Difference between revisions of "Immune Tolerance"
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| − | 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 | + | 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. |
===Central Tolerance=== | ===Central Tolerance=== | ||
| Line 14: | Line 16: | ||
===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 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 an 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 | ||
| Line 25: | Line 27: | ||
Anergy is easily induced in T cells ''in vivo'' by activation of T cell receptors without co-stimulation; it can be induced ''in vitro'' by the injection of potent superantigens (antigens that stimulate T cells with different receptor types, using the same T cell receptor V gene). Anergy occurs naturally when there is a downregulation of T cell receptors as a result of chronic stimulation. Anergy induced without co-stimulation can be reversed by IL-2. | Anergy is easily induced in T cells ''in vivo'' by activation of T cell receptors without co-stimulation; it can be induced ''in vitro'' by the injection of potent superantigens (antigens that stimulate T cells with different receptor types, using the same T cell receptor V gene). Anergy occurs naturally when there is a downregulation of T cell receptors as a result of chronic stimulation. Anergy induced without co-stimulation can be reversed by IL-2. | ||
| − | + | ===Cell death=== | |
| − | Deficiencies in Fas ligand lead to lymphoproliferative disorders | + | 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== | ||
| − | Mucosal tolerance is the systemic unresponsiveness towards antigens administered across mucosal surfaces | + | 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=== | ===Other mucosal surfaces=== | ||
| − | *Nasal deposition of some peptides can be used to induce tolerance, controlling both | + | *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 | + | *Administration of antigen in aerosol form to the lung has been used to control both allergic and 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 | + | 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| | + | [[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 | |
| − | Known as '''regulatory T cells''', CD4+ cells | + | * 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 | |
| − | Regulatory T cells are unique in their use of a transcription repressor known as FoxP3 | + | * 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]]== | |
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[[Category:Immunology]] | [[Category:Immunology]] | ||
Revision as of 11:15, 16 November 2010
 |
This article has been peer reviewed but is awaiting expert review. If you would like to help with this, please see more information about expert reviewing. |
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
- To prevent an immune attack against host tissue - this is known as self-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); they must be deleted or suppressed.
Central Tolerance
Tolerance at a central level takes place within the thymus, and induces both positive and negative selections:
- 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 induced apoptosis.
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:
- Ignorance
- Anergy
- Cell death
- Immune deviation/suppression
Ignorance can occur when self-reactive T cells cannot penetrate an endothelial barrier, when self-antigen is present in very low amounts, when self-antigen is present on cells that do not express or express low amounts of MHC or when self-antigen is presented without co-stimulation, which can lead to ignorance or anergy, depending on the type of antigen and the affinity to the TCR. Ignorance also occurs when the T cells are not present in sufficient numbers to mount an effective response.
Anergy is defined as a state where the T cell is still alive, but they fail to respond to stimulation from its specific T cell receptor and other receptors are required for activation. Anergy is easily induced in T cells in vivo by activation of T cell receptors without co-stimulation; it can be induced in vitro by the injection of potent superantigens (antigens that stimulate T cells with different receptor types, using the same T cell receptor V gene). Anergy occurs naturally when there is a 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.
- 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.