The objective of this project is to study immunologic cytotoxicity as a mechanism of discrete cellular lysis in cutaneous disease, with particular emphasis on antibody mediated mechanisms of lysis, especially antibody dependent cellular cytotoxicity (ADCC). The principle focus of this project is on ADCC as a mechanism of photosensitive papulosquamous cutaneous lupus erythematosus, attempting to explain the strong association of anti SSA antibodies to this clinical condition, by testing the hypothesis that SSA antigen induced by ultraviolet light on keratinocyte cell membranes binds specific anti SSA antibody, inducing cytotoxic damage to keratinocytes by lumphocyte and monocyte effectors via ADCC. The variable involved in expression of SSA and SSB on keratinocyte cell membranes will be tested and the binding of antibodies to SSA and SSB to purified antigenic components and to the molecular complex containing both antigens will be analyzed. Using this information, anti SSA and anti SSB dependent keratinocyte lysis will be analyzed in vitro and in vivo in different models using cultured human keratinocytes as target, human skin explants as targets, human skin grafted onto the nude mouse as a target, or guinea pig skin as a target. Relevant models of keratinocyte damage by anti SSA will be used to test the mechanisms of action of corticosteroids, antimalarials, dapsone, retinoids, antimetabolits, and antioxidants as useful or potentially useful drugs in the treatment of cutaneous lupus. Another important set of aims of this project involves the study of the variable susceptibility to cytotoxicity of different cutaneous targets (keratinocyts, melanocytes, endothelial cells, fibroblasts). This portion of the study will focus on antioxidant defenses of cutaneous targets, how differences in these affect the susceptibility of these cells to immunologic lysis and how therapeutic antioxidants may affect these targets in skin disease. Finally, we will begin pilot projects to study antibody dependent cytotoxicity in other skin diseases such as pemphigus vulgaris, bullous pemphigoid, alopecia areata, and vitiligo.
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