Autoimmune hepatitis induced by syngeneic liver cytosolic proteins biotransformed by alcohol metabolites.
OBJECTIVE
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.
Thiele
Geoffrey M
GM
Experimental Immunology Laboratory, Department of Internal Medicine, Section of Rheumatology, University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, Nebraska, USA.
Duryee
Michael J
MJ
Willis
Monte S
MS
Tuma
Dean J
DJ
Radio
Stanley J
SJ
Hunter
Carlos D
CD
Schaffert
Courtney S
CS
Klassen
Lynell W
LW
D000079:Acetaldehyde / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000009:adverse effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D009418:S100 Proteins / Q000138:chemical synthesis / Q000276:immunology
D011506:Proteins; D009418:S100 Proteins; D000431:Ethanol; D008315:Malondialdehyde; D000079:Acetaldehyde