免疫调节分子PD1和TIM3基因多态性与慢性HBV感染疾病进展的相关性及其机制研究

Hepatitis B virus (HBV) infection is a severe public health problem worldwide. HBV infection is associated with a variety of clinical outcomes such as acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Programmed cell death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (Tim-3) are important immunoregulatory molecules in regulating T cell immune response. These molecules are main focus of research in recent years because of the close association with the dysfunction and exhaustion of T cell response in viral infections and cancers including chronic HBV infection and HBV-related HCC. PD1 and TIM3 genes have single nucleotide polymorphisms (SNPs), which may affect the transcription and translation process. The SNPs in different genes may interact each other. The effects of polymorphisms on transcription and translation and the interaction between different gene polymorphisms may result in differences in host immune function and genetic predisposition, affecting the disease susceptibility, progression and clinical outcomes. Our preliminary studies suggested that the polymorphisms of PD1 and TIM3 genes are associated with the susceptibility and disease progression including the development of cirrhosis and HCC in chronic HBV infection. Based on these studies, we aim to further investigate the role of these polymorphisms and gene-gene interactions in the susceptibility of HBV infection, disease progression and the development of different clinical outcomes in large cohorts of populations of HBV infection. Furthermore, based on the associated polymorphisms in cohort studies, we aim to investigate the functional effects of different polymorphisms on gene transcription, translation and expression of the molecules in vivo and in vitro. These studies will shed light on understanding the role of gene polymorphisms of these important immunoregulatory molecules in HBV infection and the development of different clinical outcomes and unraveling the molecular mechanisms underlying the associations, providing immunogenetic information for the monitoring of disease progression and the prevention and therapy of HBV-associated liver diseases including chronic hepatitis, liver cirrhosis and HCC.

HBV感染可引起急、慢性肝炎，肝硬化和肝细胞癌（HCC）等明显不同的临床结局。导致不同结局的原因与宿主的T细胞功能紊乱或耗竭密切相关。免疫调节分子PD-1和Tim-3在慢性HBV感染和HBV相关HCC的T细胞功能紊乱或耗竭的发生中起着关键作用。人群中PD1和TIM3基因存在多态性，本项目组前期的研究发现，PD1和TIM3的多态性分别与HBV感染相关肝硬化和肝癌的发生相关，为解释HBV感染导致不同临床结局提供了线索，但PD1和TIM3之间的相互作用及其这种相关性的机理尚不清楚。本项目拟在此基础上，探讨这些基因多态性及其相互作用与HBV感染疾病进展的关系；研究不同基因多态性对相应基因的转录、翻译和表达的影响，明确这些重要免疫调节因子的基因多态性与HBV感染及其导致不同临床结局的关系及其分子机制。本研究对阐明HBV相关疾病的免疫遗传学机制和探讨新的疾病监测和预警指标以及新的治疗策略具有重要意义。

HBV感染可引起急、慢性肝炎，肝硬化和肝细胞癌（HCC）等明显不同的临床结局。导致不同结局的原因与宿主的T细胞功能紊乱或耗竭密切相关。免疫调节分子PD-1和Tim-3在慢性HBV感染和HBV相关HCC的T细胞功能紊乱或耗竭的发生中起着关键作用。人群中PD1和TIM3基因存在多态性，本项目组前期的研究发现，PD1和TIM3的多态性分别与HBV感染相关肝硬化和肝癌的发生相关，为解释HBV感染导致不同临床结局提供了线索，但PD1和TIM3之间的相互作用及其这种相关性的机理尚不清楚。本项目在此基础上，探讨这些基因多态性及其相互作用与HBV感染疾病进展的关系；研究不同基因多态性对相应基因的转录、翻译和表达的影响，明确这些重要免疫调节因子的基因多态性与HBV感染及其导致不同临床结局的关系及其分子机制。结果发现，PD1 rs41386349、PD1 rs6710479和TIM3 rs246871多态性与慢性HBV感染相关；PD1 rs2227982、PD1 rs6710479、PD1 rs7421861和PD1 rs7565639多态性可能与慢性HBV感染疾病进展相关；PD1和TIM3基因在慢性HBV感染中存在交互作用；PD1 rs6710479、PD1 rs10204525和TIM3 rs10053538多态性影响HBV相关HCC的预后，可能是HCC患者预后的新指标。PD-1和TIM-3在肝组织中均高表达，而且分别与HBV相关HCC患者PD1 rs10204525和TIM3 rs10053538多态性相关，该发现提示通过同时阻断PD-1和TIM-3可能提高免疫检查点靶向治疗效率和降低耐药性，并提示将PD1 rs10204525和TIM3 rs10053538的基因型测定用作免疫检查点治疗的生物标志的可能性。PD1 3'UTR rs10204525多态性与HBV病毒复制有关，而miR-4717可能通过与相互作用等位基因与PD1 mRNA的3'UTR结合特异性调节PD-1表达，导致免疫调节的改变，影响慢性HBV感染的易感性和病程。这些结果对阐明HBV相关疾病的免疫遗传学机制和探讨新的疾病监测和预警指标以及新的治疗策略具有重要意义。