Autoimmune hepatitis induced by syngeneic liver cytosolic proteins biotransformed by alcohol metabolites

Geoffrey Milton Thiele, Michael J. Duryee, Monte S. Willis, Dean J. Tuma, Stanley J Radio, Carlos D. Hunter, Courtney S. Schaffert, Lynell Warren Klassen

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2126-2136
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Volume34
Issue number12
DOIs
StatePublished - Dec 1 2010

Fingerprint

Autoimmune Hepatitis
Metabolites
Liver
Alcohols
Proteins
Cytosol
Animals
T-cells
Aldehydes
Autoimmune Diseases
T-Lymphocytes
Alcoholic Liver Diseases
Acetaldehyde
Histocompatibility Antigens Class II
Aspartate Aminotransferases
Malondialdehyde
Alanine Transaminase
Inbred C57BL Mouse
Pathology
Lipid Peroxidation

Keywords

  • Alcohol Adducts
  • Alcoholic Liver Disease
  • Aldehyde-Modified Proteins
  • Experimental Autoimmune Liver Disease
  • Smooth Muscle Actin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Autoimmune hepatitis induced by syngeneic liver cytosolic proteins biotransformed by alcohol metabolites. / Thiele, Geoffrey Milton; Duryee, Michael J.; Willis, Monte S.; Tuma, Dean J.; Radio, Stanley J; Hunter, Carlos D.; Schaffert, Courtney S.; Klassen, Lynell Warren.

In: Alcoholism: Clinical and Experimental Research, Vol. 34, No. 12, 01.12.2010, p. 2126-2136.

Research output: Contribution to journalArticle

Thiele, Geoffrey Milton ; Duryee, Michael J. ; Willis, Monte S. ; Tuma, Dean J. ; Radio, Stanley J ; Hunter, Carlos D. ; Schaffert, Courtney S. ; Klassen, Lynell Warren. / Autoimmune hepatitis induced by syngeneic liver cytosolic proteins biotransformed by alcohol metabolites. In: Alcoholism: Clinical and Experimental Research. 2010 ; Vol. 34, No. 12. pp. 2126-2136.
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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 na{\"i}ve 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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AU - Thiele, Geoffrey Milton

AU - Duryee, Michael J.

AU - Willis, Monte S.

AU - Tuma, Dean J.

AU - Radio, Stanley J

AU - Hunter, Carlos D.

AU - Schaffert, Courtney S.

AU - Klassen, Lynell Warren

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KW - Smooth Muscle Actin

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