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Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease
Author(s) -
Vidali Matteo,
Stewart Stephen F.,
Rolla Roberta,
Daly Ann K.,
Chen Yuanneng,
Mottaran Elisa,
Jones David E. J.,
Leathart Julian B.,
Day Christopher P.,
Albano Emanuele
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50049
Subject(s) - autoantibody , alcoholic liver disease , immunology , antigen , autoimmunity , allele , antibody , cyp2e1 , liver disease , biology , medicine , cirrhosis , gene , endocrinology , cytochrome p450 , genetics , metabolism
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.