Autoimmune Disease: Genetics

Autoimmune diseases result from a breakdown of the mechanisms that control thymus (T-) and bursa-derived (B-) lymphocytes tolerance towards self antigens. B lymphocytes recognize antigens as conformation-dependent entities via the B-cell receptor (BCR) for antigen, a cell surface immunoglobulin molecule. Engagement of antigens by the BCR leads to B-lymphocyte activation and differentiation into antibody-secreting plasma cells. The B-cell repertoire develops in the bone marrow. Immature B cells that encounter antigen in the marrow (autoreactive B cells) undergo cell death (negative selection). Alternatively, these cells becomedevelopmentally arrestedandattempt tochange the specificity of their BCR upon reactivation of the immunoglobulin gene-rearrangement machinery (receptor editing). If they do not succeed at this task, they die. In some cases, autoreactive B cells undergo functional unresponsiveness (anergy), which often precedes cell death. B cells surviving the B-cell selection process in the marrow mature and migrate to the secondary lymphoid organs, where they undergo affinity maturation (somatic hypermutation of BCR genes). In the periphery, mature B cells with autoreactive BCRs may also undergo deletion or anergy, or may ignore the target autoantigen altogether. See also: B lymphocytes; B lymphocytes: receptors; Immunological discrimination: self/non-self; Immunological tolerance: Mechanisms; Somatic hypermutation in antibody evolution UnlikeB cells, T cells recognize short peptide fragments in the context of selfmajor histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) via the T-cell receptor (TCR) for antigen. During T-cell development, CD4+ CD8+ thymocytes bearing TCRs capable of recognizing self peptide–MHC complexes on cortical thymic epithelial cells above certain affinity–avidity thresholds mature into CD4+CD82 or CD42CD8+ cells, and exit the thymic cortex towards the thymic medulla (positive selection).High-affinity–avidity engagementof self peptide– MHC complexes by positively selected thymocytes, usually on bone marrow-derived APCs of the thymic medulla, leads to thymocyte death (negative selection) or functional unresponsiveness. These processes ensure that the only T cells exiting the thymus are capable of recognizing foreign, but not self, antigens in the context of self MHC. As in the case of B-cell development, mature self-reactive T cells that escape the thymic selection process may undergo one or more forms of tolerance in the periphery, including deletion, anergy or immune deviation (into nonpathogenic cells). It is now clear, however, that even in normal, nonautoimmuneprone individuals, autoreactive T and B cells can escape the central and peripheral selection processes that shape an individual’s immune repertoire. In most instances, however, these autoreactive cells ignore their target autoantigen(s) or are kept in check by immunoregulatory processes. See also: Major histocompatibility complex (MHC); T lymphocytes: cytotoxic; T lymphocytes: helpers Whether B or T cells bearing self-reactive antigen receptors will be susceptible to one or more forms of tolerance or will ignore their target autoantigens depends on multiple factors, including the timing, amount and source of expression of the autoantigen and themanner inwhich it is presented to them. Furthermore, since CD4+ T-cell, CD8+ T-cell and B-cell responses are often interdependent, tolerance or ignorance in one lymphocyte subpopulation may sometimes be the result of an indirect effect of active tolerance or ignorance in another subpopulation. Tolerance of certain autoreactive B and T cells, for example, may be achieved if appropriate T-cell help is not available, or if B cells cannot present the antigen properly or present it in a tolerogenic manner. Autoimmune diseases thus probably result from a breakdown in several of the mechanisms that normally maintain lymphocyte tolerance and ignorance against self autoantigens. See also: Autoimmune disease; Autoimmune disease: pathogenesis