Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection.
Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection.
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DOI：
10.1084/jem.20071859
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发表时间：
2008-06-09
影响因子：
15.3
通讯作者：
Christen, Urs
中科院分区：
文献类型：
--
作者：
Holdener, Martin;Hintermann, Edith;Bayer, Monika;Rhode, Antje;Rodrigo, Evelyn;Hintereder, Gudrun;Johnson, Eric F.;Gonzalez, Frank J.;Pfeilschifter, Josef;Manns, Michael P.;Herrath, Matthias von G.;Christen, Urs
自身免疫性肝病，如自身免疫性肝炎（AIH）和原发性胆汁性肝硬化，通常会对患者造成严重后果。由于缺乏合适的动物模型，对其潜在的病毒病因学知之甚少。嗜肝病毒感染是自身耐受性破坏的一种可能性。因此，我们用表达人细胞色素P450 2D 6的腺病毒Ad 5（Ad-2D 6）感染小鼠。Ad-2D 6感染的小鼠发生持续性自身免疫性肝病，表现为细胞浸润、肝纤维化、“融合”肝小叶和坏死。与2型AIH患者相似，Ad-2D 6感染的小鼠产生1型肝肾微粒体样抗体，识别细胞色素P450 2D 6（CYP 2D 6）的免疫显性表位WDPAQPPRD。有趣的是，与在肝脏中表达相同的人CYP 2D 6蛋白的转基因小鼠相比，Ad-2D 6感染的野生型FVB/N小鼠显示出加重的肝损伤，表明CYP 2D 6小鼠中存在更强的免疫耐受性。我们首次证明了表达天然人类自身抗原的病毒感染会破坏耐受性，导致慢性严重的自身免疫性肝损伤。我们的新模型系统应有助于研究病毒诱导的自身免疫性肝病的启动，传播和沉淀机制。
Autoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis, often have severe consequences for the patient. Because of a lack of appropriate animal models, not much is known about their potential viral etiology. Infection by liver-tropic viruses is one possibility for the breakdown of self-tolerance. Therefore, we infected mice with adenovirus Ad5 expressing human cytochrome P450 2D6 (Ad-2D6). Ad-2D6–infected mice developed persistent autoimmune liver disease, apparent by cellular infiltration, hepatic fibrosis, “fused” liver lobules, and necrosis. Similar to type 2 AIH patients, Ad-2D6–infected mice generated type 1 liver kidney microsomal–like antibodies recognizing the immunodominant epitope WDPAQPPRD of cytochrome P450 2D6 (CYP2D6). Interestingly, Ad-2D6–infected wild-type FVB/N mice displayed exacerbated liver damage when compared with transgenic mice expressing the identical human CYP2D6 protein in the liver, indicating the presence of a stronger immunological tolerance in CYP2D6 mice. We demonstrate for the first time that infection with a virus expressing a natural human autoantigen breaks tolerance, resulting in a chronic form of severe, autoimmune liver damage. Our novel model system should be instrumental for studying mechanisms involved in the initiation, propagation, and precipitation of virus-induced autoimmune liver diseases.
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