Although the studies discussed herein focused attention on unique forms of apopto-sis (e. g., UV radiation and antibody-dependent cellular cytotoxicity) as candidate processes associated with the initiation and propagation of cutaneous and systemic lupus, other cellular stress factors (e.g.,infectious agents or drugs) might contribute to the pathogenic process. In the genetically susceptible individual (e. g., someone who has a defect in the ability to efficiently phagocytose and degrade apoptotic cells and debris, or to mount an adequate anti-inflammatory response after ingestion of apoptotic material), the confluence of several forces allows the generation of suprathreshold concentrations of nontolerized structure. If such material accesses the major histocompatibility complex class II antigen-presenting pathway in the presence of appropriate co-stimulatory signals, a primary T-cell response directed at modified antigens will be efficiently initiated and will drive the production of autoantibodies to these antigens. The low frequency of this form of autoimmunity in the population is likely to reflect this need to simultaneously satisfy several stringent criteria to initiate the primary immune response. The molecules targeted are unified by their susceptibility to modification (e. g., cleavage by caspases and/or granzyme B; oxidation) during the perturbing process, likely revealing a previously cryptic structure. Such modifications could include novel UVB-induced RNA/protein cross-linked structures that are generated in cells undergoing UVB-induced apoptosis. Once primary immunization has occurred, the repeated generation of apoptotic material (e. g., during sun exposure, viral infection, or drug exposure) might efficiently rechallenge the primed immune system (the stringency of this secondary response being significantly lower than that of the primary response). The effector pathways activated by the primed immune system include several that generate loads of apoptotic material (e. g., cellular cytotoxicity and inflammatory cell apoptosis). The opsonization of apoptotic material by antibodies against ribonucleoprotein complexes (specifically in photosensitive lupus) may increase the efficiency of apoptotic antigen capture and induce the production of proinflammatory rather than anti-inflammatory cytokines, potentially further driving the immune response. This capacity for immune-driven autoamplification may be one of the critical principles underlying severe systemic autoimmune disease. An important target of future therapeutic intervention may include interrupting the autoamplifying loop by decreasing apoptosis during flares. Identifying the factors that have an impact on the production of unique forms and proper clearance of apoptotic cells may suggest other novel pathways for intervention.

Acknowledgements. These studies were supported by National Institutes of Health grants AR44684 and DE 12354 and the SLE Foundation. A. Rosen is supported by a Burroughs Wellcome Fund Translational Research Award. L. Casciola-Rosen is a recipient of a research grant from the Arthritis Foundation, MD Chapter, MARRC Program.

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