The general and long-term goal of my laboratory is to study autoantibody-mediated skin diseases in order to further our understanding not only of the pathophysiology of these diseases but also of the structure and function of normal epidermis. Specifically, we have found that autoantibodies from these patients, who develop blistering diseases due to defects in epidermal cell adhesion, are directed against adhesion molecules. We have characterized, by immunochemical and molecular biologic means, the antigens defined by three of these diseases: bullous pemphigoid (BP), pemphigus vulgaris (PV), and pemphigus foliaceus (PF). This then allows us to study their cell biologic function. BP antigen 1 (BPAG1) is in the plaque of the hemidesmosome. Molecular cloning of the full length coding sequence for BPAG1 indicates a similar domain structure to desmoplakin I, a desmosomal plaque protein. The deduced amino acid sequence of PV antigen indicates that it is in the cadherin family of calcium- dependent cell adhesion molecules and is closely related to the PF antigen. PV antigen was localized ultrastructurally to the desmosome. Current studies are aimed at dissecting the functions of various extracellular and intracellular domains of PV antigen in cell adhesion and in binding to molecules (e.g. plakoglobin) in the desmosomal plaque. We have determined that the extracellular domain of PV antigen mediates weak homophilic adhesion. We have dissected the cytoplasmic subdomains of PV antigen that bind plakoglobin and that can confer adhesive function in the extracellular domain of E- cadherin.
