The human dermatological diseases pemphigus and pemphigoid are true autoimmune disorders in which patients become sensitizied to epidermal antigens, producing autoantibodies which in turn are rsponsible for the severe blistering eruption that occurs in the skin. This competitive renewal application represents a collection of ongoing research projects that started several years ago. The highlights of these studies, listed in the progress report, include the development of the first animal models for pemphigus and pemphigoid, studies on the evolution of the epidermal lesions that are induced in the pemphigus animal model, studies on the fate of pemphigus antibodies after binding the keratinocyte cell surface in vitro, the localization of pemphigoid antigen in the epidermal basal cell hemidesmosome-cytoskeleton complex and the development of hybridomas that secrete antibodies with specificity for the epidermal-dermal junction that is similar to human pemphigoid autoantibodies antibodies by immunofluorescene criteria. This application describes studies which will a) define the role of keratinocyte surface cross-linking, complement, and neutrophils in the pathogenesis of pemphigus scantholysis in vivo, b) further define the nature of pemphigoid antigen which is currently partially purified, and c) continue the cloning and characterization of the pemphigoid monoclonal antibodies referred to above. In the present application, we also include sections dealing with the purification of pemphigus antigens and the development of monoclonal antibodies against these antigens using unique approaches, i.e., the human-human system. At the end of the funding period we anticipate that we will have: (a) a pure, highly specific marker of basal cell hemidesosomes, i.e., the pemphigoid antigen as defined by the human autoantibodies and our monoclonal antibodies, (b) a pure, and highly specific keratinocyte cell surface marker, i.e., the pemphigus antigen and its corresponding human autoantibodies and monoclonal antibodies, and (c) a better understanding of the molecular mechanisms by which pemphigus autoantibodies trigger acentholysis in vivo.
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