Apotopes and the biliary specificity of primary biliary cirrhosis

Authors

  • Ana Lleo,

    1. Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA
    2. Division of Internal Medicine, IRCCS-Istituto Clinico Humanitas, University of Milan, Rozzano, Milan, Italy
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  • Carlo Selmi,

    1. Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA
    2. Division of Internal Medicine, IRCCS-Istituto Clinico Humanitas, University of Milan, Rozzano, Milan, Italy
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  • Pietro Invernizzi,

    1. Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA
    2. Division of Internal Medicine, Hepatobiliary Immunopathology Unit, IRCCS-Istituto Clinico Humanitas, Rozzano, Milan, Italy
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  • Mauro Podda,

    1. Division of Internal Medicine, IRCCS-Istituto Clinico Humanitas, University of Milan, Rozzano, Milan, Italy
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  • Ross L. Coppel,

    1. Department of Medical Microbiology, Monash University, Melbourne, Australia
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  • Ian R. Mackay,

    1. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
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  • Gregory J. Gores,

    1. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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  • Aftab A. Ansari,

    1. Department of Pathology, Emory University School of Medicine, Atlanta, GA
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  • Judy Van de Water,

    1. Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA
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  • M. Eric Gershwin

    Corresponding author
    1. Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA
    • Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616
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    • fax: 530-752-4669.


  • Potential conflict of interest: Nothing to report.

Abstract

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Notwithstanding the presence of mitochondria in virtually all nucleated cells, the destruction in PBC is limited to small intrahepatic bile ducts. The reasons for this tissue specificity remain unknown, although biliary epithelial cells (BECs) uniquely preserve the PDC-E2 epitope following apoptosis. Notably, PBC recurs in an allogeneic transplanted liver, suggesting generic rather than host PBC–specific susceptibility of BEC. We used cultured human intrahepatic BECs (HIBECs) and other well-characterized cell lines, including, HeLa, CaCo-2 cells, and nontransformed human keratinocytes and bronchial epithelial cells, to determine the integrity and specific localization of PDC-E2 during induced apoptosis. All cell lines, both before and after apoptosis, were tested with sera from patients with PBC (n = 30), other autoimmune liver and rheumatic diseases (n = 20), and healthy individuals (n = 20) as well as with a mouse monoclonal antibody against PDC-E2 and AMA with an immunoglobulin A isotype. PDC-E2 was found to localize unmodified within apoptotic blebs of HIBECs, but not within blebs of various other cell lineages studied. The fact that AMA-containing sera reacted with PDC-E2 on apoptotic BECs without a requirement for permeabilization suggests that the autoantigen is accessible to the immune system during apoptosis. Conclusion: Our data indicate that the tissue (cholangiocyte) specificity of the autoimmune injury in PBC is a consequence of the unique characteristics of HIBECs during apoptosis and can be explained by exposure to the immune system of intact immunoreactive PDC-E2 within apoptotic blebs. (HEPATOLOGY 2009.)

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