediated haemolytic anaemia (IMHA) || Systemic Lupus Erythematosus (SLE) || Rheumatoid arthritis
|-
| || Immune mediated thrombocytopaenia (IMTP)|| || Diabetes Mellitus type 1
|-
| || Myasthenia gravis || || Hypothyroidism (lymphocytic throiditis)
|-
| || Pemphigus Vulgaris || || Hypoadrenocorticism (Addisons disease)
|-
| || Bullous pemphigoid || ||
|}

==Antibody mediated autoimmune diseases==
[[Image:Large.jpg|right|thumb|150px|Myasthenia gravis - From Immunity: The Immune Response in Infectious and Inflammatory Disease DeFranco, Locksley and Robertson New Science Press 1999-2007]]

===1. Immune Mediated Haemolytic Anaemia (IMHA)===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* Autoantibody attack on the red blood cells causing extravascular and intravascular lysis which causes anaemia.
* The in saline autoagglutination test and the coombes test is used to diagnose the disorder.

===2. Immune Mediated Thrombocytopaenia (IMTP) ===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* There is an immunological attack on the platelets which reduces the ability for clotting.
* A reduced platelet count and detection of anti-platelet antibodies in the serum are used for diagnosis of this disorder.

===3. Myasthenia gravis===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===4. Bullous Pemphigoid===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===5. Pemphigus Vulgaris===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===6. Systemic Lupus Erythematosus (SLE)/Multi-systemic immune mediated disease===

'''Pathogenesis:''' [[Type III Hypersensitivity - WikiBlood|Type III hypersensitivity]]

==Cell mediated autoimmune diseases==
[[Image:Rheumatoid Arthritis Type IV hypersensitivity.jpg|right|thumb|150px|Rheumatoid Arthritis-Brian Catchpole RVC 2008]]
[[Image:Diabetes Mellitus Type IV hypersensitivity.jpg|right|thumb|150px|Diabetes Mellitus-Brian Catchpole RVC 2008]]

===1. Rheumatoid arthritis===

'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]: CD4 Th-1 cell mediated.
* Macrophages phagocytose self antigens and can present peptides on their MHC Class II molecules. The autoreactive TH-1 cells release IFN-gamma which activates macrophages to release prostaglandins, MMP enzymes and TNF-alpha (pro-inflammatory mediator), see diagram. These cytokines cause inflammation and tissue destruction.

===2. Diabetes Mellitus type I===
'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]
* The CTLs think that all the beta cells in the pancreas are infected by a virus, as it wrongly detects a self antigen presented by the MHC class I on the surface of the cell as foreign.
* Autoreactive CD8+ CTLs are inadvertently activated, destroying the beta cells, thus preventing the secretion of insulin and causing diabetes type 1 (see diagram).

===3. Hypothyroidism (lymphocytic throiditis)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

* T cell mediated

===4. Hypoadrenocorticism (Addisons disease)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

==References==

Autoimmune Diseases

2009-08-15T11:01:17Z

Kwhittle: /* Environmental factors */

{{review}}

{{toplink
|linkpage =WikiClinical
|linktext =WikiClinical
|maplink = WikiClinical Content Map
|pagetype = Clinical
|sublink1 = Immunology - WikiBlood
|subtext1 = IMMUNOLOGY
}}
 
==Introduction==

'''Autoimmune disease''' is defined as ''a disease state characterised by a specific antibody or cell mediated response against the body's own tissues ('self' antigens).

The breakdown of [[Immune Tolerance - WikiBlood|tolerance]] to self antigens and the failure to regulate pathological immune responses are both responsible for autoimmune diseases. It has been shown in mice that thymectomy causes autoimmune disease, and plays a very important role in the recognition of 'self'.

Particular individuals may be more susceptible to autoimmune diseases due to:

===Genetic factors===

Many autoimmune diseases have a familiar component and the Human Leucocyte Antigen (HLA) haplotype is the predominant genetic factor, however having a particular HLA haplotype does not automatically result in the development of an autoimmune disease.

* HLA-DR3/DR4 (MHC Class II):
1. Diabetes Mellitus

2. Rheumatoid Arthritis

* HLA-B27 (MHC Class I):
1. Ankylosing spondylitis

* TNF alpha

* CTLA-4

===Hormonal factors===

Testosterone is protective against Systemic Lupus Erythematosus (SLE) and thus it is not seen in males.

===Environmental factors===

'''''Infection'''''

1. Molecular mimicry

* Some bacteria and viruses have antigens that resemble host-cell components and the body can then also initiate an immune response against itself.

2. Polyclonal activation

* T and B cells activation can occur as a result of an infection resulting in polyclonal activation. This can then cause autoreactive autoantibodies or mediate autoimmunity.

3. Inappropriate MHC expression

* Autoreactive T cells are activated because infection stimulates APC and upregulates MHC class II.

'''''Diet'''''

'''''Stress'''''

{| border="1" cellpadding="2"
!width="150"|
!width="150"|Antibody mediated
!width="50"|Antibody mediated
!width="200"|Cell mediated
|-
| '''Type of hypersensitivity''' || [[Type II Hypersensitivity - WikiBlood|Type II]] || [[Type III Hypersensitivity - WikiBlood|Type III]] || [[Type IV Hypersensitivity - WikiBlood|Type IV]]
|-
| '''Pathogenesis''' || Antibody to cell surface or matrix antigens || Antibody to soluble self antigens || T cell and macrophage activation to self antigens
|-
| '''Examples of diseases''' || Immune mediated haemolytic anaemia (IMHA) || Systemic Lupus Erythematosus (SLE) || Rheumatoid arthritis
|-
| || Immune mediated thrombocytopaenia (IMTP)|| || Diabetes Mellitus type 1
|-
| || Myasthenia gravis || || Hypothyroidism (lymphocytic throiditis)
|-
| || Pemphigus Vulgaris || || Hypoadrenocorticism (Addisons disease)
|-
| || Bullous pemphigoid || ||
|}

==Antibody mediated autoimmune diseases==
[[Image:Large.jpg|right|thumb|150px|Myasthenia gravis - From Immunity: The Immune Response in Infectious and Inflammatory Disease DeFranco, Locksley and Robertson New Science Press 1999-2007]]

===1. Immune Mediated Haemolytic Anaemia (IMHA)===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* Autoantibody attack on the red blood cells causing extravascular and intravascular lysis which causes anaemia.
* The in saline autoagglutination test and the coombes test is used to diagnose the disorder.

===2. Immune Mediated Thrombocytopaenia (IMTP) ===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* There is an immunological attack on the platelets which reduces the ability for clotting.
* A reduced platelet count and detection of anti-platelet antibodies in the serum are used for diagnosis of this disorder.

===3. Myasthenia gravis===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===4. Bullous Pemphigoid===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===5. Pemphigus Vulgaris===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===6. Systemic Lupus Erythematosus (SLE)/Multi-systemic immune mediated disease===

'''Pathogenesis:''' [[Type III Hypersensitivity - WikiBlood|Type III hypersensitivity]]

==Cell mediated autoimmune diseases==
[[Image:Rheumatoid Arthritis Type IV hypersensitivity.jpg|right|thumb|150px|Rheumatoid Arthritis-Brian Catchpole RVC 2008]]
[[Image:Diabetes Mellitus Type IV hypersensitivity.jpg|right|thumb|150px|Diabetes Mellitus-Brian Catchpole RVC 2008]]

===1. Rheumatoid arthritis===

'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]: CD4 Th-1 cell mediated.
* Macrophages phagocytose self antigens and can present peptides on their MHC Class II molecules. The autoreactive TH-1 cells release IFN-gamma which activates macrophages to release prostaglandins, MMP enzymes and TNF-alpha (pro-inflammatory mediator), see diagram. These cytokines cause inflammation and tissue destruction.

===2. Diabetes Mellitus type I===
'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]
* The CTLs think that all the beta cells in the pancreas are infected by a virus, as it wrongly detects a self antigen presented by the MHC class I on the surface of the cell as foreign.
* Autoreactive CD8+ CTLs are inadvertently activated destroying the beta cells thus preventing the secretion of insulin and causing diabetes type 1 (see diagram).

===3. Hypothyroidism (lymphocytic throiditis)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

* T cell mediated

===4. Hypoadrenocorticism (Addisons disease)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

==References==

Autoimmune Diseases

2009-08-15T10:59:25Z

Kwhittle: /* Genetic factors */

{{review}}

{{toplink
|linkpage =WikiClinical
|linktext =WikiClinical
|maplink = WikiClinical Content Map
|pagetype = Clinical
|sublink1 = Immunology - WikiBlood
|subtext1 = IMMUNOLOGY
}}
 
==Introduction==

'''Autoimmune disease''' is defined as ''a disease state characterised by a specific antibody or cell mediated response against the body's own tissues ('self' antigens).

The breakdown of [[Immune Tolerance - WikiBlood|tolerance]] to self antigens and the failure to regulate pathological immune responses are both responsible for autoimmune diseases. It has been shown in mice that thymectomy causes autoimmune disease, and plays a very important role in the recognition of 'self'.

Particular individuals may be more susceptible to autoimmune diseases due to:

===Genetic factors===

Many autoimmune diseases have a familiar component and the Human Leucocyte Antigen (HLA) haplotype is the predominant genetic factor, however having a particular HLA haplotype does not automatically result in the development of an autoimmune disease.

* HLA-DR3/DR4 (MHC Class II):
1. Diabetes Mellitus

2. Rheumatoid Arthritis

* HLA-B27 (MHC Class I):
1. Ankylosing spondylitis

* TNF alpha

* CTLA-4

===Hormonal factors===

Testosterone is protective against Systemic Lupus Erythematosus (SLE) and thus it is not seen in males.

===Environmental factors===

'''''Infection'''''

1. Molecular mimicry

* Some bacteria and viruses have antigens that resemble host-cell components and the body then also can initiate an immune response against itself.

2. Polyclonal activation

* T and B cells activation can occur as a result of an infection resulting in polyclonal activation. This can then cause autoreactive autoantibodys or mediate autoimmunity.

3. Inappropriatee MHC expression

* Autoreactive T cells are activated because infection stimulates APC and upregulates MHC class II.

'''''Diet'''''

'''''Stress'''''

{| border="1" cellpadding="2"
!width="150"|
!width="150"|Antibody mediated
!width="50"|Antibody mediated
!width="200"|Cell mediated
|-
| '''Type of hypersensitivity''' || [[Type II Hypersensitivity - WikiBlood|Type II]] || [[Type III Hypersensitivity - WikiBlood|Type III]] || [[Type IV Hypersensitivity - WikiBlood|Type IV]]
|-
| '''Pathogenesis''' || Antibody to cell surface or matrix antigens || Antibody to soluble self antigens || T cell and macrophage activation to self antigens
|-
| '''Examples of diseases''' || Immune mediated haemolytic anaemia (IMHA) || Systemic Lupus Erythematosus (SLE) || Rheumatoid arthritis
|-
| || Immune mediated thrombocytopaenia (IMTP)|| || Diabetes Mellitus type 1
|-
| || Myasthenia gravis || || Hypothyroidism (lymphocytic throiditis)
|-
| || Pemphigus Vulgaris || || Hypoadrenocorticism (Addisons disease)
|-
| || Bullous pemphigoid || ||
|}

==Antibody mediated autoimmune diseases==
[[Image:Large.jpg|right|thumb|150px|Myasthenia gravis - From Immunity: The Immune Response in Infectious and Inflammatory Disease DeFranco, Locksley and Robertson New Science Press 1999-2007]]

===1. Immune Mediated Haemolytic Anaemia (IMHA)===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* Autoantibody attack on the red blood cells causing extravascular and intravascular lysis which causes anaemia.
* The in saline autoagglutination test and the coombes test is used to diagnose the disorder.

===2. Immune Mediated Thrombocytopaenia (IMTP) ===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* There is an immunological attack on the platelets which reduces the ability for clotting.
* A reduced platelet count and detection of anti-platelet antibodies in the serum are used for diagnosis of this disorder.

===3. Myasthenia gravis===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===4. Bullous Pemphigoid===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===5. Pemphigus Vulgaris===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===6. Systemic Lupus Erythematosus (SLE)/Multi-systemic immune mediated disease===

'''Pathogenesis:''' [[Type III Hypersensitivity - WikiBlood|Type III hypersensitivity]]

==Cell mediated autoimmune diseases==
[[Image:Rheumatoid Arthritis Type IV hypersensitivity.jpg|right|thumb|150px|Rheumatoid Arthritis-Brian Catchpole RVC 2008]]
[[Image:Diabetes Mellitus Type IV hypersensitivity.jpg|right|thumb|150px|Diabetes Mellitus-Brian Catchpole RVC 2008]]

===1. Rheumatoid arthritis===

'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]: CD4 Th-1 cell mediated.
* Macrophages phagocytose self antigens and can present peptides on their MHC Class II molecules. The autoreactive TH-1 cells release IFN-gamma which activates macrophages to release prostaglandins, MMP enzymes and TNF-alpha (pro-inflammatory mediator), see diagram. These cytokines cause inflammation and tissue destruction.

===2. Diabetes Mellitus type I===
'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]
* The CTLs think that all the beta cells in the pancreas are infected by a virus, as it wrongly detects a self antigen presented by the MHC class I on the surface of the cell as foreign.
* Autoreactive CD8+ CTLs are inadvertently activated destroying the beta cells thus preventing the secretion of insulin and causing diabetes type 1 (see diagram).

===3. Hypothyroidism (lymphocytic throiditis)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

* T cell mediated

===4. Hypoadrenocorticism (Addisons disease)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

==References==

Autoimmune Diseases

2009-08-15T10:57:26Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|linkpage =WikiClinical
|linktext =WikiClinical
|maplink = WikiClinical Content Map
|pagetype = Clinical
|sublink1 = Immunology - WikiBlood
|subtext1 = IMMUNOLOGY
}}
 
==Introduction==

'''Autoimmune disease''' is defined as ''a disease state characterised by a specific antibody or cell mediated response against the body's own tissues ('self' antigens).

The breakdown of [[Immune Tolerance - WikiBlood|tolerance]] to self antigens and the failure to regulate pathological immune responses are both responsible for autoimmune diseases. It has been shown in mice that thymectomy causes autoimmune disease, and plays a very important role in the recognition of 'self'.

Particular individuals may be more susceptible to autoimmune diseases due to:

===Genetic factors===

Many autoimmune diseases have a familiar component and the Human Leucocyte Antigen (HLA) haplotype is the prodomient genetic factor, however having a particular HLA haplotype does not automatically result in the development of an autoimmune disease.

* HLA-DR3/DR4 (MHC Class II):
1. Diabetes Mellitus

2. Rheumatoid Arthritis

* HLA-B27 (MHC Class I):
1. Ankylosing spondylitis

* TNF alpha

* CTLA-4

===Hormonal factors===

Testosterone is protective against Systemic Lupus Erythematosus (SLE) and thus it is not seen in males.

===Environmental factors===

'''''Infection'''''

1. Molecular mimicry

* Some bacteria and viruses have antigens that resemble host-cell components and the body then also can initiate an immune response against itself.

2. Polyclonal activation

* T and B cells activation can occur as a result of an infection resulting in polyclonal activation. This can then cause autoreactive autoantibodys or mediate autoimmunity.

3. Inappropriatee MHC expression

* Autoreactive T cells are activated because infection stimulates APC and upregulates MHC class II.

'''''Diet'''''

'''''Stress'''''

{| border="1" cellpadding="2"
!width="150"|
!width="150"|Antibody mediated
!width="50"|Antibody mediated
!width="200"|Cell mediated
|-
| '''Type of hypersensitivity''' || [[Type II Hypersensitivity - WikiBlood|Type II]] || [[Type III Hypersensitivity - WikiBlood|Type III]] || [[Type IV Hypersensitivity - WikiBlood|Type IV]]
|-
| '''Pathogenesis''' || Antibody to cell surface or matrix antigens || Antibody to soluble self antigens || T cell and macrophage activation to self antigens
|-
| '''Examples of diseases''' || Immune mediated haemolytic anaemia (IMHA) || Systemic Lupus Erythematosus (SLE) || Rheumatoid arthritis
|-
| || Immune mediated thrombocytopaenia (IMTP)|| || Diabetes Mellitus type 1
|-
| || Myasthenia gravis || || Hypothyroidism (lymphocytic throiditis)
|-
| || Pemphigus Vulgaris || || Hypoadrenocorticism (Addisons disease)
|-
| || Bullous pemphigoid || ||
|}

==Antibody mediated autoimmune diseases==
[[Image:Large.jpg|right|thumb|150px|Myasthenia gravis - From Immunity: The Immune Response in Infectious and Inflammatory Disease DeFranco, Locksley and Robertson New Science Press 1999-2007]]

===1. Immune Mediated Haemolytic Anaemia (IMHA)===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* Autoantibody attack on the red blood cells causing extravascular and intravascular lysis which causes anaemia.
* The in saline autoagglutination test and the coombes test is used to diagnose the disorder.

===2. Immune Mediated Thrombocytopaenia (IMTP) ===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

* There is an immunological attack on the platelets which reduces the ability for clotting.
* A reduced platelet count and detection of anti-platelet antibodies in the serum are used for diagnosis of this disorder.

===3. Myasthenia gravis===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===4. Bullous Pemphigoid===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===5. Pemphigus Vulgaris===

'''Pathogenesis:''' [[Type II Hypersensitivity - WikiBlood|Type II hypersensitivity]]

===6. Systemic Lupus Erythematosus (SLE)/Multi-systemic immune mediated disease===

'''Pathogenesis:''' [[Type III Hypersensitivity - WikiBlood|Type III hypersensitivity]]

==Cell mediated autoimmune diseases==
[[Image:Rheumatoid Arthritis Type IV hypersensitivity.jpg|right|thumb|150px|Rheumatoid Arthritis-Brian Catchpole RVC 2008]]
[[Image:Diabetes Mellitus Type IV hypersensitivity.jpg|right|thumb|150px|Diabetes Mellitus-Brian Catchpole RVC 2008]]

===1. Rheumatoid arthritis===

'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]: CD4 Th-1 cell mediated.
* Macrophages phagocytose self antigens and can present peptides on their MHC Class II molecules. The autoreactive TH-1 cells release IFN-gamma which activates macrophages to release prostaglandins, MMP enzymes and TNF-alpha (pro-inflammatory mediator), see diagram. These cytokines cause inflammation and tissue destruction.

===2. Diabetes Mellitus type I===
'''Pathogenesis:'''

* [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]
* The CTLs think that all the beta cells in the pancreas are infected by a virus, as it wrongly detects a self antigen presented by the MHC class I on the surface of the cell as foreign.
* Autoreactive CD8+ CTLs are inadvertently activated destroying the beta cells thus preventing the secretion of insulin and causing diabetes type 1 (see diagram).

===3. Hypothyroidism (lymphocytic throiditis)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

* T cell mediated

===4. Hypoadrenocorticism (Addisons disease)===

'''Pathogenesis:''' [[Type IV Hypersensitivity - WikiBlood|Type IV hypersensitivity]]

==References==

Type IV Hypersensitivity

2009-08-14T13:32:43Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Hypersensitivity - WikiBlood
|subtext1 =HYPERSENSITIVITY
|pagetype =Blood
}}

==Introduction==
[[Image:Sensitisation phase Type IV Hypersensitivity.jpg|right|thumb|150px|Sensitisation phase: Type VI hypersensitivity-Brian Catchpole RVC 2008]]

[[Image:Delayed type hypersensitivity.jpg|right|thumb|150px|Type VI hypersensitivity-Brian Catchpole RVC 2008]]
Cell mediated hypersensitivity:

Type IV hypersensitivity, also known as delayed hypersensitivity, involves [[Cytokines - WikiBlood|cytokines]] being secreted from the Th-I cells, which causes the activation of [[Macrophages - WikiBlood|macrophages]] and other T cells.

* [[Lymphocytes - WikiBlood#Helper CD4+|'''CD4+ (helper)''']] mediated:
** Abnormal activation of macrophages in healthy tissues.
** Macrophage production of inflammatory mediators and MMP (matrix metalloproteinase) enzymes cause tissue damage.

* [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ (cytotoxic)''']] mediated:
** Cytotoxic T lymphocytes (CTLs) kill healthy cells mistakenly thinking they are infected by a virus.

Exposure to antigen causes [[Lymphocytes - WikiBlood#Helper CD4+|'''CD4+ T helper cells''']] to be activated leading to colonal expansion (takes 1-2 weeks). On subsequent exposure with the same antigen sensitised [[Lymphocytes - WikiBlood#Helper CD4+|'''CD4+ T helper cells''']] secrete [[Cytokines - WikiBlood|cytokines]] which attract and activate macrophages. The [[Macrophages - WikiBlood|macrophages]] have an increased ability to phagocytose pathogens, which is very important for the clearance of intracellular pathogens. However if antigen exposure persists, the lytic products of the macrophages can damage healthy tissues.

==2 types:==
===1. Contact===
* Involves simple chemicals (antigens) which bind to skin proteins:
** Nickle
** Rubber
** Poison ivy
<big>'''''Distinguishing contact from immediate hypersensitivity'''''</big>
{| style="width:60%; height:200px" border="1" align=left
!
![[Allergic diseases - WikiClinical#1. Atopic dermatitis - Dogs and horses|'''Atopic dermatitis''']]
!'''Contact dermatitis'''
|-
| '''Pathogenesis'''
| [[Type I Hypersensitivity - WikiBlood|Type I]]
| [[Type IV Hypersensitivity - WikiBlood|Type IV]]
|-
| '''Time'''
| 20 mins
| 24-48 hours
|-
| '''Distribution'''
| face, nose, eyes, feet, perineum
| hairless regions
|-
| '''Antigens'''
| foods, pollens, fleas, inhaled allergens
| chemicals, dyes
|-
| '''Diagnosis'''
| "prick" test
| patch test for delayed hypersensitivity
|-
|'''Pathology'''
| [[Mast Cells - WikiBlood|mast cells]], [[Eosinophils - WikiBlood|eosinophils]]
| [[Monocytes - WikiBlood|mononuclear cells]]
|}
 

===2. Granulomatous===
* Intense activation of T cells, [[Cytokines - WikiBlood|cytokine]] release and [[Macrophages - WikiBlood|macrophage]] activation cause necrosis of surrounding tissue, granuloma formation leading to destruction of host tissue.
* Composed of epithelial cell, [[Macrophages - WikiBlood#Giant cells|giant cells]] and [[Macrophages - WikiBlood|macrophage]] in response to infection, for example:
** [[Mycobacteria spp.|''Mycobacterium tubercle'']]
** Schistosome eggs
* Granulomas can obstruct normal organ function:
** Lungs: fills up with cells leading to impaired function
** Brain/liver: very severe

===Tuberculin test===
* Injection of intradermal antigen into the skin.
* A skin reaction (infiltration of lymphocytes and monocytes) peaking at 48-72 hours indicates prior exposure to the antigen or ongoing infection.
* It is used for TB testing cattle; the antigen is purified protein derivative-PPD from [[Mycobacteria spp.|''Mycobacterium tuberculosis'']].
* Presently in the UK the animal is culled if it has a positive skin reaction.

Type III Hypersensitivity

2009-08-14T13:32:05Z

Kwhittle: /* Location of the immune complexes: */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Hypersensitivity - WikiBlood
|subtext1 =HYPERSENSITIVITY
|pagetype =Blood
}}

==Introduction==
[[Image:Type III hypersensitivity antibody excess.jpg|right|thumb|150px|Type III hypersensitivity antibody excess-Brian Catchpole RVC 2008]]

[[Image:Type III hypersensitivity antigen excess.jpg|right|thumb|150px|Type III hypersensitivity antigen excess-Brian Catchpole RVC 2008]]

In the normal animal, immune complexes (lattice of soluble antigen and antibodies) are formed and removed all the time. They are broken up by complement, transported to the spleen by RBC's and phagocytosed. When the amount of immune complexes formed (due to rapid influx of antigen) does not equal the amount that are being cleared it causes type III hypersensitivity (an excess of immune complexes).

==Location of the immune complexes:==

'''Locally:'''

1. Inhaled antigen leads to hypersensitivity pneumonitis
* Farmers lung (humans) - inhalation of fungal spores
* Pigeon fancier's disease - repeated inhalation of dried pigeon faeces
* Mouldy hay containing ''Micropolyspora felis''

2. Intradermal and subcutaneous injection of antigen (with high levels of circulating antibody) leads to localised immune complexes which cause acute inflammation.

3. Vasculitis - due to antigen deposition in blood vessels.

4. Arthritis

5. [[Kidney Glomerular Disease - Pathology|Glomerulonephritis]]
* Can occur as an adverse effect of antibody response to infection if there is significant levels of antigen in the circulation. Examples of diseases that can cause this are:
** Leishmaniasis
** Lymes disease
** African swine fever

'''Systemically:'''

Due to increased quantities of antigen systemically.

Generalised effects:
* Vasculitis
* Erythema
* Oedema
* Neutropaenia
* Proteinuria (caused by of kidney damage)

1. Drug reactions (eg. penicillins and sulphonamides)

2. [[Autoimmune diseases - WikiClinical#6. Systemic Lupus Erythematosus (SLE)/Multi-systemic immune mediated disease|Systemic lupus erythematous (SLE)]]- antigen is a self antigen (autoimmune disease of dogs and cats)

Type III Hypersensitivity

2009-08-14T13:30:58Z

Kwhittle:

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Hypersensitivity - WikiBlood
|subtext1 =HYPERSENSITIVITY
|pagetype =Blood
}}

==Introduction==
[[Image:Type III hypersensitivity antibody excess.jpg|right|thumb|150px|Type III hypersensitivity antibody excess-Brian Catchpole RVC 2008]]

[[Image:Type III hypersensitivity antigen excess.jpg|right|thumb|150px|Type III hypersensitivity antigen excess-Brian Catchpole RVC 2008]]

In the normal animal, immune complexes (lattice of soluble antigen and antibodies) are formed and removed all the time. They are broken up by complement, transported to the spleen by RBC's and phagocytosed. When the amount of immune complexes formed (due to rapid influx of antigen) does not equal the amount that are being cleared it causes type III hypersensitivity (an excess of immune complexes).

==Location of the immune complexes:==

'''Locally:'''

1. Inhaled antigen leads to hypersensitivity pneumonitis
* Farmers lung (humans)-inhalation of fungal spores
* Pigeon fancier's disease-repeated inhalation of dried pigeon faeces
* Mouldy hay containing ''Micropolyspora felis''

2. Intradermal and subcutaneous injection of antigen (with high levels of circulating antibody) leads to localised immune complexes which cause acute inflammation.

3. Vasculitis - due to antigen deposition in blood vessels.

4. Arthritis

5. [[Kidney Glomerular Disease - Pathology|Glomerulonephritis]]
* Can occur as an adverse effect of antibody response to infection if there is significant levels of antigen in the circulation. Examples of diseases that can cause this are:
** Leishmaniasis
** Lymes disease
** African swine fever

'''Systemically:'''

Due to increased quantities of antigen systemically.

Generalised effects:
* Vasculitis
* Erythema
* Oedema
* Neutropaenia
* Proteinuria (caused by of kidney damage)

1. Drug reactions (eg. penicillins and sulphonamides)

2. [[Autoimmune diseases - WikiClinical#6. Systemic Lupus Erythematosus (SLE)/Multi-systemic immune mediated disease|Systemic lupus erythematous (SLE)]]- antigen is a self antigen (autoimmune disease of dogs and cats)

Type II Hypersensitivity

2009-08-14T13:30:05Z

Kwhittle: /* Mechanism */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Hypersensitivity - WikiBlood
|subtext1 =HYPERSENSITIVITY
|pagetype =Blood
}}

[[Image:Type II Hypersensitivity.jpg|right|thumb|150px|Type II Hypersensitivity-Brian Catchpole RVC 2008]]
==Introduction==

Production of [[Immunoglobulin M - WikiBlood|IgM]] or [[Immunoglobulin G - WikiBlood|IgG]] to cell surface antigens or extracellular matrix proteins.

==Mechanism==

''' "Neutralisation" blockade of receptors:'''
* Antibodies attach to receptors, which prevents other molecules attaching.
* For example in myasthenia gravis antibodies attach to acetylcholine receptors which in turn prevents acetylcholine from attaching to the receptor and thus muscle contraction of that cell does not occur.

''' Immunological attack on target cells, destroying them by (see diagram):'''

[[Adaptive Immune System - WikiBlood#Adaptive Immunity to Viruses|1. Antibody dependent cell cytotoxicity (ADCC)]]
* [[Autoimmune diseases - WikiClinical#5. Pemhigus Vulgaris|Pemphigus vulgaris]]
* [[Autoimmune diseases - WikiClinical#4. Bullous Pemphigoid|Bullous pemphigoid]]

2. [[Complement - WikiBlood|Complement]] mediated lysis
* Self [[Erythrocytes - WikiBlood|RBC]] antigen:
** [[Autoimmune diseases - WikiClinical#1. Immune Mediated Haemolytic Anaemia (IMHA)|Immune mediated haemolytic anaemia]]
* Foreign [[Erythrocytes - WikiBlood|RBC]]:
** Blood transfusion reaction
** [[Materno-fetal immunity - WikiBlood#Alloimmune haemalytic anaemia of the newborn|Haemolytic disease of new born (Rhesus disease in humans and neonatal isoerythrolysis in foals and kittens)]]
* RBC parasite:
** Feline infectious anaemia (''Mycoplasma haemofelis'')
3. Phagocytosis

Type I Hypersensitivity

2009-08-14T13:28:30Z

Kwhittle: /* Mechanism */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Hypersensitivity - WikiBlood
|subtext1 =HYPERSENSITIVITY
|pagetype =Blood
}}
==Introduction==

* Also known as [[Immunoglobulin E - WikiBlood|IgE]]-mediated or anaphylactic hypersensitivity.
* Ranges from mild cases, such as hayfever, to life-threatening reactions, such as bee-stings.
* Antigens that induce a type I reaction are known as allergens.
* Generally affects face, eyes, nose and feet
* [[Immunoglobulin E - WikiBlood|IgE]] has a high affinity to IgE receptors on [[Mast Cells - WikiBlood|mast cells]] and [[Basophils - WikiBlood|basophils]], and so binds these receptors.

==Common allergens which elict a type I hypersensitivity reaction:==

* Proteins : Foreign serum
* Plant pollens : Rye grass, ragweed, timothy grass, birch trees
* Drugs : Penicillin, sulphonamides, local anaesthetics, salicylates
* Foods : Nuts, seafood, eggs, milk
* Insect products : Bee venom, wasp venom, dust mites faeces, flea saliva

==Mechanism==

[[Image:Sensitisation phase1.jpg|right|thumb|150px|IMAGE 1: Sensitisation phase1.jpg
-Brian Catchpole RVC 2008]]
[[Image:Immediate-type hypersensitivity.jpg|right|thumb|150px|IMAGE 2: Immesdiate-type hypersensitivity-Brian Catchpole/M Maidment RVC 2008]]

'''1. Initial antigen exposure sensitises immune system (Image 1):'''
* Allergen exposure causes IgE production.
* IgE coat mast cells by binding to Fc receptors.
* Mast cells are now sensitised to this particular allergen.

'''2. Subsequent exposure to the specific allergen (Image 2):'''
* [[Mast Cells - WikiBlood|Mast cells]] degranulate.
* [[Basophils - WikiBlood|Basophils]] with [[Immunoglobulin E - WikiBlood|IgE]] receptors are recruited and also degranulate.

Mast cells secrete mediators:
* The release of inflammatary [[Cytokines - WikiBlood|cytokines]] which can cause the dog to become itchy.
**Steroid mediators, e.g. prostaglandins and leukotriens
1. Chemoattractants (attracts mainly neutrophils but also [[Eosinophils - WikiBlood|eosinophils]], [[Monocytes - WikiBlood|monocytes]] and [[Basophils - WikiBlood|basophils]] and plasma)

2. Vasoactive and inflammatory peptides (e.g. histamine and serotonin) which causes acute contraction of smooth muscle fibres
*If the allergen is inhaled (locally) it can lead to bronchoconstriction.

3. Mucus production - due to the release of mast cell proteases

4. Vasodilation (leads to redness and heat).

5. Oedema (from leaky blood vessels).

'''3. The late phase response:'''
* Mediated by [[Eosinophils - WikiBlood|eosinophils]].
* Takes longer (several hours) as the eosinophils are mobilised from the bone marrow.

===Examples of Type I hypersensitivity===

* [[Allergic diseases - WikiClinical#Allergic diseases#1. Atopic dermatitis - Dogs and horses|Atopy]]
* [[Allergic diseases - WikiClinical#Allergic diseases#2. Flea allergic dermatitis (FAD)- Dogs and cats|Flea allergic dermatitis]]
* [[Allergic diseases - WikiClinical#Allergic diseases#3. Culicoides hypersensitivity (Sweet itch) - Horses|Sweet itch]]

Immune Tolerance

2009-08-14T13:24:11Z

Kwhittle: /* Mechanisms */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immune Tolerance(Concept Map) - WikiBlood
|pagetype =Blood
}}

=Immune Tolerance=
Immunological tolerance is the state of unresponsiveness towards particular antigens, whereby immune responses are prevented or suppressed. Tolerance is required to prevent:
* Potentially harmful inflammatory responses towards innocuous substances, such as air-borne or food antigens
* To prevent an immune attack against host tissue- described as '''self-tolerance'''

=T Cell Tolerance=

During T cell development within the thymus, genes encoding the T cell receptor are rearranged, resulting in adult cells that are able to recognise antigen fragments displayed by the host MHC molecule. Some receptors however will be self-reactive, i.e. they bind too strongly to antigens expressed by the host's own tissues ('''autoantigens'''). As these cells will induce immune reactions that could be damaging to the host ([[Autoimmune diseases - WikiClinical#Autoimmune diseases|Autoimmunity]]), they must be deleted or suppressed.

==Central Tolerance==
[[Image:Thymic selection of t cells.jpg|thumb|right|150px|Negative selection of t cells- copyright Brian Catchpole]]
*Takes place within the thymus
*Involves the processes '''positive''' and '''negative''' selection
** During positive selection, cells passing through the thymic cortex encounter cortical epithelial cells expressing MHC molecules. Those with a suitable level of binding affinity for the MHC recieve 'survival' signals and apoptosis is prevented (at the same time cells lose either their CD4 or CD8 co-receptor)
**During negative selection, cells passing through the corticomedullary junction and thymic medulla once again encounter MHC molecules, on epithelial cells, dendritic cells and macrophages, this time bound to self-peptide. Cells bearing receptors that bind too strongly to this complex are deleted through mechanisms that induce apoptosis.

==Peripheral Tolerance==
It is inevitable that some self-reactive T cells will get through the thymic selection process and into the periphery, as:
*Some self-antigens are not expressed in the thymus
*Some antigens will not show sufficient affinity to MHC to form the MHC:self-peptide complex required for negative selection in the thymus
*Conversely some T cell receptors will not have enough affinity for their respective self-antigen to induce apoptosis
Peripheral tolerance is the process in which unresponsiveness towards self-antigen is developed outside the primary lymphoid organs. There are four ways this may be achieved in T cells:
* Ignorance
* Anergy
* Cell death
* Immune deviation/suppression

===Ignorance===
Can occur if;
* Self-reactive T cells cannot penetrate an endothelial barrier
* Self-antigen is present in very low amount
* Self-antigen is present on cells that do not express/express low amount of MHC
* T cells are not present in sufficient numbers to mount effective response
* Self-antigen is presented without co-stimulation- can lead to ignorance or anergy, depending on type of antigen and affinity to TCR

===Anergy===
* Defined as a state where the T cell is still alive, but fails to respond to stimulation from its specific T cell receptor and other receptors required for activation
* Easily induced in T cells ''in vivo'' by activation of T cell receptor without co-stimulation
* Induced ''in vitro'' by injection of potent superantigens (antigens that stimulate T cells with different receptor types, using the same T cell receptor V gene)
* Can be caused by downregulation of T cell receptors as a result of chronic stimulation
** Anergy induced without co-stimulation can be reversed by IL-2

===Cell death===
Peripheral deletion of T cells requires the engagement of:
* Fas by Fas ligand
** Deficiencies in Fas ligand lead to lymphoproliferative disorders
** After activation by an antigen, T cells upregulate expression of Fas ligand
** Some tissues, such as the testis and retina, constitutively express Fas ligand to protect themselves from activated T cells
* TNF via TNF receptor
* CTLA-4 recently implicated
* Subsequent signalling cascade activates proteases, such as IL-1beta Converting Enzyme (ICE), that leads to apoptosis

===Immune deviation===
* Th2-derived cytokines, such as IL-10, typically support antibody production, but also down-regulate macrophage effector functions, such as antigen presentation, thereby suppressing inflammatory responses
* Likewise, Th1-derived gamma-IFN can prevent Th0-Th2 differentiation
** This process is described as '''immune deviation''', i.e. one response being selectively induced over the other
* In the case of self-antigens, autoimmune diseases such as diabetes are caused by Th1 cells and can be prevented by 'antigen-primed' Th2 cells.

=Mucosal tolerance=
Mucosal tolerance is the systemic unresponsiveness towards antigens administered across the mucosal surfaces
*As the highest antigenic load of the body surfaces occurs in the GI tract, it is also known as oral tolerance
*When oral tolerance towards food antigens breaks down, inflammatory autoimmune responses are induced
*Gut associated lymphoid tissue is important for developing oral tolerance:
**Animals that lack Peyer’s patches and mesenteric lymph nodes do not develop oral tolerance
**It is thought the liver and spleen may also play a role

==Mechanisms==
*High doses of antigen can cause anergy or cell death
*Low doses can induce a T cell response:
**The antigen is taken up and presented, inducing a Th2-like cell response
**This cell response produces cytokines that suppress the Th1 inflammatory response, such as IL-10 and TGF-beta
***Although the cellular response is antigen-specific, the cytokines released are not. TGF-beta is known to inhibit the proliferation and function of B-cells, cytotoxic T cells and NK cells. This means tolerance induction to one antigen suppresses an immune response to a second associated antigen- this mechanism has been used to suppress some autoimmune diseases by feeding with an antigen isolated from the affected tissue. This is known as ‘’bystander suppression’’.

==Other mucosal surfaces==
*Nasal deposition of some peptides can be used to induce tolerance, controlling both humoral and cellular responses
*Administration of antigen in aerosol form to the lung has been used to control both allergic and autoimmune responses

=Regulatory T Cells=
A number of cell populations identified during studies on autoimmunity and organ transplantation have shown the capacity to suppress responses to self-antigen and regulate rejection. Although once considered a tentative theory, this form of tolerance is now considered a major mechanism in the protection of host tissue from immune attack.
[[Image:T reg cells.JPG|thumb|right|150px|Regulatory T cells- copyright Brian Catchpole]]
* Known as '''regulatory T cells''', these CD4+ cells are antigen-specific
* Currently thought to develop in the thymus
* They usually release inhibitory cytokines, e.g. IL-4, IL-10 and TGF-beta
* When their TCRs bind to an antigen, they do not proliferate themselves but suppress the proliferation of other ''naive'' T cells responding to that antigen
* Mechanism of suppression is dependent on:
** CTLA-4 on the regulatory T cell binding with B7 on the target T cell
* Both cells binding the same antigen
* Regulatory T cells are unique in their use of a transcription repressor known as FoxP3
** Encoded by a gene on the X chromosome, rare deficiencies in FoxP3 are characterised by autoimmunity, primarily towards gut tissue, the thyroid, pancreative beta-cells and the skin. Sufferers are unable to produce regulatory T cells and the only known treatment is a bone marrow transplant from a MHC-identical sibling.

==[[Immune tolerance flashcards - Wikiblood|Immune tolerance flashcards]]==

==Creators==

[[Edward Ayton]]

Western blot

2009-08-14T13:18:10Z

Kwhittle:

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

Also known as immunoblotting, the Western blot technique is used to identify specific proteins or antibodies in complex mixtures and has largely overtaken the use of immunoelectrophoresis in research and diagnosis.

===Principle===
In the Western blot technique, a protein mixture is electrophoretically separated onto a denaturing gel, separating the proteins according to molecular weight. The bands can then be identified by applying enzyme-/radio-labeled antibodies to the mixture and the resulting complexes visualised either by ELISA technique or autoradiography.

===Method===
# Protein mixture is treated with sodium dodecyl sulfate (SDS), a strong dissociating agent
# Mixture is separated by electrophoresis - takes place in SDS polyacrylamide gel (SDS-PAGE)
# The gel is removed and applied to a protein-binding sheet of nitrocellulose/nylon and an electric current passed through it
# The antigens of interest are detected using enzyme-linked antibodies
# An ELISA reaction is used to detect the position of the antibodies

===Applications===
*'''HIV testing'''- this is the most widely used application of this test, used to determine whether a patient is producing antibodies specific to viral proteins present during an HIV infection

Immunodiffusion

2009-08-14T13:08:09Z

Kwhittle:

{{review}}

{{toplink
|backcolour = FFE4E1
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|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
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}}

Immunodiffusion reactions are diagnostic tests that use the diffusion of particles through a medium (such as agar) to measure:
*Relative concentrations of antibodies/antigens
*Relative purity of an antigen preparation

There are two types of immunodiffusion reaction, both being carried out on a semisolid medium:
*'''Radial immunodiffusion''': also known as the Mancini method. The medium is prepared with a suitable dilution of antiserum and the antigen sample placed on top and allowed to diffuse. As diffusion takes place, large insoluble complexes form creating a ring of precipitation (precipitin). By comparing the area of the ring with a standard curve, the concentration of the antigen sample can be determined.
*'''Double immunodiffusion''': also known as the Ouchterlony method. Antigen and antibody preparations are placed on the medium and both allowed to diffuse radially from the wells towards each other. This establishes a concentration gradient, forming an area of equivalence and line of precipitin.

Radioimmunoassay

2009-08-14T13:05:14Z

Kwhittle: /* Technique */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
The radioimmunoassay (RIA) is a sensitive technique used to detect the presence of antigen in a sample using radiolabelled antibodies. Developed in the 1960's, the RIA proved a powerful tool in antigen detection, although the procedure was soon overtaken by ELISA, which utilises enzymes rather than radioactive labels. RIAs are still used today however, to measure:
*Hormone levels in blood and tissue fluids
*Serum proteins
*Drugs
*Vitamins
**Levels can be detected when as low as 0.001 micrograms per millilitre, therefore this technique can be use to detect trace amounts of drug

==Principle==
*The general priniciple behind the RIA is the competitive binding of a radiolabeled antigen and unlabeled antigen to a high-affinity antibody.
*Labeled antigen is mixed with antibody until binding sites are saturated
*Samples of unlabeled antigen (unknown concentration) are added in progressively increasing amounts
**The two different antigens compete for the binding sites on the antibody
**As the concentration of unlabeled antibody increases, more labeled antigen will be displaced
*The decrease in bound-radiolabeled antigen is measured - an indication of the amount of antigen present in sample

==Technique==
*The antigen is often labeled with a gamma-emitting isotope, e.g. iodine-125
**Beta-emitting isotopes such as tritium are also often used

# Determine the amount of antibody required to bind ~50% of radiolabeled antigen in mixture- ''required to ensure the number of epitopes presented by labeled antigen exceeds number of antibody binding sites''
# Add unlabeled antigen to mixture
# Separate antigen-antibody complex from free antigen by precipitation
# Measure radioactivity in precipitate
*There are various methods to separate the antigen-antibody complexes from the free antigen:
**Precipitate complexes using secondary isotype-specific anti-immunoglobulin
**If complex contains IgG, it can be removed by mixing with formalin-killed ''Staphylococcus aureus''- protein A of ''S. aureus'' has a high affinity for IgG
*** Removal of the complex by either of these methods leaves an amount of free labeled antigen in the supernatant (liquid section from precipitation)- the radioactivity of this can be measured and the value taken away from the total amount of labeled antigen added (known amount)= amount of bound labeled antigen
**A number of solid-phase RIAs have been developed
***Sometimes the antibody can be absorbed onto the surface- the amount of radiolabeled antigen bound to the beads can be measured after washing
***Antibody can be immobilised on PVC or polystyrene

==Applications==
*As the technique requires small amounts of sample it can be conducted on 96-well microtiter plates and large numbers of samples can be tested
**RIA used in this way has been employed in the detection of the hepatitis B surface antigen in donor blood, reducing the occurrence of hepatitis infections as a result of blood transfusions in humans
*Measuring plasma levels of hormones and controlled substances
*Measuring anti-DNA antibodies present in systemic lupus erythematosus (SLE)

=Drawbacks=
Although the RIA is a very sensitive test, and therefore widely-used, there are disadvantages to its use:
*The substances being used are radioactive
*Gamma radiation needs special counting equipment for detection
*Iodine is naturally concentrated in the thyroid gland, whether radioactive or not, and incorporated into thyroxine
Consequently, ELISA has largely overtaken RIA as a preferred diagnostic tool

Radioimmunoassay

2009-08-14T13:03:35Z

Kwhittle: /* Principle */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
The radioimmunoassay (RIA) is a sensitive technique used to detect the presence of antigen in a sample using radiolabelled antibodies. Developed in the 1960's, the RIA proved a powerful tool in antigen detection, although the procedure was soon overtaken by ELISA, which utilises enzymes rather than radioactive labels. RIAs are still used today however, to measure:
*Hormone levels in blood and tissue fluids
*Serum proteins
*Drugs
*Vitamins
**Levels can be detected when as low as 0.001 micrograms per millilitre, therefore this technique can be use to detect trace amounts of drug

==Principle==
*The general priniciple behind the RIA is the competitive binding of a radiolabeled antigen and unlabeled antigen to a high-affinity antibody.
*Labeled antigen is mixed with antibody until binding sites are saturated
*Samples of unlabeled antigen (unknown concentration) are added in progressively increasing amounts
**The two different antigens compete for the binding sites on the antibody
**As the concentration of unlabeled antibody increases, more labeled antigen will be displaced
*The decrease in bound-radiolabeled antigen is measured - an indication of the amount of antigen present in sample

==Technique==
*The antigen is often labelled with a gamma-emitting isotope, e.g. iodine-125
**Beta-emtting isotopes such as tritium are also often used

# Determine the amount of antibody required to bind ~50% of radiolabelled antigen in mixture- ''required to ensure the number of epitopes presented by labelled antigen exceeds number of antibody binding sites''
# Add unlabelled antigen to mixture
# Separate antigen-antibody complex from free antigen by precipitation
# Measure radioactivity in precipitate
*There are various methods to separate the antigen-antibody complexes from the free antigen:
**Precipitate complexes using secondary isotype-specific antiimmunoglobulin
**If complex contains IgG, it can be removed by mixing with formalin-killed ''Staphylococcus aureus''- protein A of ''S. aureus'' has a high affinity for IgG
*** Removal of the complex by either of these methods leaves an amount of free labelled antigen in the supernatant (liquid section from precipitation)- the radioactivity of this can be measured and the value taken away from the total amount of labelled antigen added (known amount)= amount of bound labelled antigen
**A number of solid-phase RIAs have been developed
***Sometimes the antibody can be absorbed onto the surface- the amount of radiolabelled antigen bound to the beads can be measured after washing
***Antibody can be immobilised on PVC or polystyrene

==Applications==
*As the technique requires small amounts of sample it can be conducted on 96-well microtiter plates and large numbers of samples can be tested
**RIA used in this way has been employed in the detection of the hepatitis B surface antigen in donor blood, reducing the occurrence of hepatitis infections as a result of blood transfusions in humans
*Measuring plasma levels of hormones and controlled substances
*Measuring anti-DNA antibodies present in systemic lupus erythematosus (SLE)

=Drawbacks=
Although the RIA is a very sensitive test, and therefore widely-used, there are disadvantages to its use:
*The substances being used are radioactive
*Gamma radiation needs special counting equipment for detection
*Iodine is naturally concentrated in the thyroid gland, whether radioactive or not, and incorporated into thyroxine
Consequently, ELISA has largely overtaken RIA as a preferred diagnostic tool

Radioimmunoassay

2009-08-14T12:49:15Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
The radioimmunoassay (RIA) is a sensitive technique used to detect the presence of antigen in a sample using radiolabelled antibodies. Developed in the 1960's, the RIA proved a powerful tool in antigen detection, although the procedure was soon overtaken by ELISA, which utilises enzymes rather than radioactive labels. RIAs are still used today however, to measure:
*Hormone levels in blood and tissue fluids
*Serum proteins
*Drugs
*Vitamins
**Levels can be detected when as low as 0.001 micrograms per millilitre, therefore this technique can be use to detect trace amounts of drug

==Principle==
*The general priniciple behind the RIA is the competitive binding of a radiolabelled antigen and unlabelled antigen to a high-affinity antibody.
*Labelled antigen is mixed with antibody until binding sites are saturated
*Samples of unlabelled antigen (unknown concentration) are added in progressively increasing amounts
**The two different antigens compete for the binding sites on the antibody
**As the concentration of unlabelled antibody increases, more labelled antigen will be displaced
*The decrease in bound-radiolabelled antigen is measured- an indication of the amount of antigen present in sample

==Technique==
*The antigen is often labelled with a gamma-emitting isotope, e.g. iodine-125
**Beta-emtting isotopes such as tritium are also often used

# Determine the amount of antibody required to bind ~50% of radiolabelled antigen in mixture- ''required to ensure the number of epitopes presented by labelled antigen exceeds number of antibody binding sites''
# Add unlabelled antigen to mixture
# Separate antigen-antibody complex from free antigen by precipitation
# Measure radioactivity in precipitate
*There are various methods to separate the antigen-antibody complexes from the free antigen:
**Precipitate complexes using secondary isotype-specific antiimmunoglobulin
**If complex contains IgG, it can be removed by mixing with formalin-killed ''Staphylococcus aureus''- protein A of ''S. aureus'' has a high affinity for IgG
*** Removal of the complex by either of these methods leaves an amount of free labelled antigen in the supernatant (liquid section from precipitation)- the radioactivity of this can be measured and the value taken away from the total amount of labelled antigen added (known amount)= amount of bound labelled antigen
**A number of solid-phase RIAs have been developed
***Sometimes the antibody can be absorbed onto the surface- the amount of radiolabelled antigen bound to the beads can be measured after washing
***Antibody can be immobilised on PVC or polystyrene

==Applications==
*As the technique requires small amounts of sample it can be conducted on 96-well microtiter plates and large numbers of samples can be tested
**RIA used in this way has been employed in the detection of the hepatitis B surface antigen in donor blood, reducing the occurrence of hepatitis infections as a result of blood transfusions in humans
*Measuring plasma levels of hormones and controlled substances
*Measuring anti-DNA antibodies present in systemic lupus erythematosus (SLE)

=Drawbacks=
Although the RIA is a very sensitive test, and therefore widely-used, there are disadvantages to its use:
*The substances being used are radioactive
*Gamma radiation needs special counting equipment for detection
*Iodine is naturally concentrated in the thyroid gland, whether radioactive or not, and incorporated into thyroxine
Consequently, ELISA has largely overtaken RIA as a preferred diagnostic tool

Immunofluorescence

2009-08-14T12:43:05Z

Kwhittle: /* Techniques */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
[[Image:763px-Cryptosporidium parvum 01.jpg|thumb|right|150px|Immunofluorescence of ''Cryptosporidium parvum'' spores]]
Immunofluorescence is a technique used to detect cell or tissue-associated antigens using antibodies labeled with fluorescent tags. The stained tissues are then detected by immunofluorescence microscopy (qualitative) or flow cytometry (quantitative). Antibodies bind stably and specifically to their corresponding antigen and the technique makes use of the fact that they can be coupled to fluorescent dyes, such as fluorescein and rhodamine, with no effect on specificity. These conjugates bind to antigens present in a sample and can then be visualised under a microscope with a suitable light source, such as UV light.

==Fluorescent dyes==

If a molecule has the property of fluorescence, it can absorb light of one wavelength (excitation) and emit light of another (emission). Antibodies tagged with these dyes (known as '''fluorochromes''') form immune complexes with specific antigens which can then be indirectly visualised when excited by light of the appropriate wavelength.

===Commonly used fluorochromes===
*'''Fluorescein:''' organic (carbon-based) dye, most widely used. Absorbs blue (490nm) and emits yellow green fluorescence (517nm)
*'''Rhodamine:''' organic dye, absorbs yellow-green light and emits deep red fluorescence (546nm).
**As fluorescein and rhodamine fluorescences are easy to distinguish from one another, it is possible to conjugate them to different antibodies and simultaneously visualise two different antigens on the same cell or tissue.
*'''Phycoerythrin:''' can absorb light from the blue-green (495nm) and the yellow wavelengths, emits bright red fluorescence

==Techniques==
'''Direct staining'''
*An antibody directed against a specific antigen is directly conjugated with the fluorescent dye and applied to the sample.
'''Indirect staining'''
*Utilizes a double layer technique - a primary, unlabelled antibody is applied to the sample, followed by a secondary antibody, an anti-immunoglobulin that has been conjugated to a fluorochrome.
**Indirect staining has several advantages:
***Several secondary antibodies bind to each primary antibody, so the resulting fluorescence is brighter than that of the direct staining.
***One preparation of secondary antibody can be used to test many sera
***By using a mixture of primary antibodies, it is possible to detect the relative expressions of different antigens in the same cell
***Quite often loss of antibody is sustained during the conjugation- in the indirect method the primary antibodies do not need to be conjugated, so this limiting factor is reduced.

==Applications==
*Immunofluorescence is often used to identify populations of cells, and was successfully employed in the identification of the CD4+ and CD8+ subpopulations of T cells
*Identifying bacterial and viral species
*Detecting antigen-antibody complexes in autoimmune diseases
*Detecting complement components in tissues
*Localising hormones, antigens and other cellular products in tissue samples and subcellular compartments
*Mapping the molecular architecture of tissues in relation to gross anatomy

==Developments==
===Confocal microscopy===
*The scanning confocal fluorescent microscope is a recent development that uses computer-aided techniques to produce a high-resolution thin optical section of a sample without the need for further, complex sample preparation. Fluorescent images were previously hard to resolve as the picture was subject to glare from planes above and below that in focus, resulting in a blurred image.
*To obtain an image, a laser light is focused on a fine plane within the sample. The resulting fluorescent emission is collected in a photomultiplier tube (PMT) with a confocal aperture. The fluorescence from planes above and below the optical section fails to reach this aperture, resulting in a sharper image.
*The resolution can be further increased by using low-level illumination, meaning the fluorescent dye can only be excited by two photons. When a pulsed laser is used, it only reaches sufficient intensity to excite fluorescence when the beam is focused onto the focal plane of the microscope. This minimises fluorescence to the desired optical section itself.

===Time-lapse video microscopy===
*Sensitive digital video cameras can be used to record the movement of fluorescently tagged molecules, for example to track the movement of such molecules in cell membranes or during interaction between cells.

===Flow cytometry===
*The flow cytometer is an instrument that directs cells in single file through a narrow chamber illuminated by a laser beam. As fluorescently-tagged cells pass through the laser beam, the fluorochrome is excited and emits light that is detected by a PMT-like detector
*This detector is capable of measuring the strength of emission, so it is possible to sort cells that are negative, slightly positive and highly positive for a specific antigen
*Flow cytometry provides a rapid quantitative technique for antigen detection

Immunofluorescence

2009-08-14T12:42:25Z

Kwhittle: /* Fluorescent dyes */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
[[Image:763px-Cryptosporidium parvum 01.jpg|thumb|right|150px|Immunofluorescence of ''Cryptosporidium parvum'' spores]]
Immunofluorescence is a technique used to detect cell or tissue-associated antigens using antibodies labeled with fluorescent tags. The stained tissues are then detected by immunofluorescence microscopy (qualitative) or flow cytometry (quantitative). Antibodies bind stably and specifically to their corresponding antigen and the technique makes use of the fact that they can be coupled to fluorescent dyes, such as fluorescein and rhodamine, with no effect on specificity. These conjugates bind to antigens present in a sample and can then be visualised under a microscope with a suitable light source, such as UV light.

==Fluorescent dyes==

If a molecule has the property of fluorescence, it can absorb light of one wavelength (excitation) and emit light of another (emission). Antibodies tagged with these dyes (known as '''fluorochromes''') form immune complexes with specific antigens which can then be indirectly visualised when excited by light of the appropriate wavelength.

===Commonly used fluorochromes===
*'''Fluorescein:''' organic (carbon-based) dye, most widely used. Absorbs blue (490nm) and emits yellow green fluorescence (517nm)
*'''Rhodamine:''' organic dye, absorbs yellow-green light and emits deep red fluorescence (546nm).
**As fluorescein and rhodamine fluorescences are easy to distinguish from one another, it is possible to conjugate them to different antibodies and simultaneously visualise two different antigens on the same cell or tissue.
*'''Phycoerythrin:''' can absorb light from the blue-green (495nm) and the yellow wavelengths, emits bright red fluorescence

==Techniques==
'''Direct staining'''
*An antibody directed against a specific antigen is directly conjugated with the fluorescent dye and applied to the sample.
'''Indirect staining'''
*Utilizes a double layer technique- a primary, unlabelled antibody is applied to the sample, followed by a secondary antibody, an anti-immunoglobulin that has been conjugated to a fluorochrome.
**Indirect staining has several advantages:
***Several secondary antibodies bind to each primary antibody, so the resulting fluorescence is brighter than that of the direct staining.
***One preparation of secondary antibody can be used to test many sera
***By using a mixture of primary antibodies, it is possible to detect the relative expressions of different antigens in the same cell
***Quite often loss of antibody is sustained during the conjugation- in the indirect method the primary antibodies do not need to be conjugated, so this limiting factor is reduced.

==Applications==
*Immunofluorescence is often used to identify populations of cells, and was successfully employed in the identification of the CD4+ and CD8+ subpopulations of T cells
*Identifying bacterial and viral species
*Detecting antigen-antibody complexes in autoimmune diseases
*Detecting complement components in tissues
*Localising hormones, antigens and other cellular products in tissue samples and subcellular compartments
*Mapping the molecular architecture of tissues in relation to gross anatomy

==Developments==
===Confocal microscopy===
*The scanning confocal fluorescent microscope is a recent development that uses computer-aided techniques to produce a high-resolution thin optical section of a sample without the need for further, complex sample preparation. Fluorescent images were previously hard to resolve as the picture was subject to glare from planes above and below that in focus, resulting in a blurred image.
*To obtain an image, a laser light is focused on a fine plane within the sample. The resulting fluorescent emission is collected in a photomultiplier tube (PMT) with a confocal aperture. The fluorescence from planes above and below the optical section fails to reach this aperture, resulting in a sharper image.
*The resolution can be further increased by using low-level illumination, meaning the fluorescent dye can only be excited by two photons. When a pulsed laser is used, it only reaches sufficient intensity to excite fluorescence when the beam is focused onto the focal plane of the microscope. This minimises fluorescence to the desired optical section itself.

===Time-lapse video microscopy===
*Sensitive digital video cameras can be used to record the movement of fluorescently tagged molecules, for example to track the movement of such molecules in cell membranes or during interaction between cells.

===Flow cytometry===
*The flow cytometer is an instrument that directs cells in single file through a narrow chamber illuminated by a laser beam. As fluorescently-tagged cells pass through the laser beam, the fluorochrome is excited and emits light that is detected by a PMT-like detector
*This detector is capable of measuring the strength of emission, so it is possible to sort cells that are negative, slightly positive and highly positive for a specific antigen
*Flow cytometry provides a rapid quantitative technique for antigen detection

Immunofluorescence

2009-08-14T12:30:47Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
[[Image:763px-Cryptosporidium parvum 01.jpg|thumb|right|150px|Immunofluorescence of ''Cryptosporidium parvum'' spores]]
Immunofluorescence is a technique used to detect cell or tissue-associated antigens using antibodies labeled with fluorescent tags. The stained tissues are then detected by immunofluorescence microscopy (qualitative) or flow cytometry (quantitative). Antibodies bind stably and specifically to their corresponding antigen and the technique makes use of the fact that they can be coupled to fluorescent dyes, such as fluorescein and rhodamine, with no effect on specificity. These conjugates bind to antigens present in a sample and can then be visualised under a microscope with a suitable light source, such as UV light.

==Fluorescent dyes==

If a molecule has the property of fluorescence, it can absorb light of one wavelength (excititation) and emit light of another (emission). Antibodies tagged with these dyes (known as '''fluorochromes''') form immune complexes with specific antigens which can then be indirectly visualised when excited by light of the appropriate wavelength.

===Commonly used fluorochromes===
*'''Fluorescein:''' organic (carbon-based) dye, most widely used. Absorbs blue (490nm) and emits yellow green fluorescence (517nm)
*'''Rhodamine:''' organic dye, absorbs yellow-green light and emits deep red fluorescence (546nm).
**As fluorescein and rhodamine fluorescences are easy to distinguish from one another, it is possible to conjugate them to different antibodies and simultaneously visualise two different antigens on the same cell or tissue.
*'''Phycoerythrin:''' can absorb light from the blue-green (495nm) and the yellow wavelengths, emits bright red fluorescence

==Techniques==
'''Direct staining'''
*An antibody directed against a specific antigen is directly conjugated with the fluorescent dye and applied to the sample.
'''Indirect staining'''
*Utilizes a double layer technique- a primary, unlabelled antibody is applied to the sample, followed by a secondary antibody, an anti-immunoglobulin that has been conjugated to a fluorochrome.
**Indirect staining has several advantages:
***Several secondary antibodies bind to each primary antibody, so the resulting fluorescence is brighter than that of the direct staining.
***One preparation of secondary antibody can be used to test many sera
***By using a mixture of primary antibodies, it is possible to detect the relative expressions of different antigens in the same cell
***Quite often loss of antibody is sustained during the conjugation- in the indirect method the primary antibodies do not need to be conjugated, so this limiting factor is reduced.

==Applications==
*Immunofluorescence is often used to identify populations of cells, and was successfully employed in the identification of the CD4+ and CD8+ subpopulations of T cells
*Identifying bacterial and viral species
*Detecting antigen-antibody complexes in autoimmune diseases
*Detecting complement components in tissues
*Localising hormones, antigens and other cellular products in tissue samples and subcellular compartments
*Mapping the molecular architecture of tissues in relation to gross anatomy

==Developments==
===Confocal microscopy===
*The scanning confocal fluorescent microscope is a recent development that uses computer-aided techniques to produce a high-resolution thin optical section of a sample without the need for further, complex sample preparation. Fluorescent images were previously hard to resolve as the picture was subject to glare from planes above and below that in focus, resulting in a blurred image.
*To obtain an image, a laser light is focused on a fine plane within the sample. The resulting fluorescent emission is collected in a photomultiplier tube (PMT) with a confocal aperture. The fluorescence from planes above and below the optical section fails to reach this aperture, resulting in a sharper image.
*The resolution can be further increased by using low-level illumination, meaning the fluorescent dye can only be excited by two photons. When a pulsed laser is used, it only reaches sufficient intensity to excite fluorescence when the beam is focused onto the focal plane of the microscope. This minimises fluorescence to the desired optical section itself.

===Time-lapse video microscopy===
*Sensitive digital video cameras can be used to record the movement of fluorescently tagged molecules, for example to track the movement of such molecules in cell membranes or during interaction between cells.

===Flow cytometry===
*The flow cytometer is an instrument that directs cells in single file through a narrow chamber illuminated by a laser beam. As fluorescently-tagged cells pass through the laser beam, the fluorochrome is excited and emits light that is detected by a PMT-like detector
*This detector is capable of measuring the strength of emission, so it is possible to sort cells that are negative, slightly positive and highly positive for a specific antigen
*Flow cytometry provides a rapid quantitative technique for antigen detection

ELISA testing

2009-08-14T12:29:17Z

Kwhittle: /* Non-competitive ELISA */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
[[Image:ELISA.jpg|thumb|right|150px|Double Antibody Sandwich ELISA]]
The Enzyme Linked Immunosorbent Assay (ELISA) is an immunoassay commonly used to detect the presence of an antigen or antibody in a sample. It is a powerful tool in clinical immunology and can be used to determine whether an individual has been exposed to a specified pathogen. Utilising the principle of antigen-antibody interaction, the test allows easy visualisation of results and, since its introduction in 1971, has quickly replaced radioimmunoassays for diagnostic purposes.

*There are two basic types of ELISA:
**'''Homogenous'''- completed in one step, all reagents added simultaneously. Primarily used to detect small molecules such as digoxin and gentamicin
**'''Heterogenous'''- various reagents added sequentially, primarily used to detect microbial antigens and antibodies

This article describes the '''heterogenous''' type

==Applications==
*Detection and identification of disease agents, e.g. type and subtype
*Identification of specific antibodies, e.g. used in serodiagnosis for epidemiological studies
*Quantification of specific antibody isotypes, e.g. IgM/IgG ratio

==Techniques==

There are many methods of ELISA, but each assay involves these basic steps:
*The adsorption of antibody/antigen to solid phase (the medium)
*The addition of the chosen sample and reagents
*Incubation and washing
*The addition of enzyme-labeled antigen/antibody
*The addition of a specific substrate

'''Competitive VS Non-competitive'''
*As their name implies, competitive assays measure the competition between a pre-titrated (fixed amount) of labeled antigen and an unknown quantity of sample antigen in their affinity to an antibody. The process can be reversed to measure the competition between labeled and unlabeled antibody.
*Competitive techniques:
**Easier to quantify
**Less likely to be influenced by contaminants
**However they are more demanding with regard to the accuracy of the reagents and the purity of the labeled ligand
*Non-competitive assays:
**Errors in dispensing reagents have little effect on the result
**Therefore they are easier to control and yield accurate results
**However they are easily influenced by cross reactions and non-specific binding

'''Solid VS Fluid-phase'''
[[Image:800px-Microtiter plate.jpg|thumb|right|150px|96-well microtiter plate, Copyright Jeffrey M. Vinocur 2006]]

An important consideration is the medium in which the assay is carried out, largely dependent on what is being tested:
*Fluid-phase (''in solution'')
**Main advantage is that the behaviour of molecules in solution is easier to predict
*Solid-phase (''surface of protein-binding material, e.g. plastic'')
**Easier to perform and more sensitive
**The most widely used solid-phase is the 96-well microtiter plater, manufactured as PVC flexible plates or polystyrene rigid plates

----

===Non-competitive ELISA===
[[Image:Sandwich elisa.png|thumb|right|100px|The sandwich ELISA - Copyright J M Vincour]]
'''Double Antibody Sandwich''' (for antigen detection)
# Antibody is adsorbed onto solid phase
# Wash
# Sample serum is added- specific antigen binds to antibody
# Wash
# Enzyme-labeled specific antibody is added- attaches to bound antigen
# Wash
# Enzyme substrate is added (with dye for visualisation)
''visualised product = amount of antigen in the serum''

'''Antibody Class Capture Assay''' (for antibody detection)
# Class-specific antiglobulin is adsorbed onto solid phase
# Wash
# Sample serum is added- class-specific antibody in the serum binds to antiglobulin
# Wash
# Antigen is added - attaches to specific antibody
# Wash
# Enzyme-labeled antibody is added
# Wash
# Enzyme substrate is added
''visualised product = amount of specific antibody in serum''

'''Indirect Method''' (for antibody detection)
# Specific antigen (i.e. not from sample) is adsorbed onto solid phase
# Wash
# Serum is added- any specific antibody present in sample binds to antigen
# Wash
# Enzyme-labeled antiglobulin is added- attaches to antibody
# Wash
# Enzyme substrate is added
''visualised product = amount of antibody in the serum''

===Competitive ELISA===
'''Direct Antibody Competition''' (for antibody detection)
# Antigen is adsorbed onto solid phase
# Wash
# Enzyme-labeled antibody (pre-titrated- optimal colour development) and serum are added
# Wash
# Enzyme substrate is added
''visualised product = amount of antigen in serum sample''

'''Direct Antigen Competition''' (for antigen detection)
# Antigen is adsorbed onto solid phase
# Wash
# Antigen in serum is incubated with enzyme-labelled antibody (again pre-titrated): this is directed against the antigen on the solid phase
# Wash
# Enzyme substrate is added
''visualised product = amount of enzyme-labelled antigen''

ELISA testing

2009-08-14T11:43:41Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|backcolour = FFE4E1
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|sublink1 =Immunological testing - WikiBlood
|subtext1 =IMMUNOLOGICAL TESTING
|pagetype =Blood
}}

==Introduction==
[[Image:ELISA.jpg|thumb|right|150px|Double Antibody Sandwich ELISA]]
The Enzyme Linked Immunosorbent Assay (ELISA) is an immunoassay commonly used to detect the presence of an antigen or antibody in a sample. It is a powerful tool in clinical immunology and can be used to determine whether an individual has been exposed to a specified pathogen. Utilising the principle of antigen-antibody interaction, the test allows easy visualisation of results and, since its introduction in 1971, has quickly replaced radioimmunoassays for diagnostic purposes.

*There are two basic types of ELISA:
**'''Homogenous'''- completed in one step, all reagents added simultaneously. Primarily used to detect small molecules such as digoxin and gentamicin
**'''Heterogenous'''- various reagents added sequentially, primarily used to detect microbial antigens and antibodies

This article describes the '''heterogenous''' type

==Applications==
*Detection and identification of disease agents, e.g. type and subtype
*Identification of specific antibodies, e.g. used in serodiagnosis for epidemiological studies
*Quantification of specific antibody isotypes, e.g. IgM/IgG ratio

==Techniques==

There are many methods of ELISA, but each assay involves these basic steps:
*The adsorption of antibody/antigen to solid phase (the medium)
*The addition of the chosen sample and reagents
*Incubation and washing
*The addition of enzyme-labeled antigen/antibody
*The addition of a specific substrate

'''Competitive VS Non-competitive'''
*As their name implies, competitive assays measure the competition between a pre-titrated (fixed amount) of labeled antigen and an unknown quantity of sample antigen in their affinity to an antibody. The process can be reversed to measure the competition between labeled and unlabeled antibody.
*Competitive techniques:
**Easier to quantify
**Less likely to be influenced by contaminants
**However they are more demanding with regard to the accuracy of the reagents and the purity of the labeled ligand
*Non-competitive assays:
**Errors in dispensing reagents have little effect on the result
**Therefore they are easier to control and yield accurate results
**However they are easily influenced by cross reactions and non-specific binding

'''Solid VS Fluid-phase'''
[[Image:800px-Microtiter plate.jpg|thumb|right|150px|96-well microtiter plate, Copyright Jeffrey M. Vinocur 2006]]

An important consideration is the medium in which the assay is carried out, largely dependent on what is being tested:
*Fluid-phase (''in solution'')
**Main advantage is that the behaviour of molecules in solution is easier to predict
*Solid-phase (''surface of protein-binding material, e.g. plastic'')
**Easier to perform and more sensitive
**The most widely used solid-phase is the 96-well microtiter plater, manufactured as PVC flexible plates or polystyrene rigid plates

----

===Non-competitive ELISA===
[[Image:Sandwich elisa.png|thumb|right|100px|The sandwich ELISA - Copyright J M Vincour]]
'''Double Antibody Sandwich''' (for antigen detection)
# Antibody is adsorbed onto solid phase
# Wash
# Sample serum is added- specific antigen binds to antibody
# Wash
# Enzyme-labeled specific antibody is added- attaches to bound antigen
# Wash
# Enzyme substrate is added (with dye for visualisation)
''visualised product = amount of antigen in the serum''

'''Antibody Class Capture Assay''' (for antibody detection)
# Class-specific antiglobulin is adsorbed onto solid phase
# Wash
# Sample serum is added- class-specific antibody in the serum binds to antiglobulin
# Wash
# Antigen is added- attaches to specific antibody
# Wash
# Enzyme-labeled antibody is added
# Wash
# Enzyme substrate is added
''visualised product = amount of specific antibody in serum''

'''Indirect Method''' (for antibody detection)
# Specific antigen (i.e. not from sample) is adsorbed onto solid phase
# Wash
# Serum is added- any specific antibody present in sample binds to antigen
# Wash
# Enzyme-labeled antiglobulin is added- attaches to antibody
# Wash
# Enzyme substrate is added
''visualised product = amount of antibody in the serum''

===Competitive ELISA===
'''Direct Antibody Competition''' (for antibody detection)
# Antigen is adsorbed onto solid phase
# Wash
# Enzyme-labeled antibody (pre-titrated- optimal colour development) and serum are added
# Wash
# Enzyme substrate is added
''visualised product = amount of antigen in serum sample''

'''Direct Antigen Competition''' (for antigen detection)
# Antigen is adsorbed onto solid phase
# Wash
# Antigen in serum is incubated with enzyme-labelled antibody (again pre-titrated): this is directed against the antigen on the solid phase
# Wash
# Enzyme substrate is added
''visualised product = amount of enzyme-labelled antigen''

Vaccines

2009-08-14T11:30:48Z

Kwhittle: /* When do we vaccinate? */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses create [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs), so that it is less able to replicate when introduced to the host, and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occurring avirulent strains can also be used
**Response takes place at the site of natural infection, producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides, can be synthetically produced
**E.g. Being developed constantly to fight the Influenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injections needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection needs [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates, as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:29:36Z

Kwhittle: /* Immunity to Bacterial Infection */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses create [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs), so that it is less able to replicate when introduced to the host, and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occurring avirulent strains can also be used
**Response takes place at the site of natural infection, producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides, can be synthetically produced
**E.g. Being developed constantly to fight the Influenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injections needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection needs [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:27:42Z

Kwhittle: /* Adjuvants */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses create [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs), so that it is less able to replicate when introduced to the host, and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occurring avirulent strains can also be used
**Response takes place at the site of natural infection, producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides, can be synthetically produced
**E.g. Being developed constantly to fight the Influenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injections needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:26:47Z

Kwhittle: /* Subunit Vaccine (part of the organism) */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses create [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs), so that it is less able to replicate when introduced to the host, and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occurring avirulent strains can also be used
**Response takes place at the site of natural infection, producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides, can be synthetically produced
**E.g. Being developed constantly to fight the Influenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:23:57Z

Kwhittle: /* Whole Organism */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses create [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs), so that it is less able to replicate when introduced to the host, and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occurring avirulent strains can also be used
**Response takes place at the site of natural infection, producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:22:36Z

Kwhittle: /* Active immunisation */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses create [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:20:15Z

Kwhittle: /* Passive immunisation */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesises [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses creates [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:19:34Z

Kwhittle: /* Passive immunisation */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) which is injected into the host animal
**The immune system of that animal synthesised [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses creates [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:18:31Z

Kwhittle: /* Passive immunisation */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]], not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) is injected into the host animal
**The immune system of that animal synthesised [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses creates [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:18:10Z

Kwhittle: /* Passive immunisation */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], and catabolised by the body, meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]] not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) is injected into the host animal
**The immune system of that animal synthesised [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses creates [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:17:43Z

Kwhittle: /* Passive immunisation */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The acquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] and catabolised by the body meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]] not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) is injected into the host animal
**The immune system of that animal synthesised [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]

===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses creates [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Vaccines

2009-08-14T11:17:07Z

Kwhittle: /* How do vaccines work? */

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Vaccines(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Why Vaccinate?==

*To protect against infectious diseases

*Where there is no effective treatment once infected
**E.g. [[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|FeLV]], FIV

*Where disease is life-threatening
**E.g. Canine Parvovirus

*To prevent the spread of disease by virus excretion
**E.g. Rabies, FMDV

*The goal is to vaccinate 90% of the population to reduce the amount of '''endemic''' virus until no new infections occur

*Once the disease risk is low, vaccination can be replaced by an eradication or quarantine programme

==How do vaccines work?==

*Vaccination sets up memory to the viral infection

*High levels of [[T cell differentiation - WikiBlood#Cytotoxic T-Cells|cytotoxic T cells]] and neutralising [[Immunoglobulins - WikiBlood|antibody]] are activated in 1-2 days as a [[B cell differentiation - WikiBlood#Secondary T Cell Dependent Response|secondary response]] (instead of 4-10 days as a [[B cell differentiation - WikiBlood#T-Cell Dependent Response|primary response]])

*The infection is therefore prevented from taking hold causing lesions to develop

*Neutralising [[Immunoglobulins - WikiBlood|antibody]] blocks the attachment of virus to host cell receptors

*'''Endogenous vaccines''' are where the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] are made as new proteins by the cell, bacterium or virus
**Involves [[MHC - WikiBlood#MHC I|MHC class I]] processing
**E.g. live virus, recombinant virus and DNA vaccines

*'''Exogenous vaccines''' are when the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is processed from the outside by endocytosis without any new proteins being made by the host cell
**involves [[MHC - WikiBlood#MHC II|MHC class II]] processing
**E.g. Inactivated and subunit vaccines

==How do we vaccinate?==

*Usually by subcutaneous injection for '''systemic''' protection ([[Immunoglobulin G - WikiBlood|IgG]])

*For '''mucosal''' immune response, intranasal administration is best ([[Immunoglobulin A - WikiBlood|IgA]])

==What do we vaccinate with?==
[[Image:Passive Immunisation.jpg|thumb|right|150px|Passive Immunisation - Copyright nabrown RVC]]
===Passive immunisation===

'''Advantages'''
*Immediate protection

'''Disadvantages:'''
*Short duration of action
**Temporary protection by the administration of preformed [[Immunoglobulins - WikiBlood|antibody]] from another individual of the same or of a different species
**The aquired [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] and catabolised by the body meaning protection is gradually lost
*Injection of antiserum may cause an [[Allergic diseases - WikiClinical|allergic response]]
*Antiserum contains many [[Immunoglobulins - WikiBlood|antibodies]] not just the specific [[Immunoglobulins - WikiBlood|antibodies]] needed

'''Types of [[Immunoglobulins - WikiBlood|antibodies]] administered:'''
*Maternally-derived [[Immunoglobulins - WikiBlood|antibodies]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
*Antiserum (artificial)
**The [[Immunoglobulins - WikiBlood|antibodies]] are used in combination with [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] (and often an [[Vaccines - WikiBlood#Adjuvants|adjuvant]]) is injected into the host animal
**The immune system of that animal synthesised [[Immunoglobulins - WikiBlood|antibodies]]
**Repeated injections at intervals increases the total [[Immunoglobulins - WikiBlood|antibody]] production
**The immunised animal is bled and the serum collected which contains the newly made [[Immunoglobulins - WikiBlood|antibodies]]. The serum is called '''antiserum'''.
**The serum can then be injected into a different animal to confer passive immunisation

*Example of when passive immunisation is used:
**Suspect tetanus

'''Passive Immunotherapy with Antibody'''
{| style="width:60%; height:200px" border="1" align=left
!INFECTION
!HUMAN SOURCE OF ANTIBODY
!EQUINE SOURCE OF ANTIBODY
!USE
|-
| '''Tetanus Diptheria'''
| Used
| Used
| Prophylaxis treatment
|-
| '''Botulism'''
| Not used
| Used
| Treatment
|-
| '''Venomous bite'''
| Not used
| Used
| Treatment
|-
| '''Rabies'''
| Used
| Not used
| Post-exposure to vaccine
|}
 
 
[[Image:Active Immunisation.jpg|thumb|right|150px|Active Immunisation - Copyright nabrown RVC]]
===Active immunisation===
*Administer [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] so the patient develops its own [[Immunoglobulins - WikiBlood|antibodies]] to protect against disease
**Living organisms
**Dead organisms
**Toxoids
**Subunit antigens
**DNA

'''Advantages'''
*Long duration of action
**Once [[Immunoglobulins - WikiBlood|antibody]] is produced against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]], [[B cell differentiation - WikiBlood#Memory cells|memory cells]] are formed which continue circulating in the body
**For further information on memory cells click [[B cell differentiation - WikiBlood|here]]

'''Disadvantages'''
*Delay in protection
**The host's immune system needs to evoke an immune response against the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] which can take a few days
**For further information on the [[Immunoglobulins - WikiBlood|antibody]] response click [[Adaptive Immune System - WikiBlood|here]]

*Often needs two or more doses
**The first dose initiates the '''priming''' reaction where [[Immunoglobulins - WikiBlood|antibody]] production ceases after a few weeks, but the second and subsequent doses creates [[B cell differentiation - WikiBlood#Memory cells|memory cells]] which remain in the circulation for a much longer period of time
**For further information on the T cell independent and dependent responses click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]]

==What antigen(s) do we use in the vaccine?==

===Whole Organism===

*Live attenuated organism
**Virulent organisms cannot be used as vaccines as they would cause disease
**Virulence is reduced by growing the organism in altered conditions (e.g. in cells or eggs) so that it is less able to replicate when introduced to the host and therefore less likely to cause disease
**Produces a superior response to disease than using killed organisms as the dose of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] is larger and more sustained
**Virulence can also be reduced by genetic engineering
**Naturally occuring avirulent strains can also be used
**Response takes place at site of natural infection producing a greater local response than with killed organism vaccines
**E.g. The current vaccine for Tuberculosis (called BCG) contains an attenuated form of a mycobacteria
**E.g. Vaccines for Leishmaniasis
**E.g. Vaccines for parainfluenza virus 3 of calves is developed to be temperature-sensitive so that it grows at 34 C in the upper respiratory tract but not at 38 C in the lungs

*Killed inactivated organism or toxin (toxoid)
**Virulent and toxic organisms cannot be used as vaccines as they would cause disease
**Organisms can be killed using radiation or chemicals so that they still possess the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] to stimulate an immune response, but the organisms are unable to replicate inside the host
**Toxins are inactivated to produce a toxoid which will still have the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]] needed to produce an immune response but will not be harmful to the host
**Needs two doses (for an explanation on the [[Lymphocytes - WikiBlood#T cells|T cell]] response click [[B cell differentiation - WikiBlood#T-Cell Dependent and Independent Responses|here]])
**1:4000 formaldehyde is the current preparation
**Inactivants containing azuridines and beta propiolactone are being developed which do not leave a persistent infectious viral fraction (like formaldehyde)

===Subunit Vaccine (part of the organism)===

*Purified protein
**Single envelope protein separated from a purified virus by detergent then centrifuged (traditional method)
**Genetic engineering can now make single protein vaccines

*Recombinant or synthetic protein
**The gene for the [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] required is inserted into a virus vector or cloned into bacteria allowing endogenous expression
**Small [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]], such as peptides can be synthetically produced
**E.g. Being developed constantly to fight the Inflenza viruses
**E.g. Canary pox vaccines encoding rabies or FeLV spike proteins (canary pox is safe as it undergoes incomplete replication in mammalian skin cells)

*DNA coding for proteins ([[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]])
**Circular DNA plasmids expanded in disabled E.coli strains and then purified
**Plasmids express the foreign gene insert at the site of injection
**Can be vaccinated directly into the host

===Adjuvants===

*Used with vaccines containing inactivated organisms which alone only stimulate a weak immune response

*Some create a depot of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] at the injection site allowing a steady flow of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] into the afferent lymph

*Some stimulate the immune system to amplify the adaptive immune response to [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]]
**E.g. Pathogen-associated molecular patterns (PAMPs)
**E.g. PAMP-like adjuvants which assist naive [[Lymphocytes - WikiBlood#T cells|T cell]] priming

*Different subtypes of [[Lymphocytes - WikiBlood#Helper CD4+|T helper cells]] are stimulated by different adjuvants
**E.g. Aluminium salts generate bias [[T cell differentiation - WikiBlood#TH2 Cells|T helper II]] responses for [[Immunoglobulins - WikiBlood|'''antibody''']]-mediated immunity
**E.g. Killed mycobacteria generate IL-12 producing good '''cell'''-mediated immunity

*Adjuvants decrease the number of injection needed and the amount of [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigen]] administered

===Marker Vaccines===

*Distinguish infected from vaccinated animals

*Have a deleted protein or gene

*Vaccinated animals cannot make antibody to the missing protein whereas infected animals can

*Helps immunosurveillance for animals infected by a virus in countries that vaccinate against the virus

==Which type of vaccine is used for each disease?==

*The life-cycle of the organisms needs to be understood to ascertain the best type of immune response for fighting the particular infection

*A vaccine can be created to provide specific immunity which is best suited for fighting the specific infection

===Immunity to Virus Infection===
[[Image:Virus Life Cycle.jpg|thumb|right|150px|Virus Life Cycle - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*The virus life cycle consists of an extracellular phase, a replicative intracellular phase and another extracellular phase spreading viral particles to other cells to begin the life cycle again

*Immunity for the extracellular phase requires neutralising [[Immunoglobulins - WikiBlood|'''antibody''']]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed (for the [[MHC - WikiBlood#MHC II|MHC class II pathway]])
**Live vaccine can be used
**Killed vaccine can be used
**Subunit vaccine can be used

*Immunity for the intracellular phase requires [[Lymphocytes - WikiBlood#Cytotoxic CD8+|'''CD8+ cytotoxic T cells''']]
**[[MHC - WikiBlood#MHC I|MHC class I pathway]]
**Only live vaccine can be used to get into cells (entering via the endogenous pathway)

===Immunity to Bacterial Infection===

*Extracellular bacterial infection need [[Immunoglobulins - WikiBlood|'''antibody''']] production for [[Complement - WikiBlood#Opsonisation|opsonisation]] and to activate the [[Complement - WikiBlood|complement pathways]]
**[[Lymphocytes - WikiBlood#B Cells|B cells]] needed
**[[T cell differentiation - WikiBlood#TH2 Cells|T helper type II cells]] needed

*Vesicular infections can only be cured by organisms being destroyed inside [[Macrophages - WikiBlood|'''macrophages''']]
**[[T cell differentiation - WikiBlood#TH1 Cells|T helper type I cells]] needed

==When do we vaccinate?==
[[Image:Colostrum Intake.jpg|right|thumb|150px|Colostrum Intake - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
[[Image:Vaccinating puppies with Parvo.jpg|right|thumb|150px|Response to vaccination against canine parvovirus depending on antibody titre of puppies - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
*Usually when animals are young

*Breeding females so immunity is passed to offspring via the [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]]
**Protects neonates for the first 8-12 weeks of life

*Vaccination of young animals should be when the natural passive immunity decreases below the threshold for providing protection. Active immunity should then be stimulated so that the animal has constant protection. The vaccination should not be given too early, as the natural immunity can interfere with immunisation by binding and neutralising the vaccine [[Adaptive Immune System - WikiBlood#Antigen Recognition|antigens]].

*2 vaccines are usually given to allow for differences between neonates as the point where natural immunity decreases and active immunity needs to be stimulated, will differ between littermates and between different animals

===Dog Vaccinations===

'''Diseases covered by Vaccination'''

*Canine [[Parvoviridae|Parvovirus]]

*Canine Distemper

*Canine Infectious Hepatitis

*Leptospirosis

*Canine Parainfluenza virus

*Kennel Cough

*Rabies

'''When to Vaccinate'''

*Puppies are usually first vaccinated between 6 to 8 weeks of age
**A second vaccination is needed 2 weeks later

*Adult dogs need booster vaccination regularly (depending on the specific vaccination)

===Cat Vaccinations===
[[Image:Sebby cat.jpg|thumb|right|150px|Cat - Copyright nabrown RVC]]
'''Diseases covered by Vaccination'''

*Feline Infectious Enteritis

*Feline Infectious Respiratory Disease 'Cat Flu'
**Feline [[Herpesviridae|Herpesvirus]]
**Feline [[Caliciviridae|Calicivirus]]

*[[Immunodeficiencies - WikiBlood#Feline Leukaemia Virus (FeLV)|Feline Leukaemia virus]]
**Killed whole virus (only used in USA)
**Purified subunit
**Recombinant subunit
**Recombinant canarypox

*[[Immunodeficiencies - WikiBlood#Feline Immunodeficiency Virus (FIV)|Feline Infectious Viraemia]]
**Killed whole virus containing A and D subtypes (only used in USA)

*Feline Chlamydophilosis

'''When to Vaccinate'''

*Kittens are usually vaccinated around 9 weeks old
**A second vaccination is needed 3 weeks later

*Adult cats need booster vaccination regularly (depending on the specific vaccination)

===Rabbit Vaccinations===
[[Image:Buzz bunny.jpg|thumb|right|150px|Rabbit - Copywright L. Drew RVC]]
'''Diseases covered by Vaccination'''

*Viral Haemorrhagic Disease

*[[Poxviruses#Leporipoxviruses|Myxomatosis]]

'''When to Vaccinate'''

*Rabbits can be vaccinated against [[Poxviruses#Leporipoxviruses|Myxomatosis]] from 6 weeks of age

*HVD from 2½ to 3 months of age

*Booster vaccinations are given every 12 months. In areas at high risk of myxomatosis, it is recommended to give myxomatosis boosters at six-monthly intervals.

==Vaccine Failure==

*Recipient is already infected with the virus or immunosuppressed

*Break down of the '''cold-chain''' during transport

*Improper administration

*Mixing of inactivated and live vaccines in the same syringe

*Recipient has maternal antibody to the vaccine

*Not enough animals vaccinated

*Boosters not done

*Vaccine is counterfeit or homeopathic

==Links==

*[[Clinical Case 3|Myxomatosis Clinical Case]]

*[[Viruses|Viruses A to Z]]

==References==

'''Textbooks'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

*Dr Peter H Russell BVSc MSc PhD MRCVS FRCPath

==Creators==

[[Natalie Brown]]

<big><center>[[Immunology - WikiBlood|'''BACK TO IMMUNOLOGY''']]</center></big>
<big><center>[[Host invasion by microorganisms - WikiBlood|'''BACK TO HOST INVASION BY MICROORGANISMS''']]</center></big>

Immunodeficiencies - WikiBlood

2009-08-14T11:14:28Z

Kwhittle: /* Iatrogenic Causes */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene coding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Laboratory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistently viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased susceptibility to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The transmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Cyclosporin
**Cytotoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T11:13:58Z

Kwhittle: /* Bovine Immunodeficiency Virus (BIV) */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene coding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Laboratory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistently viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased susceptibility to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The transmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T11:13:28Z

Kwhittle: /* Feline Immunodeficiency Virus (FIV) */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene coding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Laboratory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistently viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased susceptibility to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T11:10:54Z

Kwhittle: /* Feline Leukaemia Virus (FeLV) */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene coding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Laboratory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistently viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased suscepitbilty to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T10:35:06Z

Kwhittle: /* Labatory Examples of Severe Combined Deficiency */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene coding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Laboratory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistantly viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased suscepitbilty to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T10:33:22Z

Kwhittle: /* Canine X-Linked Severe Combined Immune Deficiency (Canine SCID) */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene coding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Labatory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistantly viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased suscepitbilty to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T10:30:07Z

Kwhittle: /* Equine Severe Combined Immune Deficiency (Equine SCID) */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually around 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene conding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Labatory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistantly viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased suscepitbilty to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-14T09:41:01Z

Kwhittle: /* Canine Cyclic Haematopoiesis */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguished from other litter mates by the diluted grey colouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying within a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually aorund 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene conding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Labatory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistantly viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased suscepitbilty to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Immunodeficiencies - WikiBlood

2009-08-13T12:12:35Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|thispagemap= Immunodeficiencies(Concept Map) - WikiBlood
|pagetype =Blood
}}

==Introduction==
[[Image:Immunodeficiencies Map.jpg|thumb|right|150px|Immunodeficiency Diagram - Copyright nabrown RVC]]
Like any system in the body the immune system can go wrong. [[Autoimmune diseases - WikiClinical|Autoimmunity]] is when the immune system begins to attack itself. Immunodeficiency is when the immune system fails to protect itself from disease.

If the immunodeficient defect is present at birth and is therefore a result of a genetic or developmental abnormality, it is called a primary immunodeficiency.

Secondary immunodeficiency, sometimes called acquired immunodeficiency, is the loss of immune function during life, caused by exposure to harmful agents.

Immunodeficiencies can be treated by the replacement of the defective or missing protein, cells or gene. However, in veterinary medicine, [[Vaccines - WikiBlood|vaccinations]] and drugs are the most common treatments for immunodeficiency.

==Primary Immunodeficiency==

*Primary immunodeficiencies may affect either the [[Innate Immune System - WikiBlood|innate immune system]] or the [[Adaptive Immune System - WikiBlood|adaptive immune system]]
*They are categorised by either the type or the developmental stage of the cells involved
*Lymphoid cell disorders affect [[Lymphocytes - WikiBlood#T cells|T cells]] or [[Lymphocytes - WikiBlood#B cells|B cells]] (or both)
*Myeloid cell disorders affect phagocytic function
*The severity of the immunodeficiency depends on at which stage in development the problem occurs
**E.g. Defects early on in development will affect the entire immune system
*[[Lymphocytes - WikiBlood#T cells|T cell]] deficiencies can affect both the cell-mediated and humoral response as [[Lymphocytes - WikiBlood#T cells|T cells]] play a central role in the immune system

===Deficiencies of Innate Immunity===
[[Image:Grey Collie Syndrome.jpg|thumb|right|150px|Appearance of a puppy with Grey Collie syndrome - Copyright Michelle Tennis & Peggy Melton]]
====Canine Cyclic Haematopoiesis====
*Also called '''Grey Collie Syndrome'''
*Autosomal recessive
*Insertion mutation in AP3B1 gene
*Diluted grey coat colour, stunted growth, poor wound healing
*Neutropenia every 2 weeks which lasts 3-4 days due to cyclic production of cells from [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Animals are prone to recurrent infections, mainly from the respiratory and gastrointestinal tract
**E.g. pyrexia, [[Intestine Diarrhoea - Pathology|diarrhoea]], gingivitis and arthritis
*Puppies can be distinguised from other litter mates by the diluted grey collouring
*Affected puppies show symptoms such as fever, joint pain and eye, skin and respiratory infections from 8 weeks of age
*Affected animals rarely live beyond 2-3 years with most puppies dying withing a few weeks of birth

====Canine Leukocyte Adhesion Deficiency (CLAD)====
*Occurs in Irish Setters
*Missence mutation of -Cys-36-Ser- in CD18 molecule
**CD18 is required for [[Neutrophils - WikiBlood|neutrophil]] migration and phagocytosis
*Recurrent bacterial infection
*Neutrophilia ([[Neutrophils - WikiBlood|neutrophils]] remain in the blood and are unable to fight infection in the tissue)

====Bovine Leukocyte Adhesion Deficiency (BLAD)====
*Occurs in Holstein cattle
*Missence mutation of -Asp-128-Gly in CD18 molecule
*Recurrent infection, e.g. pneumonia

===Deficiencies of Adaptive Immunity===

====Equine Severe Combined Immune Deficiency (Equine SCID)====
*Autosomal recessive
*Occurs in 2-3% of Arabian foals
*Defect in DNA-dependent protein kinase gene
**Gene codes for a DNA repair enzyme involved in V(D)J recombination for antigen receptors of [[Lymphocytes - WikiBlood|lymphocytes]] (e.g. Ig and TCR)
*No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]
*Foals develop infections (usually aorund 8 weeks of age as maternal [[Immunoglobulins - WikiBlood|antibody]] in [[Materno-fetal immunity - WikiBlood#Passive transfer via colostrum|colostrum]] wanes around this time)
*Foals usually die from bronchopneumonia

====Canine X-Linked Severe Combined Immune Deficiency (Canine SCID)====
*Affects Basset Hounds and Corgis
*X-linked recessive defect in the gene conding for the IL-2 receptor
**IL-2 receptor is a receptor for the cytokine IL-2 which causes [[Lymphocytes - WikiBlood#T cells|T cells]] to proliferate
*Causes lymphoid hypoplasia, stunted growth and increases the animal's susceptibility to infection
*Animal usually dies from pneumonia or sepsis as the level of maternal [[Immunoglobulins - WikiBlood|antibody]] decreases

====Selective IgA deficiency of German Shepherd Dogs====
*Poorly understood
*Linked to other disease syndromes such as deep pyoderma, inflammatory bowel disease, anal furunculosis and disseminated aspergillosis
*[[Immunoglobulin A - WikiBlood|IgA]] deficiency so more susceptible to mucosal disease

====Immunodeficiency of Weimaraners, Irish Wolfhounds and Miniature Dachshunds====
*Unknown aetiology
*Inherited defects
*Low levels of circulating [[Immunoglobulin M - WikiBlood|IgM]] and [[Immunoglobulin G - WikiBlood|IgG]]
*Impaired [[Neutrophils - WikiBlood|neutrophil]] function
*Causes recurrent pyrexia and infections
**E.g. Rhinitis and bronchopneumonia in Irish Wolfhounds due to low [[Immunoglobulin A - WikiBlood|IgA]]
**E.g. Pneumocytosis in Miniature Dachshunds due to low [[Immunoglobulin G - WikiBlood|IgG]]

===Labatory Examples of Severe Combined Deficiency===
[[Image:Nude Mouse.jpg|right|thumb|150px|Nude Mouse - Copyright Michigan State University- Carcinogenesis Laboratory]]
*Severe Combined Immune Deficiency(SCID)
**No functional [[Lymphocytes - WikiBlood#B cells|B cells]] or [[Lymphocytes - WikiBlood#T cells|T cells]]

*Athymic nude mice (no [[Thymus - Anatomy & Physiology|thymus]])
**No functional [[Lymphocytes - WikiBlood#T cells|T cells]]
**Cell-mediated immunodeficiency

*Knock-out mice
**E.g. Gene coding for CD4, CD8, IL-10 removed

==Secondary Immunodeficiency==

*There are many causes of secondary immunodeficiency
**Most deficiencies are not genetic
**Most are agent-induced, such as from X-ray radiation and immunosuppressive drugs

===Viral Causes===

====Feline Leukaemia Virus (FeLV)====
[[Image:FeLV Electron Micrograph.jpg|thumb|right|150px|FeLV Electron Micrograph [http://phil.cdc.gov/phil/home.asp Public Health Image Library] Image #5610]]
[[Image:Kinetics of FeLV 2.jpg|thumb|right|150px|Kinetics of FeLV - Copyright Dr Brian Catchpole BVetMed PhD MRCVS]]
*Oncogenic retrovirus
*Causes neoplasia (lymphoma), myelosuppression (anaemia) and immunosuppression (of [[Lymphocytes - WikiBlood#T cells|T cells]])
*2 strains:
**FeLV-A
***Natural strain
**FeLV-B
***Formed through FeLV-A recombining with endogenous retroviral sequences in the feline genome
***Increases the risks of lymphoma
**FeLV-C
***Formed from the spontaneous mutation of FeLV-A
***Is more myelosuppressive
*Virus replicates in the oropharyngeal lymphoid tissue causing a viraemia (virus circulating in the bloodstream) which then spreads to the systemic lymphoid tissue
*Shed in saliva
*Passed by oronasal route, e.g. mutual grooming
*Kittens between 6 weeks and 6 months are most susceptible
*60% of cats will become immune to the disease and recover
*Cats that are persistantly viraemic will progress to develop FeLV-associated diseases
*Some cats will become viraemic again if treated with corticosteroids or stressed if the infection lies dormant in the [[Bone Marrow - Anatomy & Physiology|bone marrow]]
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Feline Immunodeficiency Virus (FIV)====
*Lentivirus
*Subtypes A, B and D
*Causes increased suscepitbilty to infections and neoplasia
*Specifically destroys [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]]
*Virus is present in saliva, blood and other bodily fluids
*Feral and outdoor cats (mostly tom cats) are most at risk
*Virus replicates in lymphoid tissue
*Can remain asymptomatic
*Causes pyrexia and lymphadenopathy
*Transmitted by biting
*Diagnosis:
**ELISA
**Rapid-Immuno-Migration
**Western Blot
**Virus Isolation
**Immunofluorescence
**PCR
*Treatment:
**Antibiotics for secondary infection
**Anti-retroviral therapy
*For vaccinations see [[Vaccines - WikiBlood#Cat Vaccinations|here]]

====Bovine Immunodeficiency Virus (BIV)====
*Lentivirus (non-oncogenic)
*Causes a persistent viral infection and lymphocytosis
*Immunocompromised cattle may develop secondary infections
*The tranmission is not well known, but the following possibilities are being researched:
**Through milk
**Through infected semen (e.g.artificial insemination)
**Placental transfer
*Diagnosis:
**Western Blot
**PCR

===Toxic Causes===

*Poisons

===Iatrogenic Causes===

*Drugs
**Corticosteroids
**Ciclosporin
**Cytoxic cancer therapy

===Other Causes===

*Malnutrition

*Chronic disease

*Stress

*Senescence

==Links==

'''Internal'''
*[[Viruses|Viruses - WikiBugs]]

*[[Innate Immune System - WikiBlood]]

*[[Adaptive Immune System - WikiBlood]]

'''External'''
*[http://www.bitoheavencollies.com/GrayCollie.html| Grey Collie Syndrome] ''Information on Canine Cyclic Haematopoeisis (Grey Collie Syndrome) including new research into treating the condition and a clinical example''

*[http://carcino.com.msu.edu//mouse.html| Nude Mice] ''Information on nude mice and their role in cancer research''

==[[Immunodeficiencies Flashcards - WikiBlood|Immunodeficiencies Flashcards]]==

==References==
'''Books'''

*Ivan Roitt: '''Essential Immunology,''' Ninth edition

*Goldsby, Kindt, & Osbourne '''KUBY Immunology,''' Fourth edition

'''Lecture Notes'''

*Dr Brian Catchpole BVetMed PhD MRCVS

'''Websites'''

*Michelle Tennis & Peggy Melton http://www.bitoheavencollies.com

*http://carcino.com.msu.edu/mouse.html

==Creators==

[[Natalie Brown]]

Cytokines

2009-08-13T11:20:01Z

Kwhittle: /* Functions of cytokines */

{{review}}

{{toplink
|thispagemap = Cytokines (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

==Introduction==
The term cytokine is a generic name for the soluble molecules that mediate reactions between cells, acting via specific receptors on those cells. They are particularly important during effector stages of the immune system and the development of haematopoietic cells

==Nomenclature and classification==
Nomenclature of the cytokines was first based on their activity both ''in vivo'' and ''in vitro'', with the name being abbreviated to acronyms. For example, when a factor isolated from antigen-activated lymphocytes was added to non-immune peritoneal macrophages, their migration from capillary tubes was inhibited. This led to the factor being named migration inhibition factor, or MIF for short. It was then discovered that many biological functions were being produced by the same chemicals, which led to the classification of cytokines based on either the cell populations that secrete them or their function:
*'''Monokines'''- produced by myeloid cells (macrophages, monocytes)
*'''Lymphokines'''- produced primarily by lymphocytes
*'''Interleukins'''- produced by leukocytes in general
*'''Chemokines'''- directing cell migration, activating cells in response to infectious agents/tissue damage
*'''Interferons'''- produced by many different cells in response to viral infection

Common cytokines and nomenclature
{| border="1" cellpadding="2"
!width="50"|Name
!width="225"|Abbreviation
!width="225"|Examples
|-
|interleukins || IL || IL-1, IL-2
|-
|interferons || IFN || IFN-alpha
|-
|tumour necrosis factors || TNF || TNF-alpha
|-
|growth factors || GF || NGF, EGF
|-
|colony stimulating factors || CSF || M-CSF, G-CSF
|-
|chemokines || - || RANTES, MCP-1
|}
==Functions of cytokines==
'''Mediating and regulating innate immunity''': bacterial and viral products, such as LPS, stimulate macrophages and natural killer cells to secrete cytokines that primarily act on endothelial cells and leukocytes. They stimulate the early stages of the inflammatory reaction to microbes.

'''Mediating and regulating adaptive immunity''': in response to specific recognition by T lymphocytes, cytokines are produced that have a wide range of functions, including:
*regulating the growth and differentiation of some lymphocyte populations
*recruitment, activation and regulation of specialised effector cells, e.g. mononuclear phagocytes, neutrophils, eosinophils
'''Stimulating haematopoiesis''': produced primarily by bone marrow stromal cells and leukocytes, these cytokines stimulate the growth and differentiation of immature leukocytes.
By binding onto specific receptors on cell membranes, cytokines are able to exert their actions by triggering signal-cascade mechanisms that ultimately result in altered gene expression. Cytokines have an incredibly high affnity for their receptors, and are therefore able to act at picomolar concentrations. Cytokines can exert antagonistic effects on each other.

==Important cytokines==
Cytokines primarily produced by '''macrophages''':
*GM-CSF (granulocyte macrophage colony stimulating factor)- stimulates growth and differentiation of granulocytes, macrophages, neutrophils and eosinophils
*IL-1- stimulates Th2 cells and acute phase response
*IL-6- stimulates growth and differentiation of B and T cells and acute phase response
*IL-12- stimulates Th1 cells
*IL-18- stimulates IFN-gamma production by T cells and NK cells, favours Th1 response
*TNF-α- stimulates local inflammation and endothelial activation
Cytokines primarily produced by '''Th1 cells''':
*IL-2- stimulates proliferation and differentiation of T cells, activates NK cells and macrophages
*IFN-γ- activates macrophages, increases expression of MHC I and II molecules, increases antigen presentation
*TNF-β- stimlulates killing mechanisms in T and B cells and endothelial activation
Cytokines primarily produced by '''Th2 cells''':
*IL-4- activates B cells and IgE switch, supresses Th1 cells
*IL-5- stimulates eosinophil growth and differentiation
*IL-10- suppresses macrophage functions
Although neutrophils produce a lower amount of cytokines per cell than other immune cell types, they are often the first and most common cell type present at sites of infection. This makes them a physiologically important source of cytokines, such as IL-12.
==Chemokines==
The chemokines are a superfamily of cytokines, all related in terms of sequence and gene structure. The family is also known as the 'small cytokine' family (scy) or the intercrines. All have a relatively small molecular weight of ~5-10kDa and can be divided in one of two groups based on the position of the cystein residues (important for the tertiary structure):
*C-C subgroup- cysteine residues are adjacent to each other. Important members include:
**Interleukin 8
**MGSA- melanoma growth stimulatory activity
**PF4- platelet factor 4
**βTG- β-thromboglobulin
*C-X-C subgroup- residues are separated by another amino acid. Important members include:
**MCAF- macrophage chemotactic and activating factor
**RANTES
**LD-8
**ACT-2
Chemokines are released by many cell types, and are present in the earliest phase of infection, with actions including the following:
*Lymphoid trafficking
*Wound healing
*Th1/Th2 development
*Angiogenesis/angiostasis
*Lymphoid organ development
*Inflammation
*Cell recruitment
==Cytokines in pathology==
===Bacterial septic shock===
This is the overproduction of cytokines developing a few hours after infection by certain Gram-negative bacteria, including:
*''E. coli''
*''K. pneumoniae''
*''P. aeruginosa''
*''E. aerogenes''
Bacterial cell wall endotoxins are the cause of septic shock, stimulating macrophages to release IL-1 and TNF-α at excessive levels. The condition is often fatal and symptoms include a sudden drop in blood pressure, fever, diarrhoea and blood-clotting in multiple organs.
===Bacterial toxic shock===
This condition is caused by bacterial toxins known as superantigens (antigens that bind simultaneously to MHC II and the beta-V domain of the T cell receptor) that activate large numbers of T cells despite specificity. A number of bacteria have been implicated in the production of superantigens, including:
*''S. aureus''- produces enterotoxins and toxic-shock syndrome toxin
*''M. arthritidis''
The large number of T cells activated by such toxins (between 5-25% of all T cells, compared to less than 0.01% activated towards conventional antigens) means an excessive amount of cytokines produced, such as IL-1 and TNF. These elevated amounts cause the same systemic reactions as seen in bacterial septic shock.
===Lymphoid and myeloid cancers===
The excessive production of cytokines has been linked to some types of cancer, e.g. IL-6 has been shown to be secreted by myeloma cells, plasmacytoma cells and cervical and bladder cancer cells. IL-6 is known to act in an autocrine manner to stimulate cell proliferation.

==[[Cytokines flashcards- Wikiblood|Cytokines Flashcards]]==

==Creators==

[[Edward Ayton]]

Innate Immune System

2009-08-13T10:40:46Z

Kwhittle: /* Innate Immunity to Bacteria */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependant degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independant degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognise intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the body's mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localised at epithelial surfaces
** Very small numbers are present in blood
*** Less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a foreign intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate response to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and triggering the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Innate Immune System

2009-08-13T10:38:20Z

Kwhittle: /* Innate Immunity to Viruses */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependant degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independant degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognise intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the body's mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localised at epithelial surfaces
** Very small numbers are present in blood
*** Less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a foreign intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate response to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and engaging the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Innate Immune System

2009-08-12T16:58:14Z

Kwhittle: /* Basophils / Mast Cells */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependant degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independant degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognise intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the body's mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localised at epithelial surfaces
** Very small numbers are present in blood
*** Less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a forein intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate resonse to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and engaging the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Innate Immune System

2009-08-12T15:17:31Z

Kwhittle: /* Physical Barriers */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependant degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independant degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognise intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the body's mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localized at epithelial surfaces
** Very small numbers are present in blood
*** less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a forein intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate resonse to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and engaging the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Innate Immune System

2009-08-12T15:15:58Z

Kwhittle: /* Phagocytosis */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependant degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independant degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognise intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the bodies mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localized at epithelial surfaces
** Very small numbers are present in blood
*** less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a forein intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate resonse to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and engaging the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Innate Immune System

2009-08-12T15:15:21Z

Kwhittle: /* Phagocytosis */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependant degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independant degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognize intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the bodies mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localized at epithelial surfaces
** Very small numbers are present in blood
*** less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a forein intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate resonse to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and engaging the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Innate Immune System

2009-08-12T13:40:49Z

Kwhittle: /* Introduction */

{{review}}

{{toplink
|thispagemap= Innate Immune System (Concept Map) - WikiBlood
|linkpage =Immunology - WikiBlood
|linktext =IMMUNOLOGY
|pagetype =Blood
}}

=Introduction=

The Innate immune system is the body's first barrier of defence to infection. It relies on an older, more generic, and faster acting set of tools than the [[Adaptive Immune System - WikiBlood|adaptive]] system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.

* Non-specific protective mechanisms include such innate factors as:
** '''Physical barriers'''
*** Skin
*** Ciliated mucous membranes
*** Commensal organisms
** '''Humoral factors'''
*** Lysozyme
*** [[Complement - WikiBlood|Complement]]
*** Interferons
** '''Cellular mechanisms'''
*** Phagocytosis
** Factors which regulate '''species specificity'''
*** Membrane receptors for pathogens
*** Nutritional requirements
*** Temperature
*** pH
* Mechanisms of innate immunity are always present and generally unchanging
* Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen

=Actions of the Innate Immune System=
==Recognition of Microorganisms==
[[Image:PRRs.jpg|thumb|right|150px|Pattern Recognition Receptors - B. Catchpole, RVC 2008]]
* The innate immune system recognises components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
**Lipopolysaccharides of gram-negative bacteria
**Peptidoglycans of gram-positive bacteria
**Mannose sugars
**D-isoform amino acids
*These are given away as foreign by expressing '''pathogen-associated molecular patterns''' (PAMPs)
* PAMPs are recognised by '''pattern recognition receptors''' (PRRs) expressed on mammalian cells
** Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
** Not all are expressed by all cells: different cell types express a different range of PRRs
** PRRs are either intracellular, membrane-associated or soluble:
*** Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
*** Recognition of pathogens via the humoral PRRs results in various killing mechanisms
* Engagement of PRRs by PAMPs triggers:
** '''Phagocytosis'''
** The expression of '''cytokines''', which brings about [[Inflammation - WikiBlood|inflammation]] and other immune responses

<big><center>'''''Examples of Pattern Recognition Receptors'''''</center></big>

{| style="width:60%; height:200px" border="1" align=center

!'''Receptor'''
!'''Location'''
!'''Ligands'''
|-
| TLR2 (''Toll-like receptor'')
| Cell Membrane
| Peptidoglycan of gram +ve bacteria
|-
| TLR3
| Cell Membrane
| dsRNA of RNA viruses (e.g. avian influenza)
|-
| TLR4
| Cell Membrane
| Lipoplysaccharide from gram-negative bacteria (e.g. E. coli, Salmonella)
|-
| TLR5
| Cell Membrane
| Bacterial flagellin
|-
| TLR9
| Cell Membrane
| Bacterial DNA (CpG DNA)
|-
| C-type lectins
| Soluble
| Carbohydrates, all bacteria, dead cells
|-
| fmlf
| Soluble
| Formyl peptides (i.e. all bacteria)
|-
| Complement receptors
| Soluble
| Fixed complement components (e.g. iC3b)
|-
| NOD2
| Cytoplasm
| Peptidoglycan of gram +ve bacteria
|-
| dsRNA-dependent Protein Kinase Receptor
| Cytoplasm
| ds RNA of RNA viruses
|}

==Phagocytosis==
* Phagocytosis is a very primitive system of defence against infection
** Even exists in invertebrates
* Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalisation
** The internalised vesicle is referred to as the "phagosome"
** '''Lysosomes''', which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
*** Oxygen-dependent degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
*** Oxygen-independed degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
**** In addition, these granules contain antimicrobial elements such as lactoferrin
** Microbes are then digested by a number of different catabolic enzymes
*** Glycosidases: Digest carbohydrates
*** Lipases: Digest lipids
*** Proteases: Digest protein
** Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
* '''Neutrophils''' and '''macrophages''' are phagocytic
* '''Opsonins''' promote and accelerate phagocytosis
* Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognize intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Video of phagocytosis of ''Candida albicans'': [http://www.cellsalive.com/qtmovs/mac_mov.htm]

=Tools of Innate Immunity=

==Barriers==
===Physical Barriers===
[[Image:Epithelial barriers.jpg|thumb|right|150px|Epithelial Barriers - B. Catchpole, RVC 2008]]

'''''Skin'''''

The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
* Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin (and lower urinary tract).
** Infection becomes a problem when there is:
*** Skin loss: e.g. burns
*** A break in the skin: e.g. wounds

'''''Mucus Membranes'''''
* Thin epithelial surfaces are necessary for the normal physiological functions of the bodies mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
** The body uses alternative protective mechanisms in these areas:
*** The '''mucociliary escalator''' of the respiratory tract (assisted by coughing and sneezing)
*** '''Peristalsis, vomiting & diarrhoea''' when necessary removes microorganisms from the GIT

===Biochemical Barriers===
* '''Lactic and fatty acids''' in sweat and sebaceous secretions are directly bacteriocidal
* '''Enzymes''' e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
* Mucus itself is acidic, indigestible and traps microorganisms

==='''Commensal Organisms'''===
* Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
* When commensals are disturbed, infection with opportunistic organisms is increased
** E.g. [[Yeast-like fungi|''Candida'']] (thrush) or [[Clostridium species|''Clostridium difficile'']] (infectious diarrhoea)

==Humoral Factors==
===Lysozyme===
* Lysozyme is one of the major bactericidal agents in secretions
* Helps to protect vulnerable sites such as the eyes and nasal passages
* Exerts bactericidal effects by digesting bacterial cell walls
** Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
** The outer membrane of gram-negative bacteria helps to protect them

===[[Complement - WikiBlood|Complement]]===
* The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
* Complement promotes '''phagocytosis''' or causes lysis of an invading organism
* Complement acts as a cascade, like the blood clotting system
** The early enzymes in the cascade are bound to invading bacteria and fungi
*** They have an affinity for components of microbial cell membranes
** This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
* The early components act as targets for phagocytes
* The later components punch holes in bacteria, causing their lysis

===Interferons===
* Lysozyme and complement have only marginal effects on virus infections because these are intracellular
** The body has evolved non-specific mechanisms to protect against viruses
*** The most notable of these is the interferons
* Interferons are small polypeptides produced mainly by virus-infected cells
** Interact with uninfected cells and render them resistant to infection
*** This resistance is mainly due to the production of enzymes that digest viral nucleic acids

==Cellular responses==
[[Image:LH Macrophage Histology.jpg|thumb|right|125px|'''Macrophage'''© Nottingham Uni]]
* If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
* The cells involved with innate protection are:
** Blood granulocytes, or Polymorphonuclear Cells
*** Notable for their multi-lobed nuclei
*** '''Neutrophils''': phagocytose bacteria
*** '''Eosinophils''': kill parasites by the release of granules
*** '''Basophils/ mast cells''': kill parasites by the release of granules
** Blood '''monocytes''': phagocytose bacteria
** Tissue mast cells and '''macrophages''': phagocytose bacteria
*Effectively, innate cellular response seeks to hold off the infection until the [[Adaptive Immune System - WikiBlood|adaptive]] response can back it up with a more specific attack

===[[Macrophages - WikiBlood|Macrophages]]===
[[Image:Monocytes.jpg|thumb|right|150px|Monocytes - J. Bredl, RVC 2008]]
*The role of macrophages in Innate Immunity is to act as primary '''phagocytes'''
* Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
** Alveolar macrophages
** Tissue histiocytes
** Glomerular macrophages
** Hepatic Küpffer cells
** CNS microglia
** Sinus-lining macrophages of the lymph nodes and spleen
* [[Monocytes - WikiBlood|'''Monocytes''']] (immature macrophages) are circulating phagocytes
** Circulate for 6-8 hours
** Can function as phagocytes within the blood and as newly migrated cells in tissues
** Chiefly function to replace the various tissue macrophage populations

===[[Neutrophils - WikiBlood|Neutrophils]]===
[[Image:Neutrophil 2.jpg|thumb|right|150px|Neutrophils - J. Bredl, RVC 2008]]
* Neutrophils are the principal, highly active '''phagocytes''' in the blood
** Comprise 30-70% of white blood cells depending on species
** Kill and digest microbes in a similar way as macrophages
* Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
** Secrete small antibacterial peptides
*** E.g. defensins and bactenecins
* Neutrophils produce vasoactive peptides
** E.g. histamine and bradykinin
** Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
* Neutrophils are the archetypal cell associated with [[Inflammation - WikiBlood|acute inflammation]]
** Are attracted to sites of inflammation by:
*** Complement activation
*** Cytokine production
*** Changes to vascular endothelium
** Neutrophil activation in an inflammatory lesion results in the release of '''prostaglandins'''
*** Responsible for vasoactive changes and for pain
* The accumulation of dead and dying neutrophils at the site of infection is called '''pus'''
** Their removal from the site after the removal of infection is an important step in the resolution of the lesion

===[[Eosinophils - WikiBlood|Eosinophils]]===
[[Image:Eosinophil.jpg|thumb|right|150px|Eosinophil - J. Bredl, RVC 2008]]
* Eosinophils are less common than neutrophils, and they are not phagocytic
** Make up <5% of the leukocytes in normal blood
* Eosinophil numbers are increased:
** Slightly during the resolution phase of inflammation
** Many-fold in parasite-infected animals
*** The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitaemia
* Mainly function by targeting the surface of parasites by means of specific antibody or complement
** Release a large range of toxic molecules that break down the parasite integument
* Prominent in [[Allergic diseases - WikiClinical#Allergic diseases|allergic]] (anaphylactic) reactions

===[[Basophils - WikiBlood|Basophils]] / [[Mast Cells - WikiBlood|Mast Cells]]===
[[Image:Basophil and Lymphocyte.jpg|thumb|right|150px|Basophil - J. Bredl, RVC 2008]]
* Basophils/mast cells are principally localized at epithelial surfaces
** Very small numbers are present in blood
*** less than 0.5% circulating leukocytes
* They have two principal functions:
*# Induction of [[Inflammation - WikiBlood|acute inflammation]]
*#* Trauma and/ or bacterial infection causes the production of '''cytokines''' by the mast cells that induce a classical acute inflammatory response
*# Response to parasite infection
*#* Specific [[Immunoglobulins - WikiBlood|IgE]] binds cells
*#* Subsequent contact with antigen causes the mast cells to degranulate
*#* Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
* Also produce factors that influence local host cell physiology
** Various mediators increase the ratio of phagocyte to microbe

=Innate Immunity to Viruses=
[[Image:Innate viral response.jpg|thumb|right|150px|Innate response to dsRNA - B. Catchpole, RVC 2008]]
Because viruses invade host cells to take over a host's cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the '''double-stranded RNA''' (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a forein intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.

The innate resonse to viral attack also depends on the presence of '''Type-1 Interferons''', which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.

Lastly, the final line of defense for the innate response to viruses lies in the actions of [[Lymphocytes - WikiBlood#Natural Killer (NK) Cells|'''Natural Killer (NK) cells''']]. These warriors monitor the production of [[MHC - WikiBlood|MHC]] (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell's MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.

=Innate Immunity to Bacteria=
[[Image:Bacterial innate response.jpg|thumb|right|150px|Bacterial responses - B. Catchpole, RVC 2008]]
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the [[Adaptive Immune System - WikiBlood|adaptive]] response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and engaging the [[Inflammation - WikiBlood|inflammatory]] response. The release of inflammatory [[Cytokines - WikiBlood|cytokines]] will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the [[Liver - Anatomy & Physiology|liver]], and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and [[Complement - WikiBlood|complement]]-initiated phagocytosis.

=[[Interplay of Innate and Adaptive Immunity - WikiBlood|Interplay of Innate and Adaptive Immunity]]=

=[[Innate Immunity Flashcards - WikiBlood|Innate Immunity Flashcards]]=

=Links=
'''Websites'''
*http://www.cellsalive.com

=References=

=Creators=
[[Rebecca Pocock]]

[[Asher Allison]]

[[Natalie Brown]] (flashcards)

Spleen - Anatomy & Physiology

2009-08-12T13:38:51Z

Kwhittle: /* Lymphoid */

{{toplink
|linkpage =Lymphatic System - Anatomy & Physiology
|linktext =Lymphatic System
|tablelink = Lymphatic System (Table) - Anatomy & Physiology
|maplink = Lymphatic System (Content Map) - Anatomy & Physiology
|sublink1 =Secondary Lymphoid Tissue - Anatomy & Physiology
|subtext1 =Secondary Lymphoid Tissue
|pagetype =Anatomy
}}
 
{|style="border:1px solid #cedff2;" align="right"
|
{|
|[[Image:LH_Canine_labelled_lateral_abdominal_organs_radiograph.jpg|150px]]
|[[Image:LH_Canine_labelled_ventrodorsal_abdominal_organs_radiograph.jpg|150px]]
|-
!colspan="2"|<center>Location canine radiograph</center>
|-
!Lateral view
!Ventrodorsal view
|-
|colspan="2"|<center>©Nottingham Uni 2008</center>
|-
|colspan="2"|<center>[[Image:LH Spleen Gross Histology.jpg|150px]]</center>
|-
|colspan="2"|<center>'''Gross histological view'''</center>
|-
|colspan="2"|<center>©Nottingham Uni 2008</center>
|}
|}

==Introduction==
The spleen is a major lymphoid and blood filtration organ and is located in the left cranial abdomen. It is responsible for storing and removing [[Erythrocytes - WikiBlood|erythrocytes]] from the blood as well as antigen surveillance of the blood and antibody production.
==Development==
The spleen develops in association with the digestive system in the dorsal mesogastrium, and as the [[Forestomach - Anatomy & Physiology|stomach]] rotates during development the spleen comes to occupy the left cranial abdomen. Haematopoietic cells in the spleen are derived from the AGM (aorta-gonad-mesonephros) and yolk sac and as the [[Primary Lymphoid Tissue - Anatomy & Physiology|primary lymphoid organs]] become established it becomes populated with [[Lymphocytes - WikiBlood#Types|T and B lymphocytes]].
==Structure==
{|align="right"
|[[Image:LH_Spleen_Equine_Ultrasound.jpg|150px]]
|[[Image:LH_Spleen_Histology.jpg|150px]]
|-
!Normal Ultrasound (Equine)
!Histological section
|-
|colspan="2"|<center>©Nottingham Uni 2008 </center>
|}
The spleen lies vertically on the left side of the cranial abdomen. It is attached to the greater curvature of the [[Alimentary - Anatomy & Physiology#Stomach|stomach]] by the gastrosplenic ligament. The spleen is enclosed in a capsule of fibrous and elastic tissue that extends into the parenchyma as trabeculae. 
 The parenchyma is supported by a fine mesh of reticular fibres and is divided into two types of tissue, the red and the white pulp, which are separated by the marginal sinus.
===Red Pulp===
The red pulp makes up the majority of the spleen and is composed of a network of cell cords in series with vascular sinuses. The splenic cords contain [[Macrophages - WikiBlood|macrophages]], [[B cell differentiation - WikiBlood#Plasma cells|plasma cells]], [[Lymphocytes - WikiBlood|lymphocytes]] and other mature blood cells e.g. [[Granulocyte - WikiBlood|granulocytes]] and [[Erythrocytes - WikiBlood|erythrocytes]]. While the vascular sinuses are wide vascular channels lined with endothelial cells. Blood cells and fluid can pass into the splenic cords through fenestrations in the sinus walls. 
===White Pulp===
White pulp is organised in relation to the splenic arterioles and consists of discrete lymphoid tissue surrounding a central arteriole. There is a sheath of [[Lymphocytes - WikiBlood#T cells|T cells]] directly around the arteriole, the periarteriolar lymphoid sheath (PALS), which is surrounded by a marginal sinus, and then a zone of [[Lymphocytes - WikiBlood#B cells|B cells]] and [[Macrophages - WikiBlood|macrophages]] (the marginal zone). B cell follicles are associated with the marginal zone and expand and develop germinal centres after antigen activation. The marginal sinuses are linked to the red pulp sinuses. White pulp stains basophilic in a H&E stain
====Species Differences====
{|align="right"
|<center>[[Image:LH_Spleen_Equine_photo.jpg|110px]]</center>
|<center>[[Image:LH_Spleen_Bovine_photo.jpg|156px]]</center>
|-
!Equine
!Bovine
|-
|colspan="2"|<center>©Nottingham Uni 2008 </center>
|-
|<center>[[Image:LH_Spleen_Canine_Photo.jpg|110px]]</center>
|<center>[[Image:LH_Spleen_Ovine_Photo.jpg|150px]]</center>
|-
!Canine
!Ovine
|-
|colspan="2"|<center>©RVC 2008</center>
|}
The capsule and trabeculae are much more muscular in carnivores and horses than ruminants
*Carnivores
**Is elongated and dumb-bell shaped (larger ventrally)
*Ruminants
**Is flat and oblong shaped
*Horses
**Lies under the last three [[Ribs and Sternum: Anatomy and Physiology|ribs]]. Dorsally it is broad but narrows as it extends cranially and ventrally
**On rectal palpation it is located against the body wall and feels smooth with a sharp border
*Pigs
**Elongated and strap-like under the last few [[Ribs and Sternum: Anatomy and Physiology|ribs]]
*Birds ([[Media:Avian Liver and Spleen.jpg|Picture here]])
**Lies alongside, to the right, of the [[The Proventriculus - Anatomy & Physiology|proventriculus]] and is found caudodorsally to the [[Avian Liver - Anatomy & Physiology|liver]]
**Spherical in chickens, triangular in ducks & oval in pigeons

===Vasculature===
The splenic artery, a branch of the celiac artery, supplies the spleen. The artery branches into arterioles and capillaries, which may either:
*Connect with the venous sinuses, or
*Terminate with open ends in the splenic cords
Blood released into the splenic cords, either from the sinuses or capillaries, eventually filters back into the sinus network. The sinuses converge and empty into trabecular veins, which then merge into a single splenic vein which then empties into the portal vein.
[[Lymphocytes - WikiBlood|Lymphocytes]] in the arterial blood migrate from the red pulp sinuses, through the splenic cords and through the white pulp. [[Lymphocytes - WikiBlood#T cells|T cells]] specifically migrate through the PALS and [[Lymphocytes - WikiBlood#B cells|B cells]] specifically migrate through the follicles. Antigen in the blood is filtered by the large numbers of [[Macrophages - WikiBlood|macrophages]] in the splenic cords and white pulp.
====Species Differences====
The splenic artery:
*Passes through the spleen without dividing in ruminants
*Branches regularly as it passes through the spleen in horses and pigs
*Branches before it reaches the spleen in dogs and cats

===Innervation===
Innervation is purely sympathetic<ref>{{citation|initiallast = Nance|initialfirst = D.M|finallast = Sanders|finalfirst = V.M|year = 2007|jtitle = Autonomic innervation and regulation of the immune system (1987-2007)|jor = Brain, Behavior, and Immunity|vol = 21(6)|range = 736-745}}</ref> and nerve fibres travel with the artery into the spleen.
===Histology===
<gallery perrow="3">
Image:LH_Spleen_Rat_Histology.jpg|'''Gross view (rat)'''©RVC 2008
Image:LH_Spleen_Rat_Higher_Histology.jpg|'''Red & white Pulp (rat) '''©RVC 2008
Image:LH_Spleen_Rat_Higher_2_Histology.jpg|'''Central artery & PALS (rat) '''©RVC 2008
Image:LH_Spleen_Rat_Higher_3_Histology.jpg|'''Trabecula and capsule (rat) '''©RVC 2008
Image:LH_Spleen_Rat_Higher_4_Histology.jpg|'''Trabeculae & erythrocytes (rat)'''©RVC 2008
Image:LH_Spleen_Mouse_Higher_Histology.jpg|'''Megakaryocyte & macrophages (mouse)'''©RVC 2008</gallery>

==Functions==
The spleen has a number of functions:
*It filters the blood removing ageing [[Erythrocytes - WikiBlood|erythrocytes]] and antigens
*It stores [[Erythrocytes - WikiBlood|erythrocytes]] and [[Thrombocytes - WikiBlood|platelets]]
*[[Secondary Lymphoid Tissue - Anatomy & Physiology|Secondary lymphoid organ]]
===Erythrocytes & Platelets===
In the foetus the spleen also has a role in [[Overview of Haematopoiesis - WikiBlood|haematopoiesis]] when it becomes the main [[Erythrocytes - WikiBlood|erythrocyte]] producing organ during the haematopoietic transitional phase.
In the developed animal the red pulp is involved in the removal of aged, damaged or abnormal [[Erythrocytes - WikiBlood|erythrocytes]] (along with the [[Liver - Anatomy & Physiology|liver]] and [[Bone Marrow - Anatomy & Physiology|bone marrow]]). As [[Erythrocytes - WikiBlood|erythrocytes]] age they become less supple and this causes them to become damaged when they pass through the very narrow capillaries of the spleen, after which they are phagocytised by splenic [[Macrophages - WikiBlood|macrophages]]. If a splenectomy is performed the number of aged [[Erythrocytes - WikiBlood|erythrocytes]] in circulation increases.
 The red pulp also acts as a storage site for [[Erythrocytes - WikiBlood|erythrocytes]]. The degree of storage is variable between species but is particularly notable in horses which, during exercise under sympathetic activity, can contract their spleen to increase the concentration of circulating [[Erythrocytes - WikiBlood|erythrocytes]]. In some species such as cats and rodents the red pulp acts as a storage site for [[Thrombocytes - WikiBlood|platelets]] and contains [[Thrombopoiesis - WikiBlood#Megakaryocyte|megakaryocytes]].

===Lymphoid===
Blood flows through the marginal sinus. This means that most antigens present in the blood come into contact with the [[Lymphocytes - WikiBlood#B cells|B lymphocytes]] and dendritic cells in the spleen. Dendritic cells in the marginal sinus and red pulp take up antigens from the blood and transport them to the primary follicles in the white pulp. If the antigen activates the [[Lymphocytes - WikiBlood#B cells|B lymphocytes]] then a germinal centre will form in the primary follicle and this is called a splenic nodule. Antibody producing cells then migrate to the red pulp and marginal zone.
Following splenectomy this doesn’t occur and animals are predisposed to septicaemia and infection with blood [[Protozoa|protozoa]].

==In pathology==
===Direct pathology===
*Specific spleen pathology can be found [[Spleen - Pathology|here]]
*[[General Pathology - Neoplasia#Acute Undifferentiated Leukaemia|Acute undifferentiated leukaemia]] and [[General Pathology - Neoplasia#Lymphoid Neoplasms|lymphoid neoplasms]]
===Changed or affected by===
*[[General Pathology - Post-Mortem Change#Agonal Changes|Post mortem change]]
*[[Endocardial - Pathology#Haemangioendothelioma|Haemangioendotheliomas]], [[General Pathology - Neoplasia#Pancreatic carcinoma|pancreatic carcinomas]] & [[Liver Proliferative - Pathology#Haemangiosarcoma|haemangiosarcomas]]
*[[Lymphoreticular - bacterial diseases#Corynebacterium ovis|Corynebacterium ovis]], [[Erysipelothrix rhusiopathiae#Swine erysipelas|swine erysipelas]], [[Francisella tularensis#Pathogenesis and pathogenicity|francisella tularensis]], [[Salmonella#Spleen|salmonella]], [[Intestines Fibrinous/Haemorrhagic Enteritis - Pathology#enteric Salmonellosis|enteric salmonellosis]], [[Brucella species#Pathogenesis and pathogenicity|brucella]] & [[Yersinia#Clinical infections|yersinia]]
*[[Poxviruses#Histopathology|Leporipoxviruses]] & [[Cavity & Gingiva - Pathology#Erosive & Ulcerative Pathology|bovine viral diarrhoea disease]]
*[[General Pathology - Pigmentation and Calcification#Haemosiderin|Haemolytic disorders]]

==References==
<references/>