gammadelta T细胞在乙型肝炎不同疾病状态中的作用和机制
发布时间：2019-02-22 13:42
【摘要】：HBV病毒感染人类肝脏后随着疾病的进展会逐渐造成肝脏损伤并最终导致肝硬化、肝癌而人们对于这个疾病进程中的确切的免疫学机制却并不清楚。γδT细胞是一小群天然免疫细胞,在肿瘤和病毒感染中发挥一定保护和调节性作用,但是在HBV感染疾病中的作用并不清楚。在本项研究中我们探讨了在HBV感染的不同疾病状态下γδT细胞其及亚群的表型及功能的变化。在慢性乙肝疾病患者中我们通过64例免疫活化期患者(IA)、22例免疫耐受期患者(IT)以及30例健康对照(HC)分析了γδT细胞的影响。同健康对照和免疫耐受组患者相比,外周血和肝脏的Vδ2γδ T细胞频率在免疫活化期患者中显著降低,且在免疫活化期患者中降低的V82T细胞在外周血和肝脏分别同丙氨酸氨基转移酶和肝脏炎症程度显著负相关。免疫活化期患者中,呈现活化的TEM状态的Vδ2γδ T细胞增殖能力和趋化能力均受损伤,但是分泌IFN-y的能力并未变化。最为重要的是,Vδ2γδ T细胞可以在体外通过细胞接触或是IFN-γ依赖的方式显著降低Th17的产生以及Th17相关细胞因子(IL-17, IL-22)的产生。同时,在HBV急性感染中,我们首先按HBV感染发展不同进程的患者描述了外周γδT细胞频率的变化：29名急性乙肝患者、29名慢性乙肝患者、15名慢加急性肝衰竭患者、15名肝硬化患者和25名健康对照。同健康对照相比在炎症程度较为明显的急性乙肝患者、慢性乙肝患者和慢加急性肝衰竭患者而非肝硬化患者的外周γδT细胞频率显著降低,且AHB患者外周γδT细胞频率的降低同血浆丙氨酸氨基转移酶的水平显著负相关且这些活化的TEM状态的外周γδT细胞分泌颗粒酶A的能力显著降低。在随访过程中,同急性期相比患者在恢复期病毒被清除,炎症程度降低,γδT细胞的频率上升,活化程度降低,且表面NKR抑制性受体表达降低,同时我们在ConA诱导的小鼠急性肝损伤模型中证明了CD4+T细胞有可能是造成肝损伤的原因。总之,本项研究拓展了γδT细胞在HBV感染的认识,为临床HBV患者的治疗提供新的方法。
[Abstract]:When HBV virus infects the human liver, it can lead to liver damage and eventually liver cirrhosis as the disease progresses. However, the exact immunological mechanism of liver cancer is not clear. 纬 未 T cells are a small group of innate immune cells, which play a protective and regulatory role in tumor and virus infection. But its role in HBV infection is unclear. In this study, we investigated the phenotypic and functional changes of 纬 未 T cells and their subsets in different disease states of HBV infection. In patients with chronic hepatitis B disease, we analyzed the effect of 纬 未 T cells on 纬 未 T cells in 64 patients with immune activation phase (IA), (22 patients with immune tolerance phase) and 30 healthy controls (HC). The frequencies of V 未 2 纬 未 T cells in peripheral blood and liver were significantly lower in patients with immune activation than those in healthy controls and immune tolerance groups. The decreased V82T cells in patients with immune activation were negatively correlated with alanine aminotransferase and liver inflammation respectively in peripheral blood and liver. The proliferation and chemotaxis of V 未 2 纬 未 T cells with activated TEM were impaired, but the ability to secrete IFN-y did not change. Most importantly, V 未 2 纬 未 T cells can significantly reduce the production of Th17 and Th17 related cytokines (IL-17, IL-22) through cell contact or IFN- 纬 dependence in vitro. At the same time, in acute HBV infection, we first described the changes of peripheral 纬 未 T cell frequencies in patients with different stages of HBV infection: 29 patients with acute hepatitis B, 29 patients with chronic hepatitis B, 15 patients with chronic hepatitis B and 15 patients with chronic liver failure. Fifteen patients with cirrhosis and 25 healthy controls. The frequency of peripheral 纬 未 T cells in acute hepatitis B patients, chronic hepatitis B patients and patients with chronic and acute liver failure, but not cirrhosis, was significantly lower than that in healthy controls. The decreased frequency of peripheral 纬 未 T cells in patients with AHB was negatively correlated with the level of plasma alanine aminotransferase and the ability of these activated TEM peripheral 纬 未 T cells to secrete granzyme A was significantly decreased. During the follow-up period, the virus was cleared in the convalescent stage, the degree of inflammation was decreased, the frequency of 纬 未 T cells was increased, the activation degree was decreased, and the expression of NKR inhibitory receptor on the surface was decreased compared with that in the acute stage. At the same time, we demonstrated that CD4 T cells may be the cause of acute liver injury induced by ConA in mice. In conclusion, this study extends the understanding of 纬 未 T cells in HBV infection and provides a new method for the treatment of HBV patients.
【学位授予单位】：南开大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R512.62
本文编号：2428283
[Abstract]:When HBV virus infects the human liver, it can lead to liver damage and eventually liver cirrhosis as the disease progresses. However, the exact immunological mechanism of liver cancer is not clear. 纬 未 T cells are a small group of innate immune cells, which play a protective and regulatory role in tumor and virus infection. But its role in HBV infection is unclear. In this study, we investigated the phenotypic and functional changes of 纬 未 T cells and their subsets in different disease states of HBV infection. In patients with chronic hepatitis B disease, we analyzed the effect of 纬 未 T cells on 纬 未 T cells in 64 patients with immune activation phase (IA), (22 patients with immune tolerance phase) and 30 healthy controls (HC). The frequencies of V 未 2 纬 未 T cells in peripheral blood and liver were significantly lower in patients with immune activation than those in healthy controls and immune tolerance groups. The decreased V82T cells in patients with immune activation were negatively correlated with alanine aminotransferase and liver inflammation respectively in peripheral blood and liver. The proliferation and chemotaxis of V 未 2 纬 未 T cells with activated TEM were impaired, but the ability to secrete IFN-y did not change. Most importantly, V 未 2 纬 未 T cells can significantly reduce the production of Th17 and Th17 related cytokines (IL-17, IL-22) through cell contact or IFN- 纬 dependence in vitro. At the same time, in acute HBV infection, we first described the changes of peripheral 纬 未 T cell frequencies in patients with different stages of HBV infection: 29 patients with acute hepatitis B, 29 patients with chronic hepatitis B, 15 patients with chronic hepatitis B and 15 patients with chronic liver failure. Fifteen patients with cirrhosis and 25 healthy controls. The frequency of peripheral 纬 未 T cells in acute hepatitis B patients, chronic hepatitis B patients and patients with chronic and acute liver failure, but not cirrhosis, was significantly lower than that in healthy controls. The decreased frequency of peripheral 纬 未 T cells in patients with AHB was negatively correlated with the level of plasma alanine aminotransferase and the ability of these activated TEM peripheral 纬 未 T cells to secrete granzyme A was significantly decreased. During the follow-up period, the virus was cleared in the convalescent stage, the degree of inflammation was decreased, the frequency of 纬 未 T cells was increased, the activation degree was decreased, and the expression of NKR inhibitory receptor on the surface was decreased compared with that in the acute stage. At the same time, we demonstrated that CD4 T cells may be the cause of acute liver injury induced by ConA in mice. In conclusion, this study extends the understanding of 纬 未 T cells in HBV infection and provides a new method for the treatment of HBV patients.
【学位授予单位】：南开大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R512.62
【参考文献】
相关期刊论文 前2条
1 ;肝衰竭诊疗指南[J];中华肝脏病杂志;2006年09期
2 ;病毒性肝炎防治方案[J];中华内科杂志;2001年01期
，本文编号：2428283
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