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Autoimmune Hepatitis Induced by Syngeneic Liver Cytosolic Proteins Biotransformed by Alcohol Metabolites

Authors

  • Geoffrey M. Thiele,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Michael J. Duryee,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Monte S. Willis,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Dean J. Tuma,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Stanley J. Radio,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Carlos D. Hunter,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Courtney S. Schaffert,

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Lynell W. Klassen

    1. From the Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology (GMT, MJD, CDH, CSS, LWK), University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska; Experimental Immunology Laboratory, Omaha Veterans Administration Medical Center (GMT, MJD, CDH, CSS, LWK), Research Services 151, Omaha, Nebraska; Department of Internal Medicine, Section of Gastroenterology (DJT), University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology (GMT, SJR), University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, Nebraska; and Department of Pathology and Laboratory Medicine (MSW), University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
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  • Contributions: GMT, MJD, MSW, DJT, LWK: study concept and design; GMT, MJD, MSW, SJR, CDH, CSS: acquisition, analysis, and interpretation of the data; GMT, MJD: drafting of the manuscript; GMT, MJD, DJT, CSS, LWK: critical revision of the manuscript for important intellectual content; LWK: obtaining funding for the work performed.

  • All work was performed in the Experimental Immunology Laboratory at the Omaha Veterans Administration Medical Center, Research Services 151, 4101 Woolworth Avenue, Omaha, NE 68105.

Reprint requests: Michael J. Duryee, MS, Omaha VA Medical Center Research Service 151, Rm 321, 4101 Woolworth Avenue, Omaha, NE 68105; Tel.: 402-995-3429; Fax: 402-449-0604; E-mail: mduryee@unmc.edu

Abstract

Background and aims:  Aldehydes that are produced following the breakdown of ethanol (acetaldehyde) and lipid peroxidation of membranes (malondialdehyde) have been shown to bind (adduct) proteins. Additionally, these two aldehydes can combine (MAA) on nonsyngeneic and syngeneic proteins to initiate numerous immune responses to the unmodified part of the protein in the absence of an adjuvant. Therefore, these studies provide a potential mechanism for the development of antigen-specific immune responses resulting in liver damage should syngeneic liver proteins be adducted with MAA.

Methods:  This study sought to test whether MAA-modified syngeneic liver cytosolic proteins administered daily in the absence of adjuvant into C57BL/6 mice abrogates tolerance to initiate a MAA-induced autoimmune-like hepatitis.

Results:  In mice immunized with MAA-modified cytosols, there was an increase in liver damage as assessed by aspartate aminotransferase/alanine aminotransferase levels that correlated with liver pathology scores and the presence of the pro-fibrotic factors, smooth muscle actin, TGF-β, and collagen. IgG antibodies and T-cell proliferative responses specific for cytosolic proteins were also detected. Pro-inflammatory cytokines were produced in the livers of animals exposed to MAA-modified cytosols. Finally, transfer of immunized T cells to naïve animals caused biochemical and histological evidence of liver damage.

Conclusions:  These data demonstrate that a disease with an autoimmune-like pathophysiology can be generated in this animal model using soluble MAA-modified syngeneic liver cytosols as the immunogen. These studies provide insight into potential mechanism(s) that the metabolites of alcohol may play in contributing to the onset of an autoimmune-like disease in patients with alcoholic liver disease.

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