RORγt, FoxP3及SOCS-1/3在慢性乙肝Th17/Treg失衡中的作用及机制

Up to date, the pathogenesis of persistent hepatitis B virus (HBV) infection and low/non-response to antiviral treatment remains unclear. It is initial that studies have being conducted for the mechanisms of the effects of virus on host immune response and contribute to the persistent infection with high viraemia in HBV infected patients. Applicants have been conducting the series researches for the relationship between impaired host T-lymphocyte immunity function and HBV replication in chronic HBV infection patients in large sample size, multifactor and systematic basic and clinical studies for years. Our studies demonstrated an impaired balance of the T lymphocyte function related to hepatitis B virus replication. The level of the T-cell impairment had a linear dose-response relationship with the load of HBV DNA suggests a close proximity in the causal pathway between HBV viral load and the T-cell impairment. The studies also illustrated the most strong independent predictive effect of HBV load on impaired T lymphocyte function and effective antiviral treatment inhibited HBV replication may result in partial recovery of impaired immune function. Furthermore, the abnormal expression of Th1/Th2/Th3 and Th17/Treg and the imbalance between them had been found in recent studies. However, many aspects and items remain unknown. The aims of the project herein are, on the basis of these results, using gene chip technology, to further study indepth the expression level and function change of Treg and Th17 cell subsets and, the relationship between the impaired host T cellular immune function and development of the disease and HBV replication; to reveal the mechanisms of specific transcription factor RORγt and FoxP3 and important related factors of JAK/STAT signal pathway involved in the Th17/Treg imbalance; to elucidate the molecular mechanism of persistent chronic HBV infection; and provide new ideas and theoretical evidences for understanding immune pathogenesis of hepatitis B infection and progress of the disease, the immune reconstruction and antiviral treatment strategy establishment.

乙型肝炎病毒(HBV)感染持续存在的机制迄今未明，慢性乙型肝炎(CHB)抗病毒治疗低应答或无应答的机制尚未阐明。前期研究明确了T细胞免疫功能紊乱与HBV复制具有显著线性相关关系，并确立HBV载量是T细胞免疫紊乱的最重要预测因子，有效抗病毒治疗抑制HBV复制可使免疫功能获得部分恢复。还发现HBV感染及疾病进展存在不同程度的Th1/Th2和Th17/Treg表达异常和失衡，然而Th17/Treg 失衡的机制仍不清。本项目旨在此基础上，借助基因芯片技术进一步深入研究Treg和Th17细胞亚群在CHB患者体内的表达和其功能改变与疾病进展、HBV复制和抗病毒治疗低应答或无应答的相关性；揭示特异性转录因子RORγt和FoxP3及JAK/STAT信号通路重要相关因子参与Th17/Treg失衡的可能机制；阐明HBV感染慢性化的分子机制；为乙肝的免疫发病机制、免疫重建及抗病毒治疗策略提供新的思路和理论依据。

乙型肝炎病毒(HBV)感染持续存在的机制迄今未明，慢性乙型肝炎(CHB)抗病毒治疗低应答或无应答的机制尚未阐明，Th17/Treg 失衡的机制仍不清。本项目在前期基础上进一步深入研究Treg和Th17细胞亚群在CHB患者体内的表达和其功能改变与疾病进展、HBV复制和抗病毒治疗低应答或无应答的相关性；揭示特异性转录因子RORγt和FoxP3及JAK/STAT信号通路重要相关因子参与Th17/Treg失衡的可能机制；阐明HBV感染慢性化的分子机制；为乙肝的免疫发病机制、免疫重建及抗病毒治疗策略提供新的思路和理论依据。.本项目研究结果提示：（1）慢性乙型肝炎患者和乙型肝炎肝硬化患者均存在显著的Th17/Treg失衡和RORγt /Foxp3 mRNA高表达。肝硬化患者的Th17/Treg失衡程度较CHB患者显著加重。Th17/Treg失衡和RORγt和Foxp3 mRNA的高表达与HBV病毒复制水平呈显著正相关。（2）经过ETV抗病毒治疗后，HBV复制受到显著抑制，病毒复制水平显著下降，特异性转录因子RORγt和Foxp3 mRNA的高表达和其他相关免疫指标明显下降，Th17/Treg失衡可获得明显改善。（3）病毒学应答组CHB患者的RORγt和Foxp3mRNA高表达及Th17/Treg失衡状况的改善优于部分病毒学应答组CHB患者。抗病毒治疗及e抗原消失可改善Th17/Treg失衡的程度。（4）慢性乙型肝炎患者明显升高的IL-6/STAT3及IL-2/STAT5蛋白表达，与Th17/Treg细胞的失衡呈正相关，提示IL-6/STAT3和IL-2/STAT5共同作用可能参与了慢性乙型肝炎患者Th17/Treg细胞失衡的形成。（5）Th17/Treg失衡在慢性乙型肝炎和乙型肝炎肝硬化疾病进展中可能发挥重要作用，RORγt/Foxp3mRNA、IL-6/STAT3和IL-2/STAT5共同作用参与了Th17/Treg失衡的形成。（6）进一步研究Th17/Treg细胞及其特异性转录因子RORγt /Foxp3和JAK/STAT/SOCS信号通路之间的关系，可能为慢性HBV感染的防治提供新的方向和思路，以期为更多的患者可以达到临床治愈提供新的理论依据。