Matsumoto Tomonori, Takahashi Ken, Inuzuka Tadashi, Kim Soo Ki, Kurosaki Tomoaki, Kawakami Shigeru, Chiba Tsutomu, Seno Hiroshi, Marusawa Hiroyuki
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Department of Gastroenterology, Kobe Asahi Hospital, Kobe, 653-0801, Japan.
Antiviral Res. 2017 Mar;139:138-145. doi: 10.1016/j.antiviral.2017.01.004. Epub 2017 Jan 5.
Hepatitis B virus (HBV) infection evokes host immune responses that primarily determine the outcome of HBV infection and the clinical features of HBV-associated liver disease. The precise mechanisms by which host factors restrict HBV replication, however, are poorly understood due to the lack of useful animal models that recapitulate immune responses to HBV. Here, we performed comprehensive immunologic gene expression profiling of the liver of a mouse model recapitulating anti-HBV immune response using a high sensitivity direct digital counting system. Anti-HBV cellular immunity with liver inflammation was elicited in mice hydrodynamically injected with a CpG-depleted plasmid encoding hepatitis B surface antigen (HBsAg) gene after preimmunization with HBsAg vaccine. Comprehensive expression analyses revealed the upregulation of Th1-associated genes including tumor necrosis factor (Tnf) and negative regulators of T cell function in the inflamed liver. Interestingly, activation-induced cytidine deaminase (Aicda, termed AID in humans), which reportedly suppresses HBV infection in vitro, was upregulated in hepatocytes in the course of anti-HBV immunity. Hepatocytic expression of Aicda in a Tnf-dependent manner was confirmed by the administration of Tnf antagonist into Aicda-tdTomato mice with anti-HBV immunity. Our findings suggest that activation of Tnf-Aicda axis and co-inhibitory signals to T cells in coordination with Th1-type immunity has critical roles in the immune response against HBV infection.
乙型肝炎病毒（HBV）感染会引发宿主免疫反应，这种反应主要决定了HBV感染的结果以及HBV相关肝病的临床特征。然而，由于缺乏能够重现对HBV免疫反应的有用动物模型，宿主因素限制HBV复制的确切机制仍知之甚少。在此，我们使用高灵敏度直接数字计数系统，对一个重现抗HBV免疫反应的小鼠模型的肝脏进行了全面的免疫基因表达谱分析。在用HBsAg疫苗进行预免疫后，通过水动力注射编码乙型肝炎表面抗原（HBsAg）基因的CpG缺失质粒，在小鼠中引发了伴有肝脏炎症的抗HBV细胞免疫。全面的表达分析揭示了在炎症肝脏中，包括肿瘤坏死因子（Tnf）在内的Th1相关基因以及T细胞功能负调节因子的上调。有趣的是，据报道在体外可抑制HBV感染的激活诱导胞苷脱氨酶（Aicda，在人类中称为AID），在抗HBV免疫过程中在肝细胞中上调。通过向具有抗HBV免疫的Aicda-tdTomato小鼠施用Tnf拮抗剂，证实了Aicda以Tnf依赖的方式在肝细胞中表达。我们的研究结果表明，Tnf-Aicda轴的激活以及与Th1型免疫协同的对T细胞的共抑制信号，在针对HBV感染的免疫反应中起关键作用。
