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Because the brush-border (BB) of the renal proximal tubule shares antigens with other epithelia including glomerular epithelial cells (GEC) and the visceral yolk sac (VYS) of the embryo, immune reactions directed to BB antigens can induce glomerulonephritis (GN), such as Heymann's nephritis, a rat model of membranous GN (MGN) and teratogenic effects. To identify the responsible antigens, we have raised monoclonal antibodies against the BB, selected those exhibiting cross-reactivity with the GEC and/or the VYS, and tested their pathogenicity in vivo. This led us to characterize the target antigen of Heymann's nephritis as a 330 kD glycoprotein closely associated with clathrin in the intermicrovillar areas of the BB and the coated pits of the GEC. Induction of the characteristic electron -dense deposits is a dynamic process including redistribution of the antigen on the surface of GEC triggered by cross-linking by polyclonal antibodies, followed by shedding of the immune complexes from the cell membrane, and increased antigen synthesis. Gp330 is not detected in human GEC and therefore is probably not implicated in the pathogenesis of MGN in man. Other antigenic candidates for the in situ formation of epimembranous deposits in the glomerular capillary wall are dipeptidyl peptidase IV (gp90) and naeutral endopeptidase (gp85, CALLA), two enzymes shared by the BB and the GEC in numerous species including man. Using the same ""monoclonal approach"", we have identified another coated pit glycoprotein, gp280, as the main target antigen of teratogenic anti-kidney antibodies. Injection of any of the anti-gp280 monoclonal antibodies induces in a dose-dependent manner embryonic resorption and malformations in the surviving fetuses. Preliminary experiments suggest that the teratogenic effects are due to alterations of the endocytotic process that plays a key role in providing nutrients to the developing embryo. These observations indicate that binding of a monoclonal antibody to, departmental bulletin paper