本文選題：日本血吸蟲 + 濾泡輔助性T細胞��； 參考：《中國疾病預防控制中心》2016年博士論文

【摘要】：全球約有2億人感染血吸蟲,是嚴重的公共衛(wèi)生問題。我國流行的是日本血吸蟲病。日本血吸蟲感染引起宿主的免疫應答機制復雜,人們對其認識不足,這是限制血吸蟲病防治工作及日本血吸蟲疫苗研究的瓶頸。國內外很多學者關注于Th1、Th2、Th17及Treg等細胞在日本血吸蟲感染宿主中的作用,而關于濾泡輔助性T細胞(T follicular helper cells, Tfh)的研究則不多,其在日本血吸蟲感染中的作用機制尚不清楚。Tfh細胞屬于CD4+T細胞的一個亞群,促進生發(fā)中心(germinal center, GC)的生成及生發(fā)中心B細胞產生抗體。最近的研究發(fā)現(xiàn),Tfh細胞表面的ICOS分子能促進日本血吸蟲感染小鼠中肝臟肉芽腫的形成,而Tfh細胞在日本血吸蟲感染中其他方面的免疫作用及其機制還未闡明。本研究針對日本血吸蟲感染患者,探索Tfh細胞表型及功能變化；進一步以日本血吸蟲感染的C57BL/6小鼠為模型,分析Tfh細胞在感染小鼠的表型及功能；基于Tfh細胞在日本血吸蟲感染小鼠和血吸蟲病患者的研究結果,以日本血吸蟲感染小鼠為模型,采用Agilent小鼠芯片分析日本血吸蟲感染前后Tfh細胞差異表達的基因,篩選相關的免疫調控分子,為研究日本血吸蟲感染小鼠的免疫應答機制提供科學依據(jù)和分子基礎；此外,觀察日本血吸蟲感染小鼠經吡喹酮治療后對Tfh細胞的影響。本研究期望通過研究Tfh細胞在日本血吸蟲感染過程的作用,加深對宿主免疫反應機制的理解,將為血吸蟲病的免疫與疫苗的進一步研究提供科學依據(jù)和新思路。1.日本血吸蟲病患者Tfh細胞及相關分子的研究Tfh細胞屬于CD4+T細胞的一個亞群,促進生發(fā)中心的生成及生發(fā)中心B細胞產生抗體,本研究對Tfh細胞在血吸蟲病患者中的特征進行了探討。本研究通過流式細胞術檢測和分析了湖南省血吸蟲病流行區(qū)的急性日本血吸蟲病患者(12例)、慢性日本血吸蟲病患者(11例)和健康對照者(10例)外周血Tfh細胞的比例及其表面分子的表達水平,并檢測了B細胞亞群的分布情況。酶聯(lián)免疫吸附試驗(enzyme linked immunosorbent assay, ELIS A)檢測患者血清中IL-21水平及血吸蟲可溶性蟲卵抗原(soluble egg antigen, SEA)和可溶性成蟲抗原(soluble adult worm antigen, SWA)特異性抗體水平,并探討了Tfh細胞與日本血吸蟲特異性抗體之間的相關性。結果表明,急性血吸蟲病患者Tfh細胞表面的PD-1分子(7.42%±3.15%)表達比健康對照組(3.96%±1.05%)明顯增高(P0.01)；慢性血吸蟲病患者Tfh細胞比例(23.67%±3.12%)比健康對照組(18.31%±6.34%)增高(P0.01)、其表面分子ICOS(12.44%±2.84%)和PD-1(5.38%±1.42%)表達也比健康對照組(ICOS:9.51%±2.46%;PD-1:3.96%±1.05%)明顯增高(P0.05),而且慢性血吸蟲病患者的PD-1+CXCR5+CD4+Tfh細胞與血清中IL-21(rs=0.782,P=0.004)、SEA特異性的IgG(rs=0.688,P=0.028).IgGl(rs=0.709,P=0.015)及IgG4(rs=0.527,P=0.024)呈明顯的正相關。本研究首次在日本血吸蟲病患者中進行Tfh細胞的研究,Tfh細胞可通過表面分子及分泌的細胞因子參與免疫應答,PD-1+CXCR5+CD4+ Tfh細胞可能在日本血吸蟲特異性抗體的產生中發(fā)揮重要作用,有助于進一步理解血吸蟲病免疫應答機制。2.Tfh細胞在日本血吸蟲感染小鼠中的表型及功能研究本研究以日本血吸蟲感染C57BL/6純系小鼠為模型,通過免疫熒光等技術對Tfh細胞進行定位觀察。在感染的不同時間(感染后3w、5w、8w和13w)應用流式細胞術檢測Tfh細胞比例及其表型特征；分析日本血吸蟲可溶性蟲卵抗原對淋巴細胞及Tfh細胞增殖能力的影響以及生發(fā)中心B細胞的變化。首先采用免疫熒光和流式細胞術發(fā)現(xiàn)脾臟Tfh細胞表達CD4+ CXCR5+PD-1+;通過動物體內實驗進行動態(tài)觀察Tfh細胞在CD4+T細胞的比例,發(fā)現(xiàn)Tfh細胞的比例隨著日本血吸蟲感染時間的延長逐漸增高,8w到達高峰,隨后逐漸降低；日本血吸蟲SEA和SWA分別免疫小鼠后,日本血吸蟲SEA和SWA這兩種抗原均可引起Tfh細胞比例(4.868%±0.650%,4.380%±0.444%)增加(P0.01)；SEA和SWA分別在體外刺激脾臟淋巴細胞,發(fā)現(xiàn)Tfh細胞的比例(12.268%±0.672%,11.532%±1.967%)也明顯增加(P0.05)。體外實驗研究表明,日本血吸蟲感染小鼠脾臟淋巴細胞的增殖(0.573±0.021)比未感染小鼠脾臟淋巴細胞的增殖(1.407±0.147)能力降低(P0.05),但感染組Tfh細胞的增殖(1.090±0.157)和未感染組(1.41±0.155)相比,增殖能力未見明顯下降,并且感染組Tfh分泌IL-21(0.240±0.034)的能力明顯高于正常組(0.143±0.015)(P0.05)。生發(fā)中心B細胞被活化,其比例與Tfh細胞的變化趨勢一致。Tfh細胞在日本血吸蟲感染中的作用及其分子機制還有待進一步闡明。3.日本血吸蟲感染小鼠Tfh細胞差異分子篩選基于前兩部分的研究,我們發(fā)現(xiàn)Tfh細胞在日本血吸蟲感染小鼠和血吸蟲病患者的外周血或脾臟中明顯增高,且慢性日本血吸蟲病患者PD-1+CXCR5+CD4+Tfh細胞與SEA特異的IgG抗體呈明顯正相關,但其確切機制尚不清楚。本研究以日本血吸蟲感染小鼠為模型,通過小鼠基因表達譜芯片篩選日本血吸蟲感染組和正常組小鼠脾臟的Tfh細胞相關的免疫調控分子。小鼠感染日本血吸蟲后8周,與正常小鼠一起取脾臟,磁珠分選分離CD4+T細胞,再利用流式細胞儀分選PD-1+CXCR5+CD4+Tfh細胞。抽提分選細胞的總RNA進行小鼠表達譜分析,再通過生物信息學分析篩選感染前后PD-1+CXCR5+CD4+Tfh細胞的差異表達基因,并對篩選出的差異基因進行GO和KEGG注釋等分析,同時挑選部分差異表達的基因利用熒光定量PCR方法進行驗證。比較表明,感染組與未感染正常組的PD-1+CXCR5+CD4+Tfh,發(fā)現(xiàn)差異表達基因有1506個,其中上調的基因642個,下調的基因864個。這些基因的主要功能包括粒細胞遷移、炎癥反應中白細胞的遷移、粒細胞趨化、內皮細胞遷移的正調節(jié)、急性炎癥反應、細胞因子分泌的正調節(jié)和細胞因子受體活性等。挑選了15個基因,利用熒光定量PCR進行驗證,其中14個基因與芯片篩選的結果一致。進一步比較感染組小鼠PD-1+CXCR5+CD4+Tfh細胞與PD-1+CXCR5+CD4+ non-Tfh細胞的差異表達基因,差異表達基因有710個,其中上調的基因406個,下調的基因304個。這些基因的功能包括細胞遷移的正調控、免疫應答的正調控、MAPK級聯(lián)的正調節(jié)、B細胞受體信號途徑、通過MHCⅡ類抗原加工和呈遞抗原的外源肽、細胞因子受體活性等。挑選12個基因,利用熒光定量PCR進行驗證,其中10個與芯片篩選的結果一致。本研究所篩選的日本血吸蟲感染組和正常組的PD-1+CXCR5+CD4+Tfh細胞及感染組PD-1+CXCR5+CD4+Tfh細胞與PD-1-CXCR5+CD4+non-Tfh細胞之間的差異基因將為進一步研究Tfh細胞在日本血吸蟲感染中的免疫作用及其機制提供科學依據(jù)和分子基礎。4.日本血吸蟲感染小鼠吡喹酮治療后Tfh細胞及相關分子研究目前治療日本血吸蟲病唯一有效化學藥物吡喹酮影響宿主的免疫應答,我們前期研究結果表明Tfh細胞參與日本血吸蟲感染宿主的免疫應答,吡喹酮是否通過Tfh而影響宿主的免疫應答?因此本研究觀察日本血吸蟲感染小鼠經吡喹酮治療對Tfh細胞的影響。C57BL/6雌性小鼠經日本血吸蟲感染后,隨機分為日本血吸蟲感染毗喹酮治療組(治療組)、日本血吸蟲感染未治療組(未治療組),與正常未感染日本血吸蟲對照組(對照組)進行比較。治療組的小鼠于感染后6周給予200 mg/(kg·d)吡喹酮灌胃治療,每天一次,連續(xù)治療3 d。治療4周后解剖各組小鼠,觀察小鼠肝臟和脾臟病變情況,流式細胞術分析小鼠外周血和脾臟Tfh細胞及其表面分子ICOS和PD-1的表達情況。結果表明,吡喹酮治療后,日本血吸蟲感染小鼠肝臟、脾臟組織的病變明顯改善,檢獲的成蟲及蟲卵的數(shù)量明顯減少,減蟲率和肝臟減卵率分別為84.06%和69.11%(P均0.01)。治療組小鼠外周血和脾臟Tfh表面的ICOS(0.7%～1.1%和1.8%～6.8%)的表達比未治療組(1.3%～3.2%和4.1%～7.0%)顯著降低,可作為吡喹酮療效評價的參考指標之一。結論本課題探索日本血吸蟲感染對宿主Tfh細胞的影響,主要取得以下結果：1.急性和慢性血吸蟲病患者的Tfh細胞的重要表面分子發(fā)生顯著變化,急性血吸蟲病患者Tfh細胞比例未見增高,但Tfh細胞表面的PD-1分子表達增高；而慢性血吸蟲病患者Tfh細胞比例增高,其表面分子ICOS和PD-1表達也增高。慢性血吸蟲病患者的PD-1+CXCR5+ CD4+ Tfh細胞與血清中IL-21、SEA特異的IgG、IgGl及IgG4抗體呈明顯的正相關。提示Tfh細胞在日本血吸蟲感染的不同階段所發(fā)揮免疫功能隨著其表面重要分子的變化而有所不同。2.采用免疫熒光技術對小鼠脾臟中的Tfh細胞進行定位,結合流式細胞術分析本研究中小鼠Tfh細胞的表面標記為PD-1+ CXCR5+ CD4+。日本血吸蟲感染引起脾臟淋巴細胞增殖能力下降,而Tfh細胞的增殖能力未見明顯下降,且Tfh細胞分泌IL-21明顯增加,促使脾臟淋巴濾泡生發(fā)中心B細胞被活化。動態(tài)分析表明,生發(fā)中心B細胞與Tfh細胞的變化趨勢是一致的,即感染初期增高,8w時最高,隨后降低。3.采用Agilent小鼠芯片分析日本血吸蟲感染前后PD-1+ CXCR5+ CD4+ Tfh細胞及感染組PD-1+CXCR5+CD4+Tfh細胞與PD-1-CXCR5+CD4+non-Tfh細胞的差異基因,篩選出一批免疫功能相關分子,為Tfh細胞的功能深入研究提供了分子基礎。4.吡喹酮治療后,日本血吸蟲感染小鼠肝、脾組織病變明顯減輕,寄生的成蟲及蟲卵數(shù)量明顯減少。外周血和脾臟Tfh細胞ICOS的表達比未治療組顯著降低,有可能作為吡喹酮療效評價的參考指標之一。
[Abstract]:About 200 million people in the world are infected with Schistosoma japonicum, which is a serious public health problem. The epidemic of schistosomiasis in China is Japanese schistosomiasis. The immune response mechanism of the host is complicated and the understanding of it is insufficient. This is the bottleneck of the prevention and control of schistosomiasis and the research of the vaccine of Schistosoma japonicum. Many scholars at home and abroad pay attention to Th1, The role of Th2, Th17 and Treg cells in the host of Schistosoma japonicum infection, while the research on follicular auxiliary T cells (T follicular helper cells, Tfh) is not much. The mechanism of its role in Schistosoma japonicum infection is not clear that.Tfh cells belong to a subgroup of CD4+T cells and promote the generation of the germinal center (germinal). Recent studies have found that ICOS molecules on the surface of Tfh cells can promote the formation of liver granuloma in mice infected with Schistosoma japonicum, and other aspects of the immune function and mechanism of Tfh cells in Schistosoma japonicum infection have not been elucidated. This study aims at the exploration of Tfh cells in patients with Schistosoma japonicum infection. The phenotype and function change of the C57BL/6 mice infected by Schistosoma japonicum were further analyzed. The phenotype and function of Tfh cells in infected mice were analyzed. Based on the results of Tfh cells in mice infected with Schistosoma japonicum and schistosomiasis, the mice infected with Schistosoma japonicum were modeled and the Japanese blood sucking was analyzed by the Agilent mouse chip. The differentially expressed genes of Tfh cells before and after the infection and screening related immunoregulatory molecules provide a scientific basis and molecular basis for the study of the immune response mechanism of mice infected with Schistosoma japonicum. In addition, the effects of praziquantel on Tfh cells in mice infected with Schistosoma japonicum were observed. The purpose of this study was to study the Tfh cells in the day. The role of the infection process of Schistosoma japonicum will deepen the understanding of the host immune response mechanism and provide a scientific basis and new ideas for the further study of the immunization and vaccine of schistosomiasis.1.. The study of Tfh cells and related molecules of schistosomiasis japonica patients, Tfh cells belong to a subgroup of CD4+T cells, promoting the generation and development of the germinal center. This study explored the characteristics of Tfh cells in patients with schistosomiasis in this study. This study detected and analyzed the acute Japanese schistosomiasis (12 cases), chronic schistosomiasis (11 cases) and healthy controls (10 cases) of Tfh cells in the peripheral blood of the Schistosomiasis Area in Hunan province. The expression level of the proportion and its surface molecules and the distribution of B cell subsets were detected. The enzyme linked immunosorbent assay (enzyme linked immunosorbent assay, ELIS A) was used to detect the level of IL-21 in the sera and the soluble egg antigen of Schistosoma (soluble egg antigen, SEA) and soluble adult antigen The correlation between Tfh cells and the specific antibody of Schistosoma japonicum was investigated. The results showed that the expression of PD-1 (7.42% + 3.15%) on the surface of Tfh cells in patients with acute schistosomiasis was significantly higher than that in the healthy control group (3.96% + 1.05%) (P0.01), and the proportion of Tfh cells (23.67% + 3.12%) in the patients with chronic schistosomiasis was higher than that of the healthy ones. The group (18.31% + 6.34%) increased (P0.01), its surface molecules ICOS (12.44% + 2.84%) and PD-1 (5.38% + 1.42%) were also significantly higher than those of the healthy control group (ICOS:9.51% + 2.46%; PD-1:3.96% + 1.05%), and the PD-1+CXCR5+CD4+Tfh cells in the chronic schistosomiasis patients and the serum IL-21 (rs=0.782, P=0.004), SEA specific IgG 028).IgGl (rs=0.709, P=0.015) and IgG4 (rs=0.527, P=0.024) have obvious positive correlation. This study is the first time to study Tfh cells in Japanese schistosomiasis patients. Tfh cells can participate in the immune response through surface molecules and secreted cytokines, and PD-1+CXCR5+CD4+ Tfh cells may play a role in the production of specific antibodies in Schistosoma japonicum. The important role is to further understand the phenotype and function of the immune response mechanism of schistosomiasis.2.Tfh cells in mice infected with Schistosoma japonicum. This study takes the C57BL/6 mice infected with Schistosoma japonicum as a model, and localize the Tfh cells by immunofluorescence techniques. At different times of infection (after infection 3W, 5W, 8W) And 13W) use flow cytometry to detect the proportion and phenotypic characteristics of Tfh cells, analyze the effect of soluble egg antigen of Schistosoma japonicum on the proliferation of lymphocyte and Tfh cells and the changes of B cells in the germinal center. First, the expression of CD4+ CXCR5+PD-1+ in the spleen Tfh cells was detected by immunofluorescence and flow cytometry; the expression of CD4+ CXCR5+PD-1+ in the spleen was detected by the immunofluorescence and flow cytometry; The proportion of Tfh cells in CD4+T cells was observed dynamically, and the proportion of Tfh cells increased gradually with the prolongation of the time of infection of Schistosoma japonicum, the peak of 8W reached the peak and then decreased gradually. After immunization with SEA and SWA of Schistosoma japonicum, the two antigens of Schistosoma japonicum, SEA and SWA, could cause the proportion of Tfh cells (4.868% + 0.650%). 4.380% + 0.444%) increased (P0.01); SEA and SWA stimulated spleen lymphocytes in vitro, and found that the proportion of Tfh cells (12.268% + 0.672%, 11.532% + 1.967%) also increased significantly (P0.05). In vitro, the proliferation of splenic lymphocytes in mice infected with Schistosoma japonicum (0.573 + 0.021) was compared to the proliferation of spleen lymphocytes in uninfected mice. (1.407 + 0.147) decreased (P0.05), but the proliferation of Tfh cells in infected group (1.090 + 0.157) and uninfected group (1.41 + 0.155) were not significantly decreased, and the ability of Tfh to secrete IL-21 (0.240 + 0.034) in the infection group was significantly higher than that of the normal group (0.143 + 0.015) (P0.05). The B cells in the germinal center were activated, and the proportion of the cells and the changes of Tfh cells were changed. The role of trend consistent.Tfh cells in Schistosoma japonicum infection and its molecular mechanism still need to be further elucidated in the first two parts of the screening of Tfh cell differentials in.3. infected mice. We found that Tfh cells were significantly higher in peripheral blood or spleen of Schistosoma japonicum infected mice and schistosomiasis patients. The PD-1+CXCR5+CD4+Tfh cells of the chronic Japanese schistosomiasis patients are positively correlated with the specific IgG antibody of SEA, but the exact mechanism is not clear. This study uses the mice infected with Schistosoma japonicum as a model to screen the immune regulation related to the Tfh cells of the spleen of the Schistosoma japonicum infection group and the normal group of mice by the mouse gene expression chip. 8 weeks after infection of Schistosoma japonicum, mice were taken spleen with normal mice, magnetic beads were selected to separate CD4+T cells, and then PD-1+CXCR5+CD4+Tfh cells were selected by flow cytometry. The total RNA of the selected cells was extracted and the expression profiles of the mice were analyzed. Then the difference table of PD-1+CXCR5+CD4+Tfh cells before and after infection was screened by bioinformatics analysis. GO and KEGG annotations were performed on the selected genes, and the selected genes were selected by the fluorescence quantitative PCR method. The results showed that there were 1506 differentially expressed genes in the infected and uninfected PD-1+CXCR5+CD4+Tfh groups, including 642 up regulated genes and 864 down-regulated genes. The main functions of these genes include granulocyte migration, leukocyte migration in the inflammatory response, granulocyte chemotaxis, positive regulation of endothelial cell migration, acute inflammatory response, positive regulation of cytokine secretion and cytokine receptor activity. 15 genes were selected and verified by fluorescein quantitative PCR, of which 14 genes were screened with chips. The difference of expression genes between PD-1+CXCR5+CD4+Tfh cells and PD-1+CXCR5+CD4+ non-Tfh cells in infected mice was further compared. There were 710 differentially expressed genes, including 406 up-regulated genes and 304 down-regulated genes. The functions of these genes include positive regulation of cell migration, positive regulation of immune response, and positive modulation of the MAPK cascade. The B cell receptor signaling pathway, through the MHC class II antigen processing and presenting antigen exogenous peptide, cytokine receptor activity, selected 12 genes and verified by fluorescence quantitative PCR, 10 of them were consistent with the results of chip screening. The PD-1+CXCR5+CD4+Tfh cells of Schistosoma japonicum infection group and the normal group screened by this study The differential gene between PD-1+CXCR5+CD4+Tfh cells and PD-1-CXCR5+CD4+non-Tfh cells in the infected group will provide a scientific basis and molecular basis for further study of the immune function of Tfh cells in the infection of Schistosoma japonicum and its molecular basis,.4., Tfh cells and related molecules after the treatment of praziquantel in mice infected with Schistosoma japonicum, and the present Study on the treatment of Japanese blood The only effective drug, praziquantel, affects the immune response of the host. Our previous study showed that Tfh cells were involved in the immune response of the host infected with Schistosoma japonicum. Whether praziquantel could affect the host's immune response through Tfh? Therefore, this study observed the effects of praziquantel on Tfh cells in mice infected with Schistosoma japonicum. After infected with Schistosoma japonicum, the female mice of.C57BL/6 were randomly divided into the treatment group (treated group), the untreated group of Schistosoma japonicum (untreated group), compared with the normal control group (control group). The mice in the treatment group were given 200 mg/ (kg. D) praziquantel for 6 weeks after infection. Treatment, once a day, after 3 d. treatment for 4 weeks, the mice were dissected and the pathological changes of liver and spleen were observed. Flow cytometry was used to analyze the expression of Tfh cells and their surface molecules ICOS and PD-1 in the peripheral blood and spleen of mice. The results showed that after the treatment of praziquantel, the liver and spleen tissues of mice infected with Japanese Schistosoma japonicum were infected. The number of infected adults and eggs decreased significantly, the rate of worm reduction and the rate of liver reduction were 84.06% and 69.11% (P 0.01) respectively. The expression of ICOS (0.7% ~ 1.1% and 1.8% to 6.8%) on the surface of peripheral blood and spleen on the Tfh of the treatment group was significantly lower than that in the untreated group (1.3% to 3.2% and 4.1% ~ 7%), which could be used as a reference for the evaluation of the effect of praziquantel. The main results are as follows: 1. significant changes in the surface molecules of Tfh cells in patients with acute and chronic schistosomiasis have been significantly changed, and the proportion of Tfh cells in acute schistosomiasis patients has not increased, but the expression of PD-1 molecules on the surface of Tfh cells is higher. The proportion of Tfh cells in the patients with chronic schistosomiasis was increased and the expression of its surface molecules ICOS and PD-1 increased. The PD-1+CXCR5+ CD4+ Tfh cells of the patients with chronic schistosomiasis were positively correlated with the IL-21, SEA specific IgG, IgGl and IgG4 antibodies in the serum, suggesting that the immune function of the Tfh cells in different stages of the infection of Schistosoma japonicum is associated with its immune function The changes in surface important molecules are different and different.2. uses immunofluorescence technique to locate Tfh cells in the spleen of mice. In combination with flow cytometry, the surface marker of mouse Tfh cells in this study is PD-1+ CXCR5+ CD4+., and the proliferation ability of spleen lymphocyte in the spleen is decreased, but the proliferation ability of Tfh cells is not found. Obviously decreased, and the secretion of IL-21 in Tfh cells increased significantly, prompting the activation of B cells in the germinal center of the lymphoid follicle. The dynamic analysis showed that the trend of B cells in the germinal center and Tfh cells was the same, that is, the initial increase of the infection and the highest 8W, and then the.3. using Agilent mouse chip to analyze PD-1+ CXCR5+ before and after the infection of Schistosoma japonicum. CD4+ Tfh cells and infected group PD-1+CXCR5+CD4+Tfh cells and PD-1-CXCR5+CD4+non-Tfh cell differentially screened a number of immune function related molecules, providing a molecular basis for the function of Tfh cells to provide a molecular basis for the study of the molecular basis of the treatment of praziquantel, the liver of mice infected with Schistosoma japonicum, the pathological changes of spleen tissue, parasitic adults and eggs. The expression of ICOS in peripheral blood and spleen Tfh cells was significantly lower than that in the untreated group. It may be used as a reference index for the evaluation of praziquantel efficacy.

【學位授予單位】：中國疾病預防控制中心
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R532.21

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