Klinikum der Goethe-Universität Frankfurt am Main, Pharmazentrum/ZAFES, Frankfurt am Main, Germany.
Dig Dis. 2010;28(1):80-5. doi: 10.1159/000282068. Epub 2010 May 7.
Cytochrome P450 2D6 (CYP2D6) has been identified as the major autoantigen in type 2 autoimmune hepatitis (AIH). However, because of a lack of appropriate animal models, the etiology of AIH is still poorly understood. We generated a mouse model for AIH using the human CYP2D6 as a triggering molecule for autoimmunity. We infected wild-type FVB mice with an adenovirus expressing human CYP2D6 (Ad-2D6) to break self-tolerance to the mouse CYP2D6 homologues. Ad-2D6-infected mice showed persistent features of liver damage including hepatic fibrosis, cellular infiltrations, focal-to-confluent necrosis and generation of anti-CYP2D6 antibodies, which predominantly recognized the identical immunodominant epitope recognized by LKM-1 antibodies from AIH patients. Interestingly, Ad-2D6 infection of transgenic mice expressing the human CYP2D6 (CYP2D6 mice) resulted in delayed kinetics and reduced severity of liver damage. However, the quantity and quality of anti-CYP2D6 antibodies was only moderately reduced in CYP2D6 mice. In contrast, the frequency of CYP2D6-specific CD4 and CD8 T cells was dramatically decreased in CYP2D6 mice, indicating the presence of a strong T cell tolerance to human CYP2D6 established in CYP2D6 mice, but not in wild-type mice. CYP2D6-specific T cells reacted to human CYP2D6 peptides with intermediate homology to the mouse homologues, but not to those with high homology, indicating that molecular mimicry rather than molecular identity breaks tolerance and subsequently causes severe persistent autoimmune liver damage. The CYP2D6 model provides a platform to investigate mechanisms involved in the immunopathogenesis of autoimmune-mediated chronic hepatic injury and evaluate possible ways of therapeutic interference.
细胞色素 P450 2D6（CYP2D6）已被确定为 2 型自身免疫性肝炎（AIH）的主要自身抗原。然而，由于缺乏适当的动物模型，AIH 的病因仍知之甚少。我们使用人 CYP2D6 作为自身免疫的触发分子，生成了 AIH 的小鼠模型。我们用表达人 CYP2D6 的腺病毒（Ad-2D6）感染野生型 FVB 小鼠，以破坏对鼠 CYP2D6 同源物的自身耐受性。Ad-2D6 感染的小鼠表现出持续的肝损伤特征，包括肝纤维化、细胞浸润、局灶性至融合性坏死和产生抗 CYP2D6 抗体，这些抗体主要识别 AIH 患者 LKM-1 抗体识别的相同免疫优势表位。有趣的是，表达人 CYP2D6 的转基因小鼠（CYP2D6 小鼠）的 Ad-2D6 感染导致肝损伤的动力学延迟和严重程度降低。然而，CYP2D6 小鼠中抗 CYP2D6 抗体的数量和质量仅适度降低。相比之下，CYP2D6 小鼠中 CYP2D6 特异性 CD4 和 CD8 T 细胞的频率显著降低，表明 CYP2D6 小鼠中存在对人 CYP2D6 的强烈 T 细胞耐受，但在野生型小鼠中不存在。CYP2D6 特异性 T 细胞对与人 CYP2D6 具有中等同源性的肽反应，但对具有高度同源性的肽不反应，表明分子模拟而不是分子同一性打破了耐受性，随后导致严重的持续自身免疫性肝损伤。CYP2D6 模型提供了一个平台，可用于研究自身免疫介导的慢性肝损伤的免疫发病机制，并评估可能的治疗干预方法。
