| Autoimmune hepatitis induced by syngeneic liver cytosolic proteins biotransformed by alcohol metabolites. | |
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MedLine Citation:
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PMID: 20860619 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Geoffrey M Thiele; Michael J Duryee; Monte S Willis; Dean J Tuma; Stanley J Radio; Carlos D Hunter; Courtney S Schaffert; Lynell W Klassen |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-09-22 |
Journal Detail:
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Title: Alcoholism, clinical and experimental research Volume: 34 ISSN: 1530-0277 ISO Abbreviation: Alcohol. Clin. Exp. Res. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-22 Completed Date: 2011-03-15 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 7707242 Medline TA: Alcohol Clin Exp Res Country: England |
Other Details:
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Languages: eng Pagination: 2126-36 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 by the Research Society on Alcoholism. No claim to original U.S. government works. |
Affiliation:
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Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology, University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetaldehyde
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adverse effects*,
metabolism Animals Biotransformation / drug effects Cytosol / metabolism Disease Models, Animal Ethanol / adverse effects*, metabolism Female Hepatitis, Autoimmune / immunology, metabolism*, pathology Liver / drug effects*, immunology, metabolism, pathology Malondialdehyde / adverse effects*, metabolism Mice Mice, Inbred C57BL Proteins / adverse effects*, chemistry, metabolism S100 Proteins / chemical synthesis, immunology |
| Grant Support | |
ID/Acronym/Agency:
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R01 AA010435-09/AA/NIAAA NIH HHS; R01 AA10435/AA/NIAAA NIH HHS; R21 AA15505-01A2/AA/NIAAA NIH HHS; R37 AA007818-09/AA/NIAAA NIH HHS; R37 AA07818/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Proteins; 0/S100 Proteins; 542-78-9/Malondialdehyde; 64-17-5/Ethanol; 75-07-0/Acetaldehyde |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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