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Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease

Lookup NU author(s): Dr Stephen Stewart, Professor Ann Daly, Professor David Jones, Julian Leathart, Professor Chris Day

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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.


Publication metadata

Author(s): Vidali M, Stewart SF, Rolla R, Daly AK, Chen Y, Mottaran E, Jones DEJ, Leathart JB, Day CP, Albano E

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2003

Volume: 37

Issue: 2

Pages: 410-419

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1053/jhep.2003.50049

DOI: 10.1053/jhep.2003.50049

PubMed id: 12540792


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