Normal Mechanisms for Self-Tolerance

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The immune system is confronted with a variety of molecules, and it recognizes them as either self or nonself (foreign), taking action against the latter only. The repertoire of receptors on immune cells that recognize at least more than 108 foreign antigens is not destined by the genetic information encoded in the genome. This repertoire is randomly formed by gene rearrangement and so on during the development of immune cells. As a result, an enormously wide repertoire (about 1015 diversity) of receptors is acquired (1,2). This random mechanism of gene rearrangement, however, produces many receptors that react with self-antigens. Self-reactive immune cells are eliminated (negatively selected) during the development of T lymphocytes in the thymus and of B lymphocytes in the bone marrow (3–11). Only immune cells that react with foreign antigen strongly, but with self-antigen very weakly are positively selected and compose the repertoire of peripheral immune cells. This is the reason why immune cells do not react with self and only attack nonself. This selection mechanism of immune cells in thymus or bone marrow is termed “central tolerance.” The mechanism of central immunological tolerance that deletes self-reactive immune cells is not complete, and a part of self-reactive immune cells escape to the periphery. However, such self-reactive immune cells do not function in the periphery of normal subjects. They are positively managed in the periphery by the fail-safe mechanism against autoimmunity (12–15),and are eliminated (16–21),rendered unresponsive (22–25),or suppressed (26–35). This mechanism is termed “peripheral tolerance.” The failure in these mechanisms of immunological self-tolerance may involve the induction of autoimmune disease (12,14,15).