Title: Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease
Abstract: HepatologyVolume 37, Issue 2 p. 410-419 Original ArticleFree Access Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease Matteo Vidali, Matteo Vidali Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorStephen F. Stewart, Stephen F. Stewart Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom S.F.S. is recipient of Clinical Training Fellowship by the Medical Research Council (United Kingdom).Search for more papers by this authorRoberta Rolla, Roberta Rolla Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorAnn K. Daly, Ann K. Daly Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorYuanneng Chen, Yuanneng Chen Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorElisa Mottaran, Elisa Mottaran Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorDavid E. J. Jones, David E. J. Jones Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorJulian B. Leathart, Julian B. Leathart Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorChristopher P. Day, Christopher P. Day Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorEmanuele Albano, Corresponding Author Emanuele Albano [email protected] Department of Medical Sciences, University of East Piedmont, Novara, ItalyDepartment of Medical Science, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy; fax: (39) 0321 620421===Search for more papers by this author Matteo Vidali, Matteo Vidali Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorStephen F. Stewart, Stephen F. Stewart Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom S.F.S. is recipient of Clinical Training Fellowship by the Medical Research Council (United Kingdom).Search for more papers by this authorRoberta Rolla, Roberta Rolla Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorAnn K. Daly, Ann K. Daly Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorYuanneng Chen, Yuanneng Chen Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorElisa Mottaran, Elisa Mottaran Department of Medical Sciences, University of East Piedmont, Novara, ItalySearch for more papers by this authorDavid E. J. Jones, David E. J. Jones Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorJulian B. Leathart, Julian B. Leathart Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorChristopher P. Day, Christopher P. Day Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne, United KingdomSearch for more papers by this authorEmanuele Albano, Corresponding Author Emanuele Albano [email protected] Department of Medical Sciences, University of East Piedmont, Novara, ItalyDepartment of Medical Science, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy; fax: (39) 0321 620421===Search for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2003.50049Citations: 56 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat 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. 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