title: NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis.
abstract: 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.
authors.affiliation: Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Irie
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wu
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Daniel
authors.initials: D
authors.lastname: Rainbow
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalesnik
authors.forename: Raphael
authors.initials: R
authors.lastname: Hirsch
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Chunmei
authors.initials: C
authors.lastname: Cheng
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002761:Cholangitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002874:Chromosome Mapping; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D017252:CD3 Complex; D024101:Mitochondrial Proteins; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse