PENETRATION AND COLOCALIZATION IN MDCK CELL MITOCHONDRIA OF IGA DERIVED FROM PATIENTS WITH PRIMARY BILIARY-CIRRHOSIS

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease of unknown etiology characterized by high-titer anti-mitochondrial ant ibodies. The :major autoantigen has been identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The fact that PDC-E2 i s present in all nucleated cells, but autoimmune damage is confined to biliary epithelial cells, prompted us to investigate the possibility that mucosally-derived IgA may be pathogenic for biliary epithelial ce lls. Serum IgA was purified from six patients with PBC and its localiz ation and ability to penetrate cells was studied using Madine-Darby ca nine kidney (MDCK) cells transfected with the human IgA receptor (MDCK -pIgR). The potential of IgA to be transported through the cells was s tudied by a combination of immunohistochemistry and dual color fluores cent microscopy. Interestingly, IgA from all PBC patients co-localized with PDC-E2 (the major autoantigen of PBC) inside the cells; this was demonstrated by dual staining with anti-human IgA and a mouse monoclo nal antibody directed to PDC-E2. In contrast, no co-localization was o bserved for IgA controls. Furthermore, dual staining df liver sections from PBC patients demonstrated co-localization of IgA and PDC-E2, bot h cytoplasmically and at the apical surface. We postulate that there m ay be a direct effect of these autoantibodies on the mitochondrial fun ction of biliary epithelial cells. (C) 1998 Academic Press