IL-21促进慢性乙型肝炎患者HBeAg血清学转换的相关机制研究

Hepatitis B e antigen (HBeAg) seroconversion, a satisfactory endpoint of antiviral therapy, reflects the restoration of the host immunity against hepatitis B virus (HBV) and significantly improves the clinical outcome in patients with chronic HBV infection. Sponsored by the Youngst item of NSFC, we explored the dynamic changes of T cell receptor (TCR) complementarity determining region 3 (CDR3) spectratypes of CD8+ T cells in patients on antiviral therapy, and found the expression of the novel multi-functional cytokine interleukin-21 (IL-21) was not associated with the level of serum alanine aminotransferase (ALT), but associated with HBeAg seroconversion during the natural history or antiviral therapy of chronic HBV infection. Furtherly, we elucidated high serum interleukin-21 (IL-21) levels after 12 weeks of antiviral therapy could predict HBeAg seroconversion in chronic hepatitis B. However, the mechanism of IL-21’s promoting HBeAg seroconversion is still not fully understood. Here, we design a series of in vitro study and animal study to explore the effects of IL-21 on anti-HBe production related candidate immunocytes (B, Tfh, Th17) and viral suppression related candidate immunocytes (CTL, NK), and hopefully would elucidate the roles of high level of IL-21 playing in persistent viral suppression and humoral immunoresponse in chronic HBV infection, and the results would provide sufficient evidences to confirm the value of clinical applications of IL-21.

HBeAg血清学转换是慢性乙型肝炎病毒（HBV）感染者抗病毒治疗满意的治疗终点，它代表了一种HBV低水平复制和产生抗HBe抗体的临床状态。在国家自然科学基金青年项目资助下，申请者研究HBV感染者抗病毒治疗CD8+T细胞TCR谱型动态变化中发现CD4+T细胞IL-21mRNA水平在治疗早期并非随着血清ALT水平降低快速下降，还发现IL-21高表达与自然发生和药物诱导的HBeAg血清学转换都有密切的关联，而关于多功能细胞因子IL-21通过何种机制影响HBeAg血清学转换有待阐明。本研究拟通过设计体外试验和动物试验，了解高水平IL-21对于与抗HBe产生相关细胞（B、Tfh、Th17）和与病毒抑制相关细胞（CTL、NK）的影响，探讨高水平IL-21环境下机体完成持续病毒控制和产生体液免疫应答的可能机制，为拓展IL-21和相关免疫细胞在慢性HBV感染者中的临床应用提供科学依据。

HBeAg血清学转换是慢性乙型肝炎病毒（HBV）感染者抗病毒治疗满意的治疗终点，它代表了一种HBV低水平复制和产生抗HBe抗体的临床状态。在国家自然科学基金青年项目资助下，申请者研究HBV感染者抗病毒治疗CD8+T细胞TCR谱型动态变化中发现CD4+T细胞IL-21mRNA水平在治疗早期并非随着血清ALT水平降低快速下降，还发现IL-21高表达与自然发生和药物诱导的HBeAg血清学转换都有密切的关联，而关于多功能细胞因子IL-21通过何种机制影响HBeAg血清学转换有待阐明。本研究拟通过设计体外试验和动物试验，了解高水平IL-21对于与抗HBe产生相关细胞（B、Tfh、Th17）和与病毒抑制相关细胞（CTL、NK）的影响，探讨高水平IL-21环境下机体完成持续病毒控制和产生体液免疫应答的可能机制，为拓展IL-21和相关免疫细胞在慢性HBV感染者中的临床应用提供科学依据。.在本项目研究中，课题组通过体外实验发现提升IL-21水平能提升表达HBeAg抗体的B细胞频数，这阐明了CXCR5+CD4+T细胞通过IL-21促进慢性HBV感染HbeAg血清学转换的机制；发现慢性HBV感染者IL-21与CD19+B细胞频数呈正相关；并且在核苷类似物抗HBV治疗停药后，高表达IL-21的患者有利于持续病毒学应答，并且IL-21水平与特异性CTL细胞频数呈正相关关系趋势；发现CXCR5+CD4+T细胞的亚型之一“滤泡调节性T细胞（Tfr）”的频数降低与慢性HBV感染性自身肝抗原抗体的过度表达负相关；并且拓展研究了慢性HBV感染者CXCR5+CD4+T细胞受体（TCR）特点；还发现树鼩和人IL-21的基因同源性和免疫交叉反应性，为进一步开展IL-21相关的体内免疫实验奠定了基础。相关论文发表在Hepatology, PloS one 和Cell Molecular Immunology等杂志上。