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Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery. The cells are controlled through peripheral tolerance mechanisms. These include the suppression of autoreactive cells by 'regulatory' T cells and the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation.

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Ignorance

Potentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance. Anatomical barriers can separate the lymphocytes from the antigen, an example is the central nervous system (the blood-brain-barrier). Naive T-cells are not present in high numbers in peripheral tissue, but stay mainly in the circulation and lymphoid tissue.

Some antigens are at too low a concentration to cause an immune response - a subthreshold stimulation will lead to apoptosis in a T cell.

Immunological priviliged areas

Includes the brain, the anterior chamber of the eye, the testis and the fetus. These areas are protected by several mechanisms: Fas-ligand expression bind Fas on lymphocytes, which dies in apoptosis, anti-inflammatoric cytokines (including TGF-beta and IL-10) and blood-tissue-barriere with tight-junctions between the endotelial cells.

In the placenta IDO (indolamine 2,3 dioxygenase) breaks down tryptophan, creating a "tryptophan desert" micro environment which inhibits lymphocyte proliferation.

Split Tolerance

As many pathways of immunity are interdependent, they do not all need to be tolerised. For example, tolerised T cells will not activate autoreactive B cells. Without this CD4+ T-cell help ,the B cells will not be activated.

Induced anergy

T-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule without co-stimulatory molecules. This will occur if there is no acute inflammation, leading to no co-stimulator upregulation due to the low concentration of cytokines.

Suppression

Auto-reactive T-cells are prevented from reacting due to the presence of T-reg cells. Experimentally, removal of T-reg cells leads to autoimmune reactions.

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