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=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 - WikiBlood|Autoimmunity]]), they must be deleted or suppressed.
==Central Tolerance==
*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 suppress 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.