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International Journal of Hepatology
Volume 2012 (2012), Article ID 369740, 12 pages
Research Article

Characterization of Autoantibodies against the E1 𝜶 Subunit of Branched-Chain 2-Oxoacid Dehydrogenase in Patients with Primary Biliary Cirrhosis

1Department of Human Lifesciences, Fukushima Medical University School of Nursing, 1 Hikarigaoka, Fukushima 960-1295, Japan
2Department of Internal Medicine II, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan
3Structural Glycobiology Team, Systems Glycobiology Research Group, Chemical Biology Department, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
4Department of Biochemistry, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan

Received 1 December 2011; Revised 16 February 2012; Accepted 26 February 2012

Academic Editor: Pierluigi Toniutto

Copyright © 2012 Tsutomu Mori et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs) that react with the lipoyl-containing E2 subunits of 2-oxoacid dehydrogenase complexes such as BCOADC and PDC. The lipoyl domains of E2 contain the major epitopes essential for immunopathology. However, the non-lipoyl-containing E1 subunits are also frequently targeted. Since anti-E1 antibodies always appear in combination with anti-E2 antibodies, the mechanisms underlying the autoimmunity against E1 may be linked to, but distinct from, those against E2. Here, we demonstrate that intermolecular and intramolecular determinant spreading underlies the autoimmunity against E1. We performed characterizations and epitope mapping for anti-BCOADC-E1 𝛼 antibodies from both the intermolecular and intramolecular points of view. The antibody reactivities form a cluster against the BCOADC complex that is distinct from that against the PDC complex, and the anti-BCOADC-E1 𝛼 antibodies arise as part of the cluster against the BCOADC complex. Multiple epitopes are present on the surface of the BCOADC-E1 𝛼 molecule, and the major epitope overlaps with the active center. Sera with anti-BCOADC-E1 𝛼 antibodies strongly inhibited the enzyme activity. These findings suggest that the E1 𝛼 subunit as part of the native BCOADC complex is an immunogen, and that determinant spreading is involved in the pathogenesis of AMA production.