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
Department of Medical Sciences, University of East Piedmont, Novara, Italy.
Hepatology. 2003 Feb;37(2):410-9. doi: 10.1053/jhep.2003.50049.
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.
自身免疫反应常与酒精性肝病相关；然而，其相关机制在很大程度上尚不清楚。本研究调查了针对羟乙基自由基（HER）衍生抗原的免疫反应以及免疫调节基因多态性在酗酒者抗细胞色素P4502E1（CYP2E1）自身抗体产生过程中的潜在作用。通过微孔板免疫吸附测定法检测了90例酒精性纤维化/肝硬化（ALD）患者、37例仅患有无肝病或脂肪变性的重度饮酒者（HD）以及59名健康受试者血清中识别人类CYP2E1和HER衍生表位的免疫球蛋白G（IgG）。通过聚合酶链反应-限制性片段长度多态性分析对白细胞介素10（IL-10）启动子和细胞毒性T淋巴细胞抗原4（CTLA-4）基因外显子1中的单核苷酸多态性进行基因分型。ALD患者中抗CYP2E1自身抗体的滴度和频率显著高于HD受试者或对照组。与无抗HER抗体的受试者相比，具有抗HER IgG的ALD患者产生抗CYP2E1自身抗体的滴度更高，风险增加4倍（比值比：4.4 [1.8 - 10.9]）。突变的CTLA-4 G等位基因而非IL-10多态性与产生抗CYP2E1 IgG的风险增加有关（比值比：3.8 [1.4 - 10.3]）。CTLA-4多态性不影响针对HER抗原的抗体形成。同时具有抗HER IgG和CTLA-4 G等位基因的ALD患者产生抗CYP2E1自身反应性的风险比这些因素均为阴性的受试者高22倍（比值比：22.9 [4.2 - 125.6]）。总之，HER修饰的CYP2E1引起的抗原刺激与CTLA-4突变导致的T细胞增殖控制受损相结合，促进了抗CYP2E1自身抗体的产生，这可能导致酒精性肝损伤。
