Innate immunity and primary biliary cirrhosis: Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis
Journal
Hepatology
Journal Volume
53
Journal Issue
3
Pages
915-925
Date Issued
2011
Author(s)
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. ? 2010 American Association for the Study of Liver Diseases.
SDGs
Other Subjects
2 octynoic acid; alpha galactosylceramide; autoantigen; bovine serum albumin; mitochondrion antibody; octanoic acid; pyruvate dehydrogenase complex; pyruvate dehydrogenase complex E2 subunit; unclassified drug; animal cell; animal experiment; animal model; animal tissue; article; autoimmune cholangitis; autoimmunity; bile duct injury; biliary tract fibrosis; CD8+ T lymphocyte; cholangitis; controlled study; disease exacerbation; female; flow cytometry; histopathology; immunomodulation; immunopathogenesis; innate immunity; lymphocytic infiltration; mouse; natural killer T cell; nonhuman; primary biliary cirrhosis; priority journal; quantitative structure activity relation; T lymphocyte activation; Animals; Autoimmune Diseases; Cholangitis; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Immunity, Innate; Liver Cirrhosis; Liver Cirrhosis, Biliary; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Natural Killer T-Cells
Type
journal article