title: Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis.
abstract: Anti-mitochondrial antibodies (AMAs) have long been recognized as a serological hallmark of primary biliary cirrhosis (PBC). Although high titers of immunoglobulin (Ig)A AMAs are found in bile, saliva, and urine of patients, a pathogenic role for this antibody has remained elusive. Functional studies of this IgA in general have been impeded by low quantities of antibody and the inability to recover antigen-specific IgA in dimeric form. Using a newly defined synthetic group A. Streptococcus derived peptide, we purified large quantities of dimeric and monomeric IgA from patient sera. The purified IgA was incubated with Madine-Darby canine kidney (MDCK) cells transfected with the human polymeric Ig receptor (pIgR) and the cells studied by flow cytometric analysis for binding of carboxyfluorescein conjugated VAD-fmk peptide to activated caspase enzymes. A total of 87% of PBC patients that were anti-PDC-E2 positive had serum IgA that increased caspase activation in MDCK-pIgR+ cells compared to serum-derived IgA from controls with a maximum reaction 48 hours after addition of IgA. The titer of anti-PDC-E2 IgA among the PBC patients strongly correlated with caspase activation (cc = 0.88). Pre-absorption of the IgA using recombinant 2-oxo-acid dehydrogenase complex significantly diminished this activation. IgG from the same PBC patients did not induce caspase activation. These data suggest that during transcytosis through pIgR-positive cells, exposure to PDC-E2-specific dimeric IgA results in the initiation of caspase activation. In conclusion, we propose that due to an even greater concentration of dimeric IgA in biliary and mucosal secretions, constant transcytosis would render the exposed cells more susceptible to apoptosis resulting in subsequent bile duct damage.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsumura
authors.forename: Judy
authors.initials: J
authors.lastname: Van De Water
authors.forename: Patrick
authors.initials: P
authors.lastname: Leung
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Odin
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.forename: Keith
authors.initials: K
authors.lastname: Mostov
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shiratori
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D020169:Caspases / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000276:immunology* / Q000378:metabolism
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D020169:Caspases