gammadelta T細(xì)胞在乙型肝炎不同疾病狀態(tài)中的作用和機(jī)制
發(fā)布時間：2019-02-22 13:42
【摘要】：HBV病毒感染人類肝臟后隨著疾病的進(jìn)展會逐漸造成肝臟損傷并最終導(dǎo)致肝硬化、肝癌而人們對于這個疾病進(jìn)程中的確切的免疫學(xué)機(jī)制卻并不清楚。γδT細(xì)胞是一小群天然免疫細(xì)胞,在腫瘤和病毒感染中發(fā)揮一定保護(hù)和調(diào)節(jié)性作用,但是在HBV感染疾病中的作用并不清楚。在本項研究中我們探討了在HBV感染的不同疾病狀態(tài)下γδT細(xì)胞其及亞群的表型及功能的變化。在慢性乙肝疾病患者中我們通過64例免疫活化期患者(IA)、22例免疫耐受期患者(IT)以及30例健康對照(HC)分析了γδT細(xì)胞的影響。同健康對照和免疫耐受組患者相比,外周血和肝臟的Vδ2γδ T細(xì)胞頻率在免疫活化期患者中顯著降低,且在免疫活化期患者中降低的V82T細(xì)胞在外周血和肝臟分別同丙氨酸氨基轉(zhuǎn)移酶和肝臟炎癥程度顯著負(fù)相關(guān)。免疫活化期患者中,呈現(xiàn)活化的TEM狀態(tài)的Vδ2γδ T細(xì)胞增殖能力和趨化能力均受損傷,但是分泌IFN-y的能力并未變化。最為重要的是,Vδ2γδ T細(xì)胞可以在體外通過細(xì)胞接觸或是IFN-γ依賴的方式顯著降低Th17的產(chǎn)生以及Th17相關(guān)細(xì)胞因子(IL-17, IL-22)的產(chǎn)生。同時,在HBV急性感染中,我們首先按HBV感染發(fā)展不同進(jìn)程的患者描述了外周γδT細(xì)胞頻率的變化：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名健康對照。同健康對照相比在炎癥程度較為明顯的急性乙肝患者、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細(xì)胞頻率顯著降低,且AHB患者外周γδT細(xì)胞頻率的降低同血漿丙氨酸氨基轉(zhuǎn)移酶的水平顯著負(fù)相關(guān)且這些活化的TEM狀態(tài)的外周γδT細(xì)胞分泌顆粒酶A的能力顯著降低。在隨訪過程中,同急性期相比患者在恢復(fù)期病毒被清除,炎癥程度降低,γδT細(xì)胞的頻率上升,活化程度降低,且表面NKR抑制性受體表達(dá)降低,同時我們在ConA誘導(dǎo)的小鼠急性肝損傷模型中證明了CD4+T細(xì)胞有可能是造成肝損傷的原因�？傊�,本項研究拓展了γδT細(xì)胞在HBV感染的認(rèn)識,為臨床HBV患者的治療提供新的方法。
[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. 緯 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 緯 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 緯 未 T cells on 緯 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 緯 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 緯 未 T cells with activated TEM were impaired, but the ability to secrete IFN-y did not change. Most importantly, V 未 2 緯 未 T cells can significantly reduce the production of Th17 and Th17 related cytokines (IL-17, IL-22) through cell contact or IFN- 緯 dependence in vitro. At the same time, in acute HBV infection, we first described the changes of peripheral 緯 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 緯 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 緯 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 緯 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 緯 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 緯 未 T cells in HBV infection and provides a new method for the treatment of HBV patients.
【學(xué)位授予單位】：南開大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R512.62
本文編號：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. 緯 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 緯 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 緯 未 T cells on 緯 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 緯 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 緯 未 T cells with activated TEM were impaired, but the ability to secrete IFN-y did not change. Most importantly, V 未 2 緯 未 T cells can significantly reduce the production of Th17 and Th17 related cytokines (IL-17, IL-22) through cell contact or IFN- 緯 dependence in vitro. At the same time, in acute HBV infection, we first described the changes of peripheral 緯 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 緯 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 緯 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 緯 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 緯 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 緯 未 T cells in HBV infection and provides a new method for the treatment of HBV patients.
【學(xué)位授予單位】：南開大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R512.62
【參考文獻(xiàn)】
相關(guān)期刊論文 前2條
1 ;肝衰竭診療指南[J];中華肝臟病雜志;2006年09期
2 ;病毒性肝炎防治方案[J];中華內(nèi)科雜志;2001年01期
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