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

• Published in: Alcoholism, clinical and experimental research Vol. 34; no. 12; pp. 2126 - 2136
• Main Authors: Thiele, Geoffrey M., Duryee, Michael J., Willis, Monte S., Tuma, Dean J., Radio, Stanley J., Hunter, Carlos D., Schaffert, Courtney S., Klassen, Lynell W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2010; Wiley
• Subjects: Acetaldehyde - adverse effects; Acetaldehyde - metabolism; Alcohol Adducts; Alcoholic Liver Disease; Alcoholism and acute alcohol poisoning; Aldehyde-Modified Proteins; Animals; Biological and medical sciences; Biotransformation - drug effects; Cytosol - metabolism; Disease Models, Animal; Ethanol - adverse effects; Ethanol - metabolism; Experimental Autoimmune Liver Disease; Female; Gastroenterology. Liver. Pancreas. Abdomen; Hepatitis, Autoimmune - immunology; Hepatitis, Autoimmune - metabolism; Hepatitis, Autoimmune - pathology; Liver - drug effects; Liver - immunology; Liver - metabolism; Liver - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Malondialdehyde - adverse effects; Malondialdehyde - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Other diseases. Semiology; Proteins - adverse effects; Proteins - chemistry; Proteins - metabolism; S100 Proteins - chemical synthesis; S100 Proteins - immunology; Smooth Muscle Actin; Toxicology; Autoimmunity; Experimental Autoimmune Liver Disease; Immunopathology; Ethanol; Digestive system; Alcoholic hepatitis; Metabolite; Liver; Aldehyde-Modified Proteins; Contractile protein; Autoimmune disease; Smooth muscle; Hepatic disease; Aldehyde; Cytosol; Alcoholic beverage; Alcohol Adducts; Actin; Alcoholic Liver Disease; Digestive diseases; Smooth Muscle Actin; Syngeneic system; Molecular adduct; Adduct
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/j.1530-0277.2010.01309.x

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.