title: Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis.
abstract: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the presence of antimitochondrial antibodies in the serum. It is possible that the PBC-specific immunoreactive trypsin-sensitive antigens on the inner mitochondrial membrane, termed M2, are important in the pathogenesis of this autoimmune disease. We have previously shown that a major M2"a" antigen is the E2 component of the pyruvate dehydrogenase multienzyme complex located within mitochondria. Analysis of the primary structure of the E2 components of all three 2-oxo acid dehydrogenase complexes reveals a high degree of homology with a similar highly segmented structure including lipoyl domains, E3-binding domains, C-terminal catalytic domains, and interdomain linker sequences. Immunoblotting of PBC patients' sera against purified E2 protein from 2-oxoglutarate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex reveals that these polypeptides are also autoantigens in this disease. Sera from 29 of 40 (72.5%) PBC patients gave a positive response against bovine 2-oxoglutarate dehydrogenase complex E2 and from 25 of 40 (62.5%) PBC patients gave a positive response against bovine branched-chain 2-oxo acid dehydrogenase complex E2. All 40 PBC patients (100%) have autoantibodies directed against at least one of the E2 components of the family of 2-oxo acid dehydrogenase complexes. Identification of these M2 mitochondrial autoantigens and detailed knowledge of their structure will allow important questions concerning this autoimmune disease to be addressed.
authors.affiliation: Department of Biochemistry, Medical School, University of Newcastle upon Tyne, United Kingdom.
authors.forename: S P
authors.initials: SP
authors.lastname: Fussey
authors.forename: J R
authors.initials: JR
authors.lastname: Guest
authors.forename: O F
authors.initials: OF
authors.lastname: James
authors.forename: M F
authors.initials: MF
authors.lastname: Bassendine
authors.forename: S J
authors.initials: SJ
authors.lastname: Yeaman
mesh_terms: D000123:Acetyltransferases / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000032:analysis*; D002417:Cattle; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D006801:Humans; D015151:Immunoblotting; D007425:Intracellular Membranes / Q000201:enzymology / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000276:immunology*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000276:immunology*; D008969:Molecular Sequence Data; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*
chemical_list: D001324:Autoantigens; D011768:Pyruvate Dehydrogenase Complex; D000123:Acetyltransferases; D051047:Dihydrolipoyllysine-Residue Acetyltransferase