Yuksel M, Xiao X, Tai N, Vijay Manakkat, Gülden E, Beland K, Lapierre P, Alvarez F, Hu Z, Colle I, Ma Y, Wen L
Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.
Clin Exp Immunol. 2016 Nov;186(2):164-176. doi: 10.1111/cei.12843. Epub 2016 Aug 23.
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (T ), which had decreased programmed death (PD)-1 expression. Splenic T from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8 T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of T and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8 T effectors, facilitating the induction of AIH and persistent liver damage.
自身免疫性肝炎（AIH）是一种慢性肝病，其特征为进行性炎症、女性居多，且在80%以上的病例中存在抗平滑肌肌动蛋白和/或抗核抗体、抗肝肾微粒体1型（抗-LKM1）和抗肝细胞溶质1型（抗-LC1）等自身抗体的血清学阳性。AIH与多个主要组织相容性复合体（MHC）等位基因密切相关，包括人类白细胞抗原（HLA）-DR3、-DR7和-DR13。HLA-DR4与成人AIH的关联强度仅次于HLA-DR3。我们通过用编码人细胞色素P450 2D6/叶酸硫胺素焦磷酸酶融合自身抗原的DNA免疫HLA-DR4（DR4）转基因非肥胖糖尿病（NOD）小鼠，研究了HLA-DR4在AIH发病中的作用。对DR4小鼠进行免疫会导致持续的轻度肝损伤，通过丙氨酸转氨酶升高进行生化评估，通过界面性肝炎、浆细胞浸润和轻度纤维化进行组织学评估，以及通过抗-LKM1/抗-LC1抗体的产生进行免疫学评估。此外，DR4小鼠的肝脏中调节性T细胞（T细胞）较少，其程序性死亡（PD）-1表达降低。这些小鼠的脾脏T细胞也表现出抑制能力受损。此外，与未免疫的野生型（WT）NOD小鼠相比，DR4的表达增强了未免疫的DR4小鼠中CD8 T细胞、巨噬细胞和树突状细胞的激活状态。我们的结果表明，HLA-DR4是AIH发病的一个易感因素。T细胞抑制功能受损和PD-1表达降低可能导致关键免疫细胞亚群（如抗原呈递细胞和CD8 T效应细胞）的自发激活，从而促进AIH的诱导和持续性肝损伤。
