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central tolerance

Tuesday 10 March 2009

Central Tolerance refers to death (deletion) of self-reactive T- and B-lymphocyte clones during their maturation in the central lymphoid organs (the thymus for T cells and the bone marrow for B cells).

Deletion of developing intrathymic T cells has been extensively investigated. Experiments with transgenic mice provide abundant evidence that T lymphocytes that bear receptors for self-antigens undergo apoptosis within the thymus during the process of T-cell maturation.

It is proposed that many autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic antigen-presenting cells in association with self-MHC molecules.

A protein called AIRE (autoimmune regulator) is thought to stimulate expression of many "peripheral" self-antigens in the thymus and is thus critical for deletion of immature self-reactive T cells.38 Mutations in the AIRE gene (either spontaneous in humans or created in knockout mice) are the cause of an autoimmune polyendocrinopathy.

The developing T cells that express high-affinity receptors for such self-antigens are negatively selected, or deleted, and therefore the peripheral T-cell pool is lacking or deficient in self-reactive cells.

What triggers apoptosis in self-reactive T-cell clones is not entirely clear. Some immature T cells that encounter self-antigens in the thymus develop into regulatory T cells, described below.

As with T cells, clonal deletion is also operative in B cells. When developing B cells encounter a membrane-bound antigen within the bone marrow, they undergo apoptosis.

Clonal deletion of self-reactive lymphocytes, however, is far from perfect. Many self-antigens may not be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery.

There is similar "slippage" in the B-cell system as well. B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be found in the peripheral blood of healthy individuals.

See also

- peripheral tolerance