Peripheral tolerance

Peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease.

Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy. Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery. Dependence of a particular antigen on either central or peripheral tolerance is determined by its abundance in the organism. B cell peripheral tolerance is much less studied and is largely mediated by B cell dependence on T cell help (see split tolerance below).

Antigens, which are present in generally low amount can be ignored by the immune system without any further mechanism, since T cells have to be activated, prior to their migration to non-lymphoid tissues. Specialized mechanisms ensuring ignorance by immune system have developed in so called immunopriviliged organs.

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.

These sites include the brain, the anterior chamber of the eye, the testes and the fetus. These areas are protected by several mechanisms: Fas-ligand expression binds Fas on lymphocytes inducing apoptosis, anti-inflammatory cytokines (including TGF-beta and interleukin 10) and blood-tissue-barrier with tight junctions between endothelial cells.

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