Yuksel Muhammed, Wang Yipeng, Tai Ningwen, Peng Jian, Guo Junhua, Beland Kathie, Lapierre Pascal, David Chella, Alvarez Fernando, Colle Isabelle, Yan Huiping, Mieli-Vergani Giorgina, Vergani Diego, Ma Yun, Wen Li
Section of Endocrinology, Yale University School of Medicine, New Haven, CT.
Laboratory of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
Hepatology. 2015 Nov;62(5):1536-50. doi: 10.1002/hep.27998. Epub 2015 Aug 25.
Autoimmune hepatitis (AIH) in humans is a severe inflammatory liver disease characterized by interface hepatitis, the presence of circulating autoantibodies, and hyper-gammaglobulinemia. There are two types of AIH, type 1 (AIH-1) and type 2 (AIH-2), characterized by distinct autoimmune serology. Patients with AIH-1 are positive for anti-smooth muscle and/or antinuclear autoantibodies, whereas patients with AIH-2 have anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 autoantibodies. Cytochrome P4502D6 is the antigenic target of anti-liver kidney microsomal type 1, and formiminotransferase cyclodeaminase is the antigenic target of anti-liver cytosol type 1. It is known that AIH, both types 1 and 2, is strongly linked to the human leukocyte antigen (HLA) alleles -DR3, -DR4, and -DR7. However, direct evidence of the association of HLA with AIH is lacking. We developed a novel mouse model of AIH using the HLA-DR3 transgenic mouse on the nonobese-diabetic background by immunization of HLA-DR3- and HLA-DR3+ nonobese-diabetic mice with a DNA plasmid, coding for human cytochrome P4502D6/formiminotransferase cyclodeaminase fusion protein. Immunization with cytochrome P4502D6/formiminotransferase cyclodeaminase leads to a sustained elevation of alanine aminotransferase, development of antinuclear autoantibodies and anti-liver kidney microsomal type 1/anti-liver cytosol type 1 autoantibodies, chronic immune cell infiltration, and parenchymal fibrosis on liver histology in HLA-DR3+ mice. Immunized mice also showed an enhanced T helper 1 immune response and paucity of the frequency of regulatory T cells in the liver. Moreover, HLA-DR3+ mice with exacerbated AIH showed reduced diversity and total load of gut bacteria.
Our humanized animal model has provided a novel experimental tool to further elucidate the pathogenesis of AIH and to evaluate the efficacy and safety of immunoregulatory therapeutic interventions in vivo.
人类自身免疫性肝炎（AIH）是一种严重的炎症性肝病，其特征为界面性肝炎、循环自身抗体的存在以及高γ球蛋白血症。AIH有两种类型，1型（AIH - 1）和2型（AIH - 2），具有不同的自身免疫血清学特征。AIH - 1患者的抗平滑肌和/或抗核自身抗体呈阳性，而AIH - 2患者具有抗肝肾微粒体1型和/或抗肝细胞溶质1型自身抗体。细胞色素P4502D6是抗肝肾微粒体1型的抗原靶点，亚胺甲基转移酶环化脱氨酶是抗肝细胞溶质1型的抗原靶点。已知1型和2型AIH均与人类白细胞抗原（HLA）等位基因 - DR3、- DR4和 - DR7密切相关。然而，缺乏HLA与AIH关联的直接证据。我们通过用编码人细胞色素P4502D6/亚胺甲基转移酶环化脱氨酶融合蛋白的DNA质粒免疫HLA - DR3转基因非肥胖糖尿病小鼠，在非肥胖糖尿病背景下建立了一种新型的AIH小鼠模型。用细胞色素P4502D6/亚胺甲基转移酶环化脱氨酶免疫导致HLA - DR3 +小鼠的丙氨酸转氨酶持续升高、抗核自身抗体以及抗肝肾微粒体1型/抗肝细胞溶质1型自身抗体的产生、慢性免疫细胞浸润和肝脏组织学上的实质纤维化。免疫小鼠还表现出增强的辅助性T细胞1免疫反应以及肝脏中调节性T细胞频率的减少。此外，AIH加重的HLA - DR3 +小鼠肠道细菌的多样性和总负荷降低。
我们的人源化动物模型提供了一种新型实验工具，以进一步阐明AIH的发病机制，并在体内评估免疫调节治疗干预的疗效和安全性。
