本文關(guān)鍵詞：固有免疫分子與細胞對中樞神經(jīng)系統(tǒng)自身免疫病的影響　出處：《華中科技大學》2011年碩士論文　論文類型：學位論文

  更多相關(guān)文章： 多發(fā)性硬化癥 腫瘤壞死因子 薈萃分析 基因多態(tài)性 自然殺傷細胞 實驗性自身免疫性腦脊髓炎

【摘要】：背景: 多發(fā)性硬化癥(multiple sclerosis,MS)是一種中樞神經(jīng)系統(tǒng)的自身免疫病,環(huán)境因素和遺傳因素共同參與MS疾病的發(fā)生與發(fā)展。其中腫瘤壞死因子α(tumor necrosis factor-α,TNF-α)基因是參與決定MS易感性的遺傳因素之一。目前已經(jīng)有許多研究TNF-α啟動子-308位點的基因多態(tài)性與MS易感性之間關(guān)系的臨床病例 對照研究,但這些研究間的結(jié)論并不一致,因此需要一個系統(tǒng)的數(shù)學方法來分析以得到更準確的結(jié)果。 EAE(experimental autoimmune encephalomyelitis)是一種能夠很好地模擬人MS疾病進程的一種動物模型,是自身MOG(myelin oligodendrocyte glycoprotein)特異性T細胞介導的自身免疫病。自然殺傷(natural killer,NK)細胞是一種固有免疫細胞,發(fā)揮著重要的免疫監(jiān)視和免疫防御的作用,同時NK細胞能夠調(diào)節(jié)獲得性免疫,對EAE的發(fā)生和發(fā)展發(fā)揮著重要的作用。但NK細胞在EAE發(fā)展早期的作用及不同的NK亞群所起的不同作用還需要進一步的闡明。 目的: (1)使用meta分析的方法來研究TNF-α-308 G/A多態(tài)性與MS易感性之間的關(guān)系; (2)研究EAE發(fā)展的早期階段NK細胞自身的變化以及NK細胞對固有免疫細胞和獲得性免疫細胞的調(diào)節(jié)作用。 方法: (1)制定標準,入選13篇關(guān)于TNF-α-308 G/A多態(tài)性與MS易感性關(guān)系的研究,計算合并的OR值及95%置信區(qū)間(confidence interval,CI)。 (2)使用MOG(myelin oligodendrocyte glycoprotein)多肽聯(lián)合弗氏完全佐劑主動免疫小鼠,誘導EAE模型。通過免疫前清除小鼠體內(nèi)NK,觀察EAE病情發(fā)展評估NK在EAE中的作用,流式檢測NK清除后固有免疫和獲得性免疫細胞的改變。 結(jié)果: (1) Meta分析中入選的研究包括1870份病例和2769份對照。合并的OR值顯示TNF-α-308 A等位基因與MS發(fā)病具有顯著的負相關(guān)性(A vs. G,p=0.022)。在AA+GA vs. GG (p=0.008)和GA vs. GG (p=0.007)得到了相似的結(jié)果。對于AA vs. GG或AA vs. GA+GG則沒有顯著的統(tǒng)計學意義,這可能是因為AA基因型頻率過低或有些研究中未檢測到。 (2)免疫前清除小鼠體內(nèi)NK會減輕EAE的發(fā)病程度;EAE進展早期,引流淋巴結(jié)中NK增加,CD27low NK亞群比例減少;NK表面的NKG2D表達下降,NKG2D的配體RAE-1在DC和Mφ上表達下調(diào);清除NK后,DC和Mφ的CD80和CD86表達下調(diào),引流淋巴結(jié)中Th17應答降低。 結(jié)論: (1) TNF-α-308 A等位基因人群,MS發(fā)病風險較低。 (2)在EAE發(fā)展早期,NK細胞可能通過刺激APC細胞的成熟促進Th17應答來促進疾病的發(fā)展,CD27low NK亞群及NKG2D與其配體RAE-1可能參與其中。
[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- 偽 is tumor necrosis factor 偽. TNF- 偽). 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- 偽 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- 偽 -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- 偽 -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- 偽 -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- 偽-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.
【學位授予單位】：華中科技大學
【學位級別】：碩士
【學位授予年份】：2011
【分類號】：R392

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本文編號：1436546