ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

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It represents a comprehensive approach to study Brazilian pemphigus foliaceus or Fogo Selvagem (FS) and describes a series of protocols aimed at uncovering the etiology of this autoimmune disease. During the previous funding period we have accumulated substantial original information which is applicable not only to understanding the pathogenesis of FS but is also relevant to other aspects of keratinocyte biology and biochemistry, i.e., we have shown that FS autoantibodies are pathogenic and restricted to the IgG4 subclass. FS autoantibodies appear to induce keratinocyte detachment by impairing the function of desmoglein 1 (a cadherin-like desmosomal glycoprotein) which is the epidermal antigen recognized by these antibodies. This proposal also describes two novel autoantibody systems in FS sera: IgG2 autoantibodies against keratin-10 and autoantibodies against a ubiquitin-carrier protein. The relevance of these autoantibodies in the etiology and pathogenesis of FS will be investigated in this proposal. Based on epidemiological data, this grant addresses the hypothesis that the humoral autoimmune response in FS is triggered and maintained by an environmental "antigenic factor(s)". FS is the ideal, and perhaps the only, human autoimmune disease in which this hypothesis could be tested since it is endemic to certain regions of Brazil, where there are currently more than 15,000 registered cases. Individuals at risk are outdoor workers living on agricultural farms. Our studies show that individuals developing FS share distinctive susceptibility HLA DR1 alleles and lack a dominant DQw2 protective gene which is present in normal people. Susceptible individuals, therefore, if exposed to unique environmental antigens, may produce antibodies which, in turn, cross-react with keratinocyte surface epitope(s) and cause acantholysis ("antigenic mimicry"?). Among a variety of etiological agents, an insect vector (a "black fly", family Simuliidae) has been suspected of precipitating the disease. Several circumstantial observations, and a recent epidemiologic case-control study (see Progress Report Section), support this hypothesis. This proposal will systematically investigate the role of black flies as a potential source of sensitizing agent that leads to autoantibody formation in FS. If successful, the information derived from these studies should be relevant to other human autoimmune diseases.