Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia

Authors

  • Cara L. Mack,

    Corresponding author
    1. Pediatric Liver Center and Liver Transplantation Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
    2. Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
    • Department of Pediatrics, The Children's Hospital, Box B290, 1056 East 19th Avenue, Denver, CO 80218
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    • fax: 303-764-8025

  • Rebecca M. Tucker,

    1. Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
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  • Brandy R. Lu,

    1. Pediatric Liver Center and Liver Transplantation Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
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  • Ronald J. Sokol,

    1. Pediatric Liver Center and Liver Transplantation Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
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  • Andrew P. Fontenot,

    1. Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
    2. Integrated Department of Immunology, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
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  • Yoshiyuki Ueno,

    1. Division of Gastroenterology, Tohoku University School of Medicine, Sendai, Japan
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  • Ronald G. Gill

    1. Integrated Department of Immunology, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, Colorado
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  • Presented as an oral presentation in a Plenary Session at the American Association for the Study of Liver Diseases Annual Meeting, November, 2005 and received the American Liver Foundation Pediatric Research Award.

  • Potential conflict of interest: Nothing to report.

Abstract

Biliary atresia is an inflammatory fibrosclerosing lesion of the bile ducts that leads to biliary cirrhosis and is the most frequent indication for liver transplantation in children. The pathogenesis of biliary atresia is not known; one theory is that of a virus-induced, subsequent autoimmune-mediated injury of bile ducts. The aim of this study was to determine whether autoreactive T cells and autoantibodies specific to bile duct epithelia are present in the rotavirus (RRV)- induced murine model of biliary atresia and whether the T cells are sufficient to result in bile duct inflammation. In vitro analyses showed significant increases in IFN-γ–producing T cells from RRV-diseased mice in response to bile duct epithelial autoantigen. Adoptive transfer of the T cells from RRV-diseased mice into naïve syngeneic SCID recipients resulted in bile duct–specific inflammation. This induction of bile duct pathology occurred in the absence of detectable virus, indicating a definite response to bile duct autoantigens. Furthermore, periductal immunoglobulin deposits and serum antibodies reactive to bile duct epithelial protein were detected in RRV-diseased mice. In conclusion, both cellular and humoral components of autoimmunity exist in murine biliary atresia, and the progressive bile duct injury is due in part to a bile duct epithelia–specific T cell–mediated immune response. The role of cellular and humoral autoimmunity in human biliary atresia and possible interventional strategies therefore should be the focus of future research. (HEPATOLOGY 2006;44:1231–1239.)

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