Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown etiology characterized by chronic, inflammatory damage of numerous tissues. The highly specific clinical phenotypes of SLE, the unique pathology, and the very specific autoantibody response associated with these phenotypes have provided critical insights into the pathogenesis of lupus. In this regard, photosensitive lupus skin disease and neonatal lupus have been particularly instructive, providing both common and unique insights into disease mechanisms (Buyon 1996, Orteu et al. 2001, Sontheimer 1989). For example, the skin is a prominent target tissue in both phenotypes, and there is a characteristic exacerbation of cutaneous disease after exposure to sunlight or to artificial sources of ultraviolet (UV) radiation (Buyon 1996, Orteu et al. 2001, Simmons-O Brian et al. 1995, Sontheimer 1989). Similarly, both phenotypes are associated with the production of autoantibodies to highly specific targets, for example, Ro/SSA and La/SSB (Lee et al. 1994a, b, Provost and Reichlin 1988). The neonatal lupus phenotype is particularly instructive in this regard, as it demonstrates that passive transfer of autoantibodies plays a critical role in lesion generation. Such lesion induction by an environmental exposure in the setting of specific autoantibodies strongly suggests that the stimulus alters the tissue to render it sensitive to autoamplifying damage by inflammatory pathways. Recent data have defined an important role for apoptotic death of cells in generating this ongoing tissue damage (Casciola-Rosen et al. 1994, Casiola-Rosen and Rosen 1997, 1999, Miranda et al. 1998, 2000, Tran et al. 2002). This review focuses on the roles of apoptosis in SLE, with particular emphasis on its relevance to skin disease. Although some aspects of the model presented have yet to be proven in vivo, recognition that apoptotic death is an important source of the ongoing antigenic drive in SLE has significant implications for rational therapy and for prevention of complications in this group of diseases.
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