Abstract | UNLABELLED: Murine models of autoimmunity allow the study of the earliest events in disease pathogenesis. Our laboratory has developed a xenobiotic induced model of primary biliary cirrhosis (PBC) following immunization of mice with 2-octynoic acid coupled to bovine serum albumin (2-OA-BSA), an antigen selected following quantitative structure-activity relationship analysis of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the immunodominant autoantigen of PBC. Recent data in humans with PBC has suggested that a major component of liver pathology is due to activation of innate immunity. We took advantage of our 2-OA-BSA model and immunized mice with and without the addition of α- galactosylceramide (α-GalCer), an invariant natural killer T cell activator. Importantly, we report herein that 2-OA-BSA-immunized mice exposed to α-GalCer develop a profound exacerbation of their autoimmune cholangitis, including significant increases in CD8(+) T-cell infiltrates, portal inflammation, granuloma formation, and bile duct damage. Furthermore, such mice produce increased levels of antimitochondrial antibodies and have evidence of fibrosis, a feature not previously reported in the murine models of PBC. CONCLUSION: Our data suggests a primary role of innate immunity in the exacerbation of autoimmune cholangitis and also become a logical explanation for the recurrence of PBC following liver transplantation in the absence of major histocompatability complex compatibility. We submit that PBC begins with loss of tolerance to PDC-E2 and a multilineage antimitochondrial response in which autoreactive CD8(+) T cells are critical. However, the perpetuation of disease and its exacerbation will also be modulated by innate immune mechanisms.
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Authors | Si-Jie Wu, Yao-Hsu Yang, Koichi Tsuneyama, Patrick S C Leung, Petr Illarionov, M Eric Gershwin, Ya-Hui Chuang |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 53
Issue 3
Pg. 915-25
(Mar 2011)
ISSN: 1527-3350 [Electronic] United States |
PMID | 21374662
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2010 American Association for the Study of Liver Diseases. |
Chemical References |
- Fatty Acids, Monounsaturated
- 2-octynoic acid
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Topics |
- Animals
- Autoimmune Diseases
(immunology)
- Cholangitis
(immunology)
- Disease Models, Animal
- Fatty Acids, Monounsaturated
- Female
- Immunity, Innate
- Liver Cirrhosis
(immunology)
- Liver Cirrhosis, Biliary
(immunology)
- Mice
- Mice, Inbred C57BL
- Mitochondria, Liver
(immunology)
- Natural Killer T-Cells
(immunology)
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