Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
Hepatology. 2014 Feb;59(2):443-52. doi: 10.1002/hep.26668. Epub 2013 Dec 24.
The liver is considered as a unique lymphoid organ favoring the induction of immune tolerance, rather than immunity. Biologists and clinicians alike have a long-standing interest in how the liver induces systemic immune tolerance, but the mechanism has not yet been well elucidated. Here, we employed hepatitis B virus (HBV)-carrier mice generated by hydrodynamically injecting phosphor-adeno-associated virus/HBV1.2 plasmid as a model for adult chronic HBV infection, which we found were unable to respond to hepatitis B surface antigen vaccination. Humoral tolerance induced in HBV-carrier mice could be transferred into Rag1(-/-) mice, because anti-HBV immunity in immunologically reconstituted Rag1(-/-) mice was inhibited by adoptive transfer of splenocytes from HBV-carrier mice. Humoral tolerance needed at least 7 days for induction and persisted to 3 months after a single HBV plasmid injection. Kupffer cell (KC) depletion or interleukin (IL-10) deficiency broke this humoral tolerance, and exogenous injection of IL-10 could effectively induce this tolerance.
KCs in HBV-carrier mice expressed more IL-10 and mediated the systemic tolerance induction in an IL-10-dependent manner. This previously undescribed humoral tolerance regarding HBV infection will help to explore new approaches to reverse liver-sustained systemic immune tolerance in liver disease.
肝脏被认为是一种独特的淋巴器官，有利于诱导免疫耐受，而不是免疫。生物学家和临床医生都对肝脏如何诱导全身免疫耐受长期以来一直很感兴趣，但该机制尚未得到很好的阐明。在这里，我们采用了通过水力注射磷酰腺嘌呤相关病毒/ HBV1.2 质粒生成的乙型肝炎病毒（HBV）携带者小鼠作为成人慢性 HBV 感染的模型，我们发现这些小鼠无法对乙型肝炎表面抗原疫苗接种产生反应。HBV 携带者小鼠中诱导的体液耐受可以转移到 Rag1（-/-）小鼠中，因为在免疫重建的 Rag1（-/-）小鼠中，通过从 HBV 携带者小鼠中过继转移脾细胞来抑制抗 HBV 免疫。体液耐受需要至少 7 天才能诱导，并在单次 HBV 质粒注射后持续 3 个月。Kupffer 细胞（KC）耗竭或白细胞介素（IL-10）缺乏破坏了这种体液耐受，而外源性注射 IL-10 可以有效地诱导这种耐受。
HBV 携带者小鼠中的 KC 表达更多的 IL-10，并以 IL-10 依赖的方式介导全身耐受诱导。这种关于 HBV 感染的未被描述的体液耐受将有助于探索新方法来逆转肝脏疾病中持续存在的全身免疫耐受。
