PATHOPHYSIOLOGY OF EXPERIMENTALLY INDUCED PEMPHIGUS

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DESCRIPTION (Adapted from the applicant's abstract): The long-term goals of the principal investigator are definition of the pathogenic role of pemphigus and pemphigoid autoantibodies in the production of cutaneous lesions, primarily through the use of an in vivo murine model. The investigators have recently identified a novel autoimmune blistering mucocutaneous syndrome that is associated with underlying neoplasms that they have termed paraneoplastic pemphigus. They believe that their preliminary studies support the following hypotheses regarding the etiology of this syndrome. (a) A subset of patients with blistering mucosal and cutaneous lesions and underlying neoplasms have a clinically and immunologically distinctive paraneoplastic syndrome. (b) They have autoantibodies that recognize a characteristic complex of epidermal antigens, Mr 250 KD, 230 KD, 210 KD, and 190 KD, by immunoprecipitation of metabolically labelled keratinocytes. (c) The tumors of these patients anomalously express antigens that are identical to or cross-reactive with the epithelial antigens. (d) The autoantibodies, directed primarily against tumor antigens, bind to and cause lesions within the skin and mucosa of the affected patients. The investigators present preliminary data showing that: (1) The autoantibodies of all cases have similar antigenic specificity; (2) the 250 KD Ag is desmoplakin 1 - a demonstrated plaque protein - and the 230 KD Ag is the 230 KD bullous pemphigoid Ag a hemidesmosomal protein; (3) the autoantibodies from these patients cause cutaneous and esophageal lesions in vivo by passive transfer into mice; (4) the tumor (a reticulum cell sarcoma) from one case possesses desmosomes and expresses desmoplakin I, that is reactive with both a monoclonal antibody against desmoplakin and the patients' serum autoantibodies. This study will examine the following points raised by these observations: (1) To define the specificity of the autoantibodies; (2) define the identity of the 210 and 190 KD antigens; (3) define the precise nature of antigens expressed by these tumors; (4) ascertain if these antigens are expressed only in the tumors of affected individuals, and (5) define the mechanisms by which the antibodies produce epithelial damage in vivo. This they believe is an unique opportunity to explore the complex relationship between tumor immunity and autoimmunity, for this disease may represent another biologic example in which immune response directed against tumor antigens may cross-react with constitutive proteins of host tissue, with disastrous "autoimmune" effects for the patient. Finally, the investigators have defined a major immunogenic region (MIR) of the 180 KD bullous pemphigoid antigen that is preferentially recognized by patients with Herpes gestationis (HG) (gestational pemphigoid). This is a 41-amino acid peptide that is bound by the majority of sera from affected patients. The investigators have preliminary data showing the BP 180 KD antigen is present in the amniotic epithelium of the placenta. The investigators will determine if the MIR for HG autoantibodies is expressed in amniotic epithelium, by use of indirect immunofluorescence, in situ and Northern blot hybridization. Polyclonal antibodies against the epitope will also be tested for their pathogenicity in vivo.