cDNA cloning has demonstrated that pemphigus autoantigens of both pemphigus vulgaris (PV) and pemphigus foliaceus are members of the desmoglein subfamily of the cadherin supergene family. The availability of these cDNAs allowed us to utilize molecular engineering to attempt to understand the pathophysiology of pemphigus. Transfection study with a chimeric molecule containing the extracellular domain of PV antigen (PVA) and the cytoplasmic domain of E-cadherin demonstrated that the extracellular domain of PVA mediates weak homophilic cell adhesion. Bacterial fusion proteins representing different parts of PVA showed that the major immunogenic domains are EC1, EC2, and EC4 and that at least one pathogenic epitope is located on the amino-terminal region of PVA, an area thought to be important for classic cadherin homophilic interaction. Further, a secreted form of PVA recombinant protein, PVIg, was produced by baculovirus expression. Immunoabsorption assay has demonstrated that PVIg is capable of absorbing pathogenic autoantibodies from patients' sera and preventing blister formation in neonatal mice.