干扰素在慢性乙型肝炎治疗过程中对单核细胞和NK细胞信号通路的免疫调控及机制研究

Interferon therapy is an important method for the treatment of chronic hepatitis B patients. Interferon is a potent activator of intracellular antiviral pathways and a mediator of numerous immunoregulatory functions. Previous studies of our group found that in chronic HBV infection, HBsAg induced the expression of HLA-E and PD-L1 in monoytes, and combined with CD94 and PD-1 receptors on the surface of NK cells, further inhibited the function of NK cells. In the previous study, the applicants found that IFN induced the expression of MICB，while HBV significantly inhibited IFN-α-induced MICB expression in monocytes, and the mechanism is unclear. Therefore, we speculate that: during the interferon treatment of chronic hepatitis B patients, interferon activated-STAT1 binds to the promoter of MICB and NKG2D genes, induces the high expression of MICB in monocytes, and induces the high expression of NKG2D in NK cells, and then activates NK cells through the combination of MICB and NKG2D, the activated-NK cells kills HBV-infected hepatocytes; while the inhibition of MICB by HBV blocks this process. The aim of this study was to elucidate the immunoregulatory mechanism of interferon on monocytes and NK cells during the treatment of chronic hepatitis B patients. It will provide a new idea for breaking the limitation of immune tolerance and treating chronic hepatitis B more effectively.

干扰素是治疗慢性乙型肝炎的重要方法。干扰素不仅能够激活细胞内的抗病毒机制，还可以介导多种免疫调节功能。本课题组前期研究发现：在HBV病毒感染中，HBsAg诱导外周血单核细胞HLA-E、PD-L1升高，与NK细胞表面CD94、PD-1受体结合，抑制NK细胞功能。本研究申请人前期发现，干扰素诱导单核细胞MICB高表达，且HBV显著抑制IFN-α诱导的MICB表达，其中机制尚不清楚。因此我们推测：在干扰素治疗慢乙肝病人过程中，干扰素激活STAT1结合到MICB与NKG2D基因启动子上，诱导单核细胞MICB高表达，同时诱导NK细胞NKG2D高表达，进而通过MICB与NKG2D的结合激活NK细胞，杀伤HBV感染的肝细胞；而同时HBV对MICB的抑制作用阻断了这一过程。本研究旨在阐明慢性乙型肝炎治疗中，干扰素对单核细胞和NK细胞免疫调控机制。将为打破免疫耐受限制，更有效地治疗慢性乙型肝炎提供新思路。

干扰素是治疗慢性乙型肝炎的重要方法。干扰素不仅能够激活细胞内的抗病毒机制，还可以介导多种免疫调节功能。干扰素调节的免疫细胞是如何抑制HBV复制的? HBV又是如何拮抗干扰素的治疗作用的？尤其是为何干扰素治疗只对部分HBV病人有效的？这些都是急待解决的科学问题。本项目以干扰素激活的单核细胞和NK细胞为切入点，在本基金支持下，研究表明，在干扰素治疗慢乙肝病人过程中，干扰素通过激活STAT1结合到MICB与NKG2D基因启动子上而诱导单核细胞MICB高表达，以及NK细胞NKG2D高表达，随后我们在共培养系统中加入MICB或者NKG2D的中和抗体，或者构建MICB或者NKG2D敲除细胞，发现MICB与NKG2D的结合能够激活NK细胞，诱导IFNγ产生，我们同时发现HBV通过HBsAg与TLR2结合抑制单核细胞MICB产生，而对MICB的抑制作用阻断了MICB与NKG2D的结合从而抑制NK细胞激活这一过程。通过上述研究，我们部分阐明了慢性乙型肝炎治疗中，干扰素对单核细胞和NK细胞免疫调控机制。将为打破免疫耐受限制，更有效地治疗慢性乙型肝炎提供新思路。