固有免疫分子与细胞对中枢神经系统自身免疫病的影响

发布时间：2018-01-17 14:04

本文关键词：固有免疫分子与细胞对中枢神经系统自身免疫病的影响　出处：《华中科技大学》2011年硕士论文　论文类型：学位论文

【摘要】：背景: 多发性硬化症(multiple sclerosis,MS)是一种中枢神经系统的自身免疫病,环境因素和遗传因素共同参与MS疾病的发生与发展。其中肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)基因是参与决定MS易感性的遗传因素之一。目前已经有许多研究TNF-α启动子-308位点的基因多态性与MS易感性之间关系的临床病例对照研究,但这些研究间的结论并不一致,因此需要一个系统的数学方法来分析以得到更准确的结果。 EAE(experimental autoimmune encephalomyelitis)是一种能够很好地模拟人MS疾病进程的一种动物模型,是自身MOG(myelin oligodendrocyte glycoprotein)特异性T细胞介导的自身免疫病。自然杀伤(natural killer,NK)细胞是一种固有免疫细胞,发挥着重要的免疫监视和免疫防御的作用,同时NK细胞能够调节获得性免疫,对EAE的发生和发展发挥着重要的作用。但NK细胞在EAE发展早期的作用及不同的NK亚群所起的不同作用还需要进一步的阐明。目的: (1)使用meta分析的方法来研究TNF-α-308 G/A多态性与MS易感性之间的关系; (2)研究EAE发展的早期阶段NK细胞自身的变化以及NK细胞对固有免疫细胞和获得性免疫细胞的调节作用。方法: (1)制定标准,入选13篇关于TNF-α-308 G/A多态性与MS易感性关系的研究,计算合并的OR值及95%置信区间(confidence interval,CI)。 (2)使用MOG(myelin oligodendrocyte glycoprotein)多肽联合弗氏完全佐剂主动免疫小鼠,诱导EAE模型。通过免疫前清除小鼠体内NK,观察EAE病情发展评估NK在EAE中的作用,流式检测NK清除后固有免疫和获得性免疫细胞的改变。结果: (1) Meta分析中入选的研究包括1870份病例和2769份对照。合并的OR值显示TNF-α-308 A等位基因与MS发病具有显著的负相关性(A vs. G,p=0.022)。在AA+GA vs. GG (p=0.008)和GA vs. GG (p=0.007)得到了相似的结果。对于AA vs. GG或AA vs. GA+GG则没有显著的统计学意义,这可能是因为AA基因型频率过低或有些研究中未检测到。 (2)免疫前清除小鼠体内NK会减轻EAE的发病程度;EAE进展早期,引流淋巴结中NK增加,CD27low NK亚群比例减少;NK表面的NKG2D表达下降,NKG2D的配体RAE-1在DC和Mφ上表达下调;清除NK后,DC和Mφ的CD80和CD86表达下调,引流淋巴结中Th17应答降低。结论: (1) TNF-α-308 A等位基因人群,MS发病风险较低。 (2)在EAE发展早期,NK细胞可能通过刺激APC细胞的成熟促进Th17应答来促进疾病的发展,CD27low NK亚群及NKG2D与其配体RAE-1可能参与其中。
[Abstract]:Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Environmental factors and genetic factors are involved in the occurrence and development of MS disease, among which tumor necrosis factor- 伪 is tumor necrosis factor 伪. TNF- 伪). Gene is one of the genetic factors involved in determining the susceptibility to MS. There have been many clinical cases that have studied the relationship between gene polymorphism of TNF- 伪 promoter -308 and susceptibility to MS. Control study. However, the conclusions of these studies are not consistent, so a systematic mathematical method is needed to obtain more accurate results. EAE(experimental autoimmune encephalomytis. It is a kind of animal model which can simulate the disease process of human MS well. Is an autoimmune disease mediated by specific T cells of self MOG(myelin oligodendrocyte glycoprotein. Natural killer. NKC cells are innate immune cells, which play an important role in immune surveillance and defense, and NK cells can regulate acquired immunity. NK cells play an important role in the development and development of EAE, but the role of NK cells in the early development of EAE and the different roles of different NK subsets need to be further elucidated. Objective: 1) using meta analysis to study the relationship between TNF- 伪 -308 G / A polymorphism and susceptibility to MS; (2) to study the changes of NK cells in the early stage of EAE development and the regulation of NK cells on innate and acquired immune cells. Methods: 1) to establish a standard for 13 studies on the association between TNF- 伪 -308 G / A polymorphism and susceptibility to MS. The combined OR value and 95% confidence interval were calculated. Mice were immunized with MOG(myelin oligodendrocyte glycoprotein polypeptide and Freund's complete adjuvant. The role of NK in EAE was evaluated by observing the development of EAE, and the changes of innate and acquired immune cells after NK clearance were detected by flow cytometry. Results: 1). In the Meta analysis, 1 870 cases and 2 769 controls were included. The associated OR values showed that TNF- 伪 -308A allele was significantly negatively correlated with the incidence of MS (P < 0.05). A vs. G. In AA GA vs. GG P0. 008) and GA vs. GG p0. 007). Similar results were obtained. There was no significant statistical significance for AA vs. GG or AA vs. GA GG. This may be due to the low frequency of AA genotypes or undetected in some studies. (2) clearance of NK in mice before immunization can reduce the severity of EAE. In the early stage of EAE, NK increased and CD27low NK subsets decreased in the drainage lymph nodes. The expression of NKG2D on NK surface decreased and the expression of NKG2D ligand RAE-1 was down-regulated on DC and M 蠁. The expressions of CD80 and CD86 in DC and M 蠁 were down-regulated and Th17 response in drainage lymph nodes was decreased after NK clearance. Conclusion: TNF- 伪-308 A allele population had a lower risk of MS. 2) in the early stage of EAE development, NK cells may promote the development of disease by stimulating the maturation of APC cells and promoting Th17 response. CD27low NK subgroup and NKG2D and its ligand RAE-1 may be involved.
【学位授予单位】：华中科技大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R392

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