The primary goal of this investigation is to define the interaction between pemphigus antibodies and its epidermal cell surface receptor (pemphigus antigen). Kinetics of antibody binding and the internalization of antibody-receptor complexes will be studied in epidermal cells in culture by immunoelectron microscopy and by a cell detachment assay developed in our laboratory. The effects of antibody fragments (Fab; F(ab1)2), enzyme inhibitors and pharmacologic agents known to impair ligand receptor metabolism in cells will also be tested. These projects are experimentally testable due to the fact that our laboratory has already defined the technology needed to study the effects of pemphigus antibodies, in vitro and in vivo. These studies show convincingly that pemphigus antibodies are pathogenic to epidermal cells (by unknown mechanisms). The present investigation will disclose the molecular mechanisms involved in triggering epidermal cell detachment following the interaction between pemphigus antibody and its cell surface antigen (receptor). Several autoimmune diseases with autoantibodies against cell surface receptors (myasthenia gravis, insulin resistant diabetes, etc.) show a common pathogenic mechanism i.e., a """"""""surface receptor-crosslinking"""""""" induced by the autoantibodies. Bound autoantibodies increase the receptor turnover with impairment of their function. We postulate the same crosslinking phenomenon occurs on the epidermal cell surface after binding of pemphigus antibodies to its surface receptor. The epidermal cell detachment may result from activation of proteolytic enzymes or impairments in the function of certain """"""""attachment"""""""" molecules (pemphigus receptor). It is possible that during internalization of the """"""""pemphigus antibody-cell surface receptor-complex"""""""" there is an associated """"""""regurgitation"""""""" of hydrolytic enzymes from the intracellular vacuolar system, which may further perpetuate the detachment process. The effects of pemphigus antibodies on the biology of the pemphigus epidermal cell receptor will probably disclose many unsuspected pathophysiologic mechanisms ongoing in the skin of pemphigus patients.
