Innate immunity and primary biliary cirrhosis: Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis

Si Jie Wu, Yao Hsu Yang, Koichi Tsuneyama, Patrick S Leung, Petr Illarionov, M. Eric Gershwin, Ya Hui Chuang

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)915-925
Number of pages11
JournalHepatology
Volume53
Issue number3
DOIs
StatePublished - Mar 2011

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Natural Killer T-Cells
Cholangitis
Biliary Liver Cirrhosis
Innate Immunity
Fibrosis
Bovine Serum Albumin
Dihydrolipoyllysine-Residue Acetyltransferase
Galactosylceramides
T-Lymphocytes
Quantitative Structure-Activity Relationship
Autoantigens
Xenobiotics
Bile Ducts
Granuloma
Autoimmunity
Liver Transplantation
Disease Progression
Immunization
Pathology
Inflammation

ASJC Scopus subject areas

  • Hepatology

Cite this

Innate immunity and primary biliary cirrhosis : Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. / Wu, Si Jie; Yang, Yao Hsu; Tsuneyama, Koichi; Leung, Patrick S; Illarionov, Petr; Gershwin, M. Eric; Chuang, Ya Hui.

In: Hepatology, Vol. 53, No. 3, 03.2011, p. 915-925.

Research output: Contribution to journalArticle

Wu, Si Jie ; Yang, Yao Hsu ; Tsuneyama, Koichi ; Leung, Patrick S ; Illarionov, Petr ; Gershwin, M. Eric ; Chuang, Ya Hui. / Innate immunity and primary biliary cirrhosis : Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. In: Hepatology. 2011 ; Vol. 53, No. 3. pp. 915-925.
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