title: Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease.
abstract: Autoimmune reactions are often associated with alcoholic liver disease; however, the mechanisms responsible are largely unknown. This study investigates the potential role of the immune response against hydroxyethyl free radical (HER)-derived antigens and of polymorphisms in immunoregulatory genes in the development of anti-cytochrome P4502E1 (CYP2E1) autoantibodies in alcohol abusers. Immunoglobulin G (IgG) recognizing human CYP2E1 and HER-derived epitopes were measured by microplate immunosorbent assay in the sera of 90 patients with alcoholic fibrosis/cirrhosis (ALD), 37 heavy drinkers without liver disease or steatosis only (HD), and 59 healthy subjects. Single nucleotide polymorphisms in the interleukin 10 (IL-10) promoter and in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The titers and frequency of anti-CYP2E1 autoantibodies were significantly higher in ALD than in HD subjects or controls. ALD patients with anti-HER IgG had higher titers and a 4-fold increased risk (OR: 4.4 [1.8-10.9]) of developing anti-CYP2E1 autoantibodies than subjects without anti-HER antibodies. The mutant CTLA-4 G allele, but not the IL-10 polymorphism, was associated with an enhanced risk of developing anti-CYP2E1 IgG (OR: 3.8 [1.4-10.3]). CTLA-4 polymorphism did not influence antibody formation toward HER-antigens. ALD patients with concomitant anti-HER IgG and the CTLA-4 G allele had a 22-fold higher (OR: 22.9 [4.2-125.6]) risk of developing anti-CYP2E1 autoreactivity than subjects negative for these factors. In conclusion, antigenic stimulation by HER-modified CYP2E1 combined with an impaired control of T-cell proliferation by CTLA-4 mutation promotes the development of anti-CYP2E1 autoantibodies that might contribute to alcohol-induced liver injury.
authors.affiliation: Department of Medical Sciences, University of East Piedmont, Novara, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vidali
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Stewart
authors.forename: Roberta
authors.initials: R
authors.lastname: Rolla
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Yuanneng
authors.initials: Y
authors.lastname: Chen
authors.forename: Elisa
authors.initials: E
authors.lastname: Mottaran
authors.forename: David E J
authors.initials: DE
authors.lastname: Jones
authors.forename: Julian B
authors.initials: JB
authors.lastname: Leathart
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
mesh_terms: D000069594:Abatacept; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000276:immunology; D000483:Alleles; D000917:Antibody Formation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D001323:Autoantibodies / Q000032:analysis; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology*; D000431:Ethanol / Q000276:immunology; D005234:Fatty Liver / Q000276:immunology; D005260:Female; D006801:Humans; D007107:Immune System / Q000503:physiopathology; D018796:Immunoconjugates; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012016:Reference Values; D012307:Risk Factors; D013601:T-Lymphocytes / Q000473:pathology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; C065424:1-hydroxyethyl radical; D000431:Ethanol; D000069594:Abatacept; D019392:Cytochrome P-450 CYP2E1