Apoptosis and necrosis can contribute to autoimmunity, both organ-specific and systemic, in many different ways. For instance, defects in genes involved in the regulation of lymphocyte activation and the deletion of autoreactive lymphocytes may lead to ineffective removal of unwanted lymphocytes during negative selection or after lymphocyte activation. Evidence for this mechanism derived from studies involving mouse models of systemic autoimmunity and patients with lymphoproliferative disorders [23-25]. In lpr/lpr mice, considered as a mouse model of lupus-like disease, a spontaneous mutation in the death receptor Fas interferes with the elimination of autoreactive lymphocytes both centrally and in the periphery, leading to lymphoproliferation, splenomegaly, and systemic autoimmunity . Similar symptoms are observed in gld/gld mice, which carry a point mutation in the intracellular apoptotic domain of FasL . The discovery of these mutations led to a search for similar mutations in patients with SLE, but the results were disappointing. FasL mutations were found only in a rare form of lupus . However, humans with Canale-Smith syndrome, also called human autoimmune lymphoproliferative syndrome, carry mutations in Fas, FasL, and caspase genes . This hereditary syndrome, which is usually diagnosed early in life, presents lymphoproliferation characterized by large numbers of double-negative CD4-CD8 lymphocytes, splenomegaly, antinuclear autoantibody production, rheumatoid factor production, thrombocytopenia, glo-merulonephritis, arthritis, and vasculitis [23-25]. Lymphocytes from these patients are resistant to FasL-induced apoptosis .
More recent evidence for the hypothesis that impaired T-cell death promotes autoimmunity derives from studies with mice deficient in the T cell-specific adapter protein (TSAd). This protein is expressed in thymocytes and in activated mature T cells and is involved in signal transduction . TSAd-deficient mice display defective T-cell death in vivo and develop lupus-like autoimmunity, suggesting that TSAd is a critical regulator of T-cell death whose absence or inacti-vation promotes systemic autoimmunity . The requirement of T-cell apoptosis for the suppression of autoimmunity was also illustrated recently by studies using BXSB lupus-prone mice deficient in the cyclin kinase inhibitor p21, a regulator of cell death and proliferation . Absence of p21 in these mice resulted in enhanced Fas/FasL-mediated activation-induced T-cell death and increased B-cell apoptosis. Consequently, the development of systemic autoimmu-nity was inhibited in these mice.
Failure of the immune system to eliminate autoreactive lymphocytes may lead to excessive cell death induced by autoreactive T cells in target organs in certain organ-specific autoimmune diseases. For instance, insulin-dependent diabetes mellitus (IDDM) is characterized by T cell-mediated selective destruction of the insulin-producing /5-cells of the Langerhans islets of the pancreas . In the non-obese diabetic (NOD) mouse model, both autoreactive CD4+ and CD8+ T cells are involved in /5-cell destruction via recognition of presented peptides derived from self-antigens such as insulin, GAD65/67, and HSP70 . CD4+ T cells can directly induce /5-cell apoptosis through FasL-Fas interactions or promote the effector functions of cytotoxic CD8+ T lymphocytes (CTL) and natural killer (NK) cells, which involve perforin-dependent delivery of cytotoxic granules. Lymphocyte-mediated cytotoxicity has been also proposed to explain the destruction of oligodendrocytes in multiple sclerosis as well as thyroid cells in Hashimoto's thyroiditis .
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