NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis

Junichiro Irie, Yuehong Wu, Linda S. Wicker, Daniel Rainbow, Michael A. Nalesnik, Raphael Hirsch, Laurence B. Peterson, Patrick S C Leung, Chunmei Cheng, Ian R. Mackay, M. Eric Gershwin, William M. Ridgway

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133 Citations (Scopus)

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. JEM

Original languageEnglish
Pages (from-to)1209-1219
Number of pages11
JournalJournal of Experimental Medicine
Volume203
Issue number5
DOIs
Publication statusPublished - 2006 May 15
Externally publishedYes

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Congenic Mice
Biliary Liver Cirrhosis
Autoimmune Diseases
T-Lymphocytes
Pyruvate Dehydrogenase Complex
Eosinophilic Granuloma
Cholangitis
Adoptive Transfer
Antibodies
Liver Cirrhosis
Epithelium
Monoclonal Antibodies
Pathology
Inflammation

ASJC Scopus subject areas

  • Immunology

Cite this

NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. / Irie, Junichiro; Wu, Yuehong; Wicker, Linda S.; Rainbow, Daniel; Nalesnik, Michael A.; Hirsch, Raphael; Peterson, Laurence B.; Leung, Patrick S C; Cheng, Chunmei; Mackay, Ian R.; Gershwin, M. Eric; Ridgway, William M.

In: Journal of Experimental Medicine, Vol. 203, No. 5, 15.05.2006, p. 1209-1219.

Research output: Contribution to journalArticle

Irie, J, Wu, Y, Wicker, LS, Rainbow, D, Nalesnik, MA, Hirsch, R, Peterson, LB, Leung, PSC, Cheng, C, Mackay, IR, Gershwin, ME & Ridgway, WM 2006, 'NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis', Journal of Experimental Medicine, vol. 203, no. 5, pp. 1209-1219. https://doi.org/10.1084/jem.20051911
Irie, Junichiro ; Wu, Yuehong ; Wicker, Linda S. ; Rainbow, Daniel ; Nalesnik, Michael A. ; Hirsch, Raphael ; Peterson, Laurence B. ; Leung, Patrick S C ; Cheng, Chunmei ; Mackay, Ian R. ; Gershwin, M. Eric ; Ridgway, William M. / NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. In: Journal of Experimental Medicine. 2006 ; Vol. 203, No. 5. pp. 1209-1219.
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