Obermayer-Straub P, Manns M P
Division of Gastroenterology and Hepatology, Medical School of Hannover, Germany.
Baillieres Clin Gastroenterol. 1996 Sep;10(3):501-32. doi: 10.1016/s0950-3528(96)90055-x.
Autoantibodies directed against cytochromes P450 or UDP-glucuronosyl-transferases (UGTs) are detected in hepatitis of different aetiology: drug-induced hepatitis autoimmune hepatitis type 2, hepatitis associated with the autoimmune polyglandular syndrome type 1 (APS1) and virus-induced autoimmunity. Autoantibodies directed against cytochrome P450 2C9 are induced by tienilic acid, and anti-P450 1A2 autoantibodies by dihydralazine. Potential mechanisms involved may be metabolic activation of the drugs by cytochromes P450, adduct formation and circumvention of T cell tolerance. In contrast, little is known about the aetiology of autoimmune hepatitis type 2. This disease is characterized by marked female predominance, hypergammaglobulinaemia, circulating autoantibodies and benefit from immunosuppression. Patients with HLA B8, DR3 or DR4 are over-represented. The major target of autoimmunity in this disease is cytochrome P450 2D6. The autoantibodies were shown to be directed against at four short linear epitopes. In addition, about 10% of the patient sera form an additional autoantibody that detects a conformational epitope on UGTs of family 1. The phenomenon of virus-associated autoimmunity is found in chronic infections with hepatitis C and D. In chronic hepatitis C the major target of the autoantibodies again is cytochrome P450 2D6. Some linear and a high proportion of conformational epitopes are recognized. The LKM3 autoantibody is found in 13% of patients with chronic hepatitis D. The target proteins are UGTs of family 1 and, in some sera also, low titres of anto-antibodies directed against UGTs of family 2 are found. The epitopes detected are conformational. In contrast to the patients suffering from autoimmune hepatitis, patients with hepatitis as part of the autoimmune polyglandular syndrome type 1 recognize cytochrome P450 1A2. Interestingly, in APS1 patients also, autoantibodies directed against cytochromes P450 c21, P450 scc and P450 c17a may be detected; these autoantibodies are associated with adrenal and ovarian failure.
在不同病因的肝炎中可检测到针对细胞色素P450或尿苷二磷酸葡萄糖醛酸转移酶（UGTs）的自身抗体，包括药物性肝炎、2型自身免疫性肝炎、与1型自身免疫性多腺体综合征（APS1）相关的肝炎以及病毒诱导的自身免疫。替尼酸可诱导针对细胞色素P450 2C9的自身抗体，肼屈嗪可诱导抗P450 1A2自身抗体。其中涉及的潜在机制可能是细胞色素P450对药物的代谢激活、加合物形成以及T细胞耐受性的规避。相比之下，2型自身免疫性肝炎的病因知之甚少。这种疾病的特点是女性明显居多、高球蛋白血症、循环自身抗体以及对免疫抑制治疗有效。携带HLA B8、DR3或DR4的患者比例过高。这种疾病自身免疫的主要靶点是细胞色素P450 2D6。已证明这些自身抗体针对四个短线性表位。此外，约10%的患者血清形成另一种自身抗体，可检测到1家族UGTs上的一个构象表位。病毒相关自身免疫现象见于丙型和丁型肝炎慢性感染。在慢性丙型肝炎中，自身抗体的主要靶点同样是细胞色素P450 2D6。可识别一些线性表位和高比例的构象表位。13%的慢性丁型肝炎患者可检测到LKM3自身抗体。其靶蛋白是1家族的UGTs，在一些血清中还可检测到低滴度的针对2家族UGTs的自身抗体。所检测到的表位为构象表位。与自身免疫性肝炎患者不同，作为1型自身免疫性多腺体综合征一部分的肝炎患者识别细胞色素P450 1A2。有趣的是，在APS1患者中也可检测到针对细胞色素P450 c21、P450 scc和P450 c17a的自身抗体；这些自身抗体与肾上腺和卵巢功能衰竭有关。
