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Primary biliary cirrhosis (PBC) is an autoimmune disease with a strong genetic component characterized by biliary ductular inflammation with eventual liver cirrhosis. The serologic hallmark of PBC is antimitochondrial antibodies that react with the pyruvate dehydrogenase complex, targeting the inner lipoyl domain of the E2 subunit (anti-PDC-E2). Herein we demonstrate that NOD.c3c4 mice congenically derived from the nonobese diabetic strain develop an autoimmune biliary disease (ABD) that models human PBC. NOD.c3c4 (at 9-10 wk, before significant biliary pathology) develop antibodies to PDC-E2 that are specific for the inner lipoyl domain. Affected areas of biliary epithelium are infiltrated with CD3+, CD4+, and CD8+ T cells, and treatment of NOD.c3c4 mice with monoclonal antibody to CD3 protects from ABD. Furthermore, NOD.c3c4-scid mice develop disease after adoptive transfer of splenocytes or CD4+ T cells, demonstrating a central role for T cells in pathogenesis. Histological analysis reveals destructive cholangitis, granuloma formation, and eosinophilic infiltration as seen in PBC, although, unlike PBC, the extrahepatic biliary ducts are also affected. Using a congenic mapping approach, we define the first ABD (Abd) locus, Abd1. These results identify the NOD.c3c4 mouse as the first spontaneous mouse model of PBC.

Original publication




Journal article


The Journal of experimental medicine

Publication Date





1209 - 1219


Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.


CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Animals, Mice, Congenic, Mice, Inbred NOD, Mice, Transgenic, Humans, Mice, Mice, SCID, Liver Cirrhosis, Biliary, Cholangitis, Liver Cirrhosis, Experimental, Granuloma, Autoimmune Diseases, Disease Models, Animal, Inflammation, Mitochondrial Proteins, Autoantibodies, Adoptive Transfer, Chromosome Mapping, Protein Structure, Tertiary, Quantitative Trait Loci, Dihydrolipoyllysine-Residue Acetyltransferase, CD3 Complex