Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 749K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Irie, J. Articles by Ridgway, W. M. Search for Related Content PubMed PubMed Citation Articles by Irie, J. Articles by Ridgway, W. M. Pubmed/NCBI databases Gene Medline Plus Health Information Autoimmune Diseases Bile Duct Diseases Cirrhosis Social Bookmarking                      What's this?

¹ Division of Rheumatology and Immunology, and ² Division of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
³ Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK
⁴ Division of Rheumatology, Children's Hospital, Pittsburgh, PA 15213
⁵ Department of Pharmacology, Merck Research Laboratory, Rahway, NJ 07065
⁶ Division of Rheumatology and Clinical Immunology, School of Medicine, University of California, Davis, Davis, CA 95616
⁷ Department of Biochemistry and Molecular Biology, Monash University, 3800 Victoria, Australia

CORRESPONDENCE William M. Ridgway: ridgway2{at}pitt.edu

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Hirschfield, G. M., Liu, X., Xu, C., Lu, Y., Xie, G., Lu, Y., Gu, X., Walker, E. J., Jing, K., Juran, B. D., Mason, A. L., Myers, R. P., Peltekian, K. M., Ghent, C. N., Coltescu, C., Atkinson, E. J., Heathcote, E. J., Lazaridis, K. N., Amos, C. I., Siminovitch, K. A. (2009). Primary Biliary Cirrhosis Associated with HLA, IL12A, and IL12RB2 Variants. NEJM 360: 2544-2555 [Abstract] [Full Text]  
• Lindor, K. (2007). Ursodeoxycholic Acid for the Treatment of Primary Biliary Cirrhosis. NEJM 357: 1524-1529 [Full Text]  
• Irie, J., Wu, Y., Kachapati, K., Mittler, R. S., Ridgway, W. M. (2007). Modulating Protective and Pathogenic CD4+ Subsets via CD137 in Type 1 Diabetes. Diabetes 56: 186-196 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS