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1. In primary biliary cirrhosis, the major M2 autoantigen, reacting with antimitochondrial antibodies in sera from >90% of patients, has been identified as the E2 component of the pyruvate dehydrogenase complex. However, two recent reports suggest that alternative polypeptides may be major autoantigens. 2. The evidence that a 75 kDa subunit of complex I of the respiratory chain is a major autoantigen (Frostell, Mendel-Hartvig, Nelson, Totterman, Bjorkland & Ragan, Scand. J. Immunol. 1988; 28, 157–65) is refuted. The findings of Frostell et al. can be explained by contamination of complex I with the pyruvate dehydrogenase complex, evidence for which is presented here. 3. Inspection of the partial amino acid sequence of an unidentified mitochondrial autoantigen (Muno, Kominami, Ishii, Usui, Saituku, Sakakibara & Namihisa, Hepatology 1990; 11, 16–23) shows that it is the El β-subunit of the pyruvate dehydrogenase complex, previously identified as a major autoantigen, and not a ‘new’ alternative major autoantigen. 4. These findings substantiate previous work showing that the mitochondrial M2 autoantigens identified so far in primary biliary cirrhosis are all polypeptide components of the pyruvate dehydrogenase complex or the other related 2-oxo acid dehydrogenase complexes.

Six components of the mammalian 2-oxo acid dehydrogenase complexes have previously been identified as M2 autoantigens in primary biliary cirrhosis. In this report, we present data showing that both polypeptide-specific and cross-reacting antibodies are present in patients' sera. Antibodies reacting with E2 of the pyruvate dehydrogenase complex cross-react with protein X but not with any other mammalian antigen. The main immunogenic region on protein X has been localized to within its single lipoyl domain. Polypeptide-specific antibodies bind to E1 alpha and E1 beta of the pyruvate dehydrogenase complex. Antibodies reacting with the E2 polypeptides of the 2-oxoglutarate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex show some cross-reactivity but do not recognize any of the antigens of the pyruvate dehydrogenase complex. Antibodies against the E2 component of the mammalian pyruvate dehydrogenase complex cross-react effectively with the corresponding protein from yeast but not with E2 from Escherichia coli. Antibody titer against mammalian antigens is significantly higher than against the bacterial antigens, arguing against a bacterial origin for primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is characterised by the presence of antimitochondrial antibodies. The PBC-specific, immunoreactive, trypsin-sensitive antigens on the inner mitochondrial membrane (M2) have hitherto not been identified. A major 70 kD M2 autoantigen is the E2 component (lipoate acetyltransferase) of the pyruvate dehydrogenase enzyme complex located within mitochondria. This has been confirmed by immunoblotting of PBC patients' sera against purified E2 protein: sera from 38/40 (95%) patients with established clinical, biochemical, and histological features of PBC (18 stage II/III, 22 stage IV) reacted positively with E2; whilst no sera from 39 controls (27 non-PBC chronic liver disease, 12 healthy normal women) gave a positive response. Immunoblotting showed that a second subunit of the pyruvate dehydrogenase complex, a 50 kD polypeptide of unknown function (component X), is also an M2 autoantigen. Identification of these M2 mitochondrial antigens should facilitate the development of a specific serological test for PBC and the study of autoimmunising epitopes.