IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B
IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B
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DOI：
10.1172/jci44198
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发表时间：
2011-03-01
影响因子：
15.9
通讯作者：
Baron, Jody L.
中科院分区：
文献类型：
--
作者：
Publicover, Jean;Goodsell, Amanda;Baron, Jody L.
HBV 是一种非细胞病变性肝炎病毒，也是导致免疫介导的急性和慢性肝炎的主要人类病原体。对 HBV 抗原的免疫反应与年龄有关：病毒清除发生在大多数成年人中，而新生儿和儿童通常会出现慢性感染和肝病。在这里，我们描述了 HBV 感染的动物模型，该模型概括了生命早期和成年期间病毒清除的关键差异，并发现 IL-21 可能是针对 HBV 的有效初级肝脏免疫反应的一部分。在我们的模型中，与年轻小鼠相比，成年小鼠肝脏中的 HBV 依赖性 IL-21 产量更高。相反，成年小鼠缺乏 IL-21 受体会导致与幼年小鼠类似的抗原持续存在。在人类中，清除病毒的急性感染成年人的血液样本中 IL-21 转录物的水平大大增加。这些观察结果表明，人类 HBV 感染的二分法、年龄依赖性结果存在不同的模型，其中年轻患者 IL-21 产生的减少可能会阻碍关键 CD8(+) T 和 B 细胞反应的产生。这些发现对于增强乙型肝炎病毒和其他潜在的持久性肝病毒的免疫反应的治疗增强具有重要意义。
HBV is a noncytopathic hepadnavirus and major human pathogen that causes immune-mediated acute and chronic hepatitis. The immune response to HBV antigens is age dependent: viral clearance occurs in most adults, while neonates and children usually develop chronic infection and liver disease. Here, we characterize an animal model for HBV infection that recapitulates the key differences in viral clearance between early life and adulthood and find that IL-21 may be part of an effective primary hepatic immune response to HBV. In our model, adult mice showed higher HBV-dependent IL-21 production in liver, compared with that of young mice. Conversely, absence of the IL-21 receptor in adult mice resulted in antigen persistence akin to that of young mice. In humans, levels of IL-21 transcripts were greatly increased in blood samples from acutely infected adults who clear the virus. These observations suggest a different model for the dichotomous, age-dependent outcome of HBV infection in humans, in which decreased IL-21 production in younger patients may hinder generation of crucial CD8(+) T and B cell responses. These findings carry implications for therapeutic augmentation of immune responses to HBV and potentially other persistent liver viruses.