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.
Autoimmune Hepatitis Induced by Syngeneic Liver Cytosolic Proteins Biotransformed by Alcohol Metabolites
Version of Record online: 22 SEP 2010
Copyright © 2010 by the Research Society on Alcoholism. No claim to original U.S. government works
Alcoholism: Clinical and Experimental Research
Volume 34, Issue 12, pages 2126–2136, December 2010
How to Cite
Thiele, G. M., Duryee, M. J., Willis, M. S., Tuma, D. J., Radio, S. J., Hunter, C. D., Schaffert, C. S. and Klassen, L. W. (2010), Autoimmune Hepatitis Induced by Syngeneic Liver Cytosolic Proteins Biotransformed by Alcohol Metabolites. Alcoholism: Clinical and Experimental Research, 34: 2126–2136. doi: 10.1111/j.1530-0277.2010.01309.x
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.
- Issue online: 18 NOV 2010
- Version of Record online: 22 SEP 2010
- Received for publication February 19, 2010; accepted June 8, 2010.
- Experimental Autoimmune Liver Disease;
- Aldehyde-Modified Proteins;
- Alcoholic Liver Disease;
- Smooth Muscle Actin;
- Alcohol Adducts
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.