Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease

• Type of Material: Article
• Authors: Kanji Wakabayashi, Keio University; Zhe-Xiong Lian, University of California, Davis; Patrick S. C. Leung, University of California, Davis; Yuki Moritoki, University of California, Davis; Koichi Tsuneyama, University of Toyama; Mark J. Kurth, University of California, Davis; S. Lam, University of California, Davis; Katsunori Yoshida, University of California, Davis; Guo-Xiang Yang, University of California, Davis; Toshifumi Hibi, Keio University; Aftab A Ansari, Emory University; William M. Ridgway, University of Pittsburgh; Ross L. Coppel, Monash University; Ian R. Mackay, Monash University; M. Eric Gershwin, University of California, Davis
• Language: English
• Date: 2008-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2008 by the American Association for the Study of Liver Diseases.
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.22390
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 48
• Issue: 2
• Start Page: 531
• End Page: 540
• Grant/Funding Information: Funded by National Institutes of Health grant, DK067003.
• Keywords: CIRRHOSIS; IDENTIFICATION; Science & Technology; T-CELLS; Gastroenterology & Hepatology; ANTIMITOCHONDRIAL AUTOANTIBODIES; COMPONENT; IMMUNIZATION; MOUSE MODEL; MONOCLONAL-ANTIBODIES; EXPRESSION; Life Sciences & Biomedicine; EXPERIMENTAL AUTOIMMUNE CHOLANGITIS
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

There have been important advances in defining effector mechanisms for several human autoimmune diseases. However, for most human autoimmune diseases, the induction stage is less well defined and there are very few clues on etiology. Our laboratory has focused on defining the molecular basis of autoantibody recognition and epitope modification in primary biliary cirrhosis (PBC). Our work has demonstrated that antibodies to mitochondria, the hallmark of disease, are directed against a very conserved site of pyruvate dehydrogenase, the E2 subunit of pyruvate dehydrogenase (PDC-E2). We have also demonstrated that several chemical xenobiotics, chosen based on quantitative structural activity relationship analysis and rigorous epitope analysis, when coupled to the lysine residue that normally binds the lipoic acid cofactor of PDC-E2, reacts as well or better to PBC sera than native autoantigen. In the present studies, we immunized C57BL/6 mice with one such xenobiotic, 2-octynoic acid, coupled to bovine serum albumin and we followed the mice for 24 weeks. Animals were studied for appearance of histologic lesions as well as appearance of antibodies to PDC-E2, serum levels of tumor necrosis factor-α and interferon-γ, and splenic and liver lymphoid phenotyping by flow cytometry. Mice immunized with 2-octynoic acid manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8 + liver infiltrating cells, particularly CD8 + T cells that coexpress CD44, and finally an elevation of serum tumor necrosis factor-α and interferon-γ. Conclusion: these data provide a persuasive argument in favor of an environmental origin for human PBC.