Changes

==Introduction==

 

Immunological tolerance occurs when there is unresponsiveness towards particular antigens, so any further immune responses are prevented or suppressed. Tolerance is required to prevent:

=Immune Tolerance=

Immunological tolerance occurs when there is an unresponsiveness towards particular antigens, so any further immune responses are prevented or suppressed. Tolerance is required to prevent:

* Potentially harmful inflammatory responses towards innocuous substances, such as air-borne or food molecules

* Potentially harmful inflammatory responses towards innocuous substances, such as air-borne or food molecules

* To prevent an immune attack against host tissue - this is known as '''self-tolerance'''

* To prevent an immune attack against host tissue - this is known as '''self-tolerance'''

==T Cell Tolerance==

==T Cell Tolerance==

During T cell development within the thymus, genes encoding the T cell receptors 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 strongly to antigens expressed by the host's own tissues ('''autoantigens'''), inducing immune reactions that could be damaging to the host ([[Autoimmune Diseases - Introduction#Autoimmune diseases|autoimmune diseases]]); they must be deleted or suppressed.  

During [[T cells|T cell]] development within the [[Thymus - Anatomy & Physiology|thymus]], genes encoding the T cell receptors are rearranged, resulting in adult cells that are able to recognise antigen fragments displayed by the host [[Major Histocompatability Complexes|MHC molecule]]. Some receptors however will be self-reactive, i.e. they bind strongly to antigens expressed by the host's own tissues ('''autoantigens'''), inducing immune reactions that could be damaging to the host ([[Autoimmune Diseases - Introduction#Autoimmune diseases|autoimmune diseases]]); they must be deleted or suppressed.  

===Central Tolerance===

===Central Tolerance===

===Peripheral Tolerance===

===Peripheral Tolerance===

It is inevitable that some self-reactive T cells will evade the thymic selection process and enter the peripheral circulation, because some self-antigens are not expressed in the thymus, and others 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 describes an unresponsiveness towards self-antigen which is developed outside the primary lymphoid organs. There are four ways this may be achieved in T cells:

It is inevitable that some self-reactive T cells will evade the thymic selection process and enter the peripheral circulation, because some self-antigens are not expressed in the thymus, and others 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 describes unresponsiveness towards self-antigen which is developed outside the primary lymphoid organs. There are four ways this may be achieved in T cells:

* Ignorance

* Ignorance

* Anergy

* Anergy

==Mucosal tolerance==

==Mucosal tolerance==

Mucosal tolerance is the systemic unresponsiveness towards antigens administered across mucosal surfaces. The highest antigenic load of the body surfaces occurs in the GI tract, so mucosal tolerance is also sometimes referred to as oral tolerance. When oral tolerance towards food antigens breaks down, inflammatory responses are induced. Gut associated lymphoid tissue is important in the development of 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.

Mucosal tolerance is the systemic unresponsiveness towards antigens administered across mucosal surfaces. The highest antigenic load of the body surfaces occurs in the GI tract, so mucosal tolerance is also sometimes referred to as oral tolerance. When oral tolerance towards food antigens breaks down, inflammatory responses are induced. [[Regional Lymphoid Tissue - Anatomy & Physiology|Gut associated lymphoid tissue]] is important in the development of oral tolerance: animals that lack [[Peyer's Patches - Anatomy & Physiology|Peyer’s patches]] and mesenteric lymph nodes do not develop oral tolerance. It is thought the [[Liver - Anatomy & Physiology|liver]] and [[Spleen - Anatomy & Physiology|spleen]] may also play a role.

In the GI tract, high doses of antigen can cause anergy or cell death. Low doses can induce a T cell response where the antigen is taken up and presented, inducing a Th2-like cell response which 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'''.

In the GI tract, high doses of antigen can cause anergy or cell death. Low doses can induce a T cell response where the antigen is taken up and presented, inducing a Th2-like cell response which 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===

===Other mucosal surfaces===

*Nasal deposition of some peptides can be used to induce tolerance, controlling both humoral and cellular responses

*Nasal deposition of some peptides can be used to induce tolerance, controlling both [[Humoral Factors of Innate Immune System|humoral]] and cellular responses

*Administration of antigen in aerosol form to the lung has been used to control both allergic and autoimmune responses

*Administration of antigen in aerosol form to the lung has been used to control both [[:Category:Allergic Respiratory Diseases|allergic]] and [[Autoimmune Diseases - Introduction#Autoimmune diseases|autoimmune]] responses

==Regulatory T Cells==

==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 therefore can be utelised to 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.  

A number of cell populations identified during studies on autoimmunity and organ transplantation have shown the capacity to suppress responses to self-antigen and therefore can be utilised to 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|200px|Regulatory T cells- copyright Brian Catchpole]]

[[Image:T reg cells.JPG|thumb|right|200px|Regulatory T cells- copyright Brian Catchpole]]

Regulatory T cells are unique in their use of a transcription repressor known as FoxP3 which is 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.

Regulatory T cells are unique in their use of a transcription repressor known as FoxP3 which is 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.

==Test yourself with the Immunology Flashcards==

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

|flashcards = [[Immune Tolerance Flashcards|Immune tolerance flashcards]]

|literature search =[http://www.cabdirect.org/search.html?q=title:(%22immune+tolerance%22)+OR+title:(%22t+cell+tolerance%22)+OR+title:(%22mucosal+tolerance%22)&fq=sc:%22ve%22 Immune Tolerance publications]

[[Category:Immunology]]

[[Category:Immunology]]