title: Penetration and co-localization in MDCK cell mitochondria of IgA derived from patients with primary biliary cirrhosis.
abstract: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease of unknown etiology characterized by high-titer anti-mitochondrial antibodies. The major autoantigen has been identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The fact that PDC-E2 is 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 cells. Serum IgA was purified from six patients with PBC and its localization and ability to penetrate cells was studied using Madine-Darby canine kidney (MDCK) cells transfected with the human IgA receptor (MDCK-pIgR). The potential of IgA to be transported through the cells was studied by a combination of immunohistochemistry and dual color fluorescent 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 monoclonal antibody directed to PDC-E2. In contrast, no co-localization was observed for IgA controls. Furthermore, dual staining of liver sections from PBC patients demonstrated co-localization of IgA and PDC-E2, both cytoplasmically and at the apical surface. We postulate that there may be a direct effect of these autoantibodies on the mitochondrial function of biliary epithelial cells.
authors.affiliation: Division of Rheumatology/Allergy Clinical Immunology, University of California, Davis, California, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Malmborg
authors.forename: D B
authors.initials: DB
authors.lastname: Shultz
authors.forename: F
authors.initials: F
authors.lastname: Luton
authors.forename: K E
authors.initials: KE
authors.lastname: Mostov
authors.forename: E
authors.initials: E
authors.lastname: Richly
authors.forename: P S
authors.initials: PS
authors.lastname: Leung
authors.forename: G D
authors.initials: GD
authors.lastname: Benson
authors.forename: A A
authors.initials: AA
authors.lastname: Ansari
authors.forename: R L
authors.initials: RL
authors.lastname: Coppel
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
authors.forename: J
authors.initials: J
authors.lastname: Van de Water
mesh_terms: D000818:Animals; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology*; D001693:Biological Transport, Active; D016022:Case-Control Studies; D002460:Cell Line; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004285:Dogs; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000201:enzymology / Q000276:immunology*; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D001324:Autoantigens; C045281:IgA receptor; D007070:Immunoglobulin A; D011768:Pyruvate Dehydrogenase Complex; D011961:Receptors, Fc; D051047:Dihydrolipoyllysine-Residue Acetyltransferase