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

Kanji Wakabayashi, Zhe Xiong Lian, Patrick S Leung, Yuki Moritoki, Koichi Tsuneyama, Mark J. Kurth, Kit Lam, Katsunori Yoshida, Guo Xiang Yang, Toshifumi Hibi, Aftab A. Ansari, William M. Ridgway, Ross L. Coppel, Ian R. Mackay, M. Eric Gershwin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)531-540
Number of pages10
JournalHepatology
Volume48
Issue number2
DOIs
StatePublished - Aug 2008

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Biliary Liver Cirrhosis
Xenobiotics
Pyruvic Acid
Inbred C57BL Mouse
Oxidoreductases
Autoantibodies
Interferons
Autoimmune Diseases
Epitopes
Liver
Tumor Necrosis Factor-alpha
Serum
Thioctic Acid
Cholangitis
Antibodies
Autoantigens
Bovine Serum Albumin
Lysine
Flow Cytometry
Mitochondria

ASJC Scopus subject areas

  • Hepatology

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Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. / Wakabayashi, Kanji; Lian, Zhe Xiong; Leung, Patrick S; Moritoki, Yuki; Tsuneyama, Koichi; Kurth, Mark J.; Lam, Kit; Yoshida, Katsunori; Yang, Guo Xiang; Hibi, Toshifumi; Ansari, Aftab A.; Ridgway, William M.; Coppel, Ross L.; Mackay, Ian R.; Gershwin, M. Eric.

In: Hepatology, Vol. 48, No. 2, 08.2008, p. 531-540.

Research output: Contribution to journalArticle

Wakabayashi, K, Lian, ZX, Leung, PS, Moritoki, Y, Tsuneyama, K, Kurth, MJ, Lam, K, Yoshida, K, Yang, GX, Hibi, T, Ansari, AA, Ridgway, WM, Coppel, RL, Mackay, IR & Gershwin, ME 2008, 'Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease', Hepatology, vol. 48, no. 2, pp. 531-540. https://doi.org/10.1002/hep.22390
Wakabayashi, Kanji ; Lian, Zhe Xiong ; Leung, Patrick S ; Moritoki, Yuki ; Tsuneyama, Koichi ; Kurth, Mark J. ; Lam, Kit ; Yoshida, Katsunori ; Yang, Guo Xiang ; Hibi, Toshifumi ; Ansari, Aftab A. ; Ridgway, William M. ; Coppel, Ross L. ; Mackay, Ian R. ; Gershwin, M. Eric. / Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. In: Hepatology. 2008 ; Vol. 48, No. 2. pp. 531-540.
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AU - Leung, Patrick S

AU - Moritoki, Yuki

AU - Tsuneyama, Koichi

AU - Kurth, Mark J.

AU - Lam, Kit

AU - Yoshida, Katsunori

AU - Yang, Guo Xiang

AU - Hibi, Toshifumi

AU - Ansari, Aftab A.

AU - Ridgway, William M.

AU - Coppel, Ross L.

AU - Mackay, Ian R.

AU - Gershwin, M. Eric

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