本文選題：淋巴細(xì)胞功能相關(guān)抗原1 + 實驗性自身免疫性腦脊髓炎��； 參考：《吉林大學(xué)》2014年碩士論文

【摘要】：多發(fā)性硬化（multiple sclerosis，MS）是典型的自身免疫性疾病，以中樞神經(jīng)系統(tǒng)脫髓鞘為特征，多在青壯年中發(fā)病，其臨床癥狀重，具有反復(fù)發(fā)病、遷延不愈的特點，具有較高的病情惡化及致殘的發(fā)生率。MS的發(fā)病是多因素綜合作用的結(jié)果，其中T淋巴細(xì)胞在MS的病理發(fā)生以及疾病進程的生物學(xué)過程中各自發(fā)揮著重要的作用。淋巴細(xì)胞功能相關(guān)抗原1（lymphocytefunction-associated antigen-1，LFA-1）參與免疫細(xì)胞的發(fā)育和分化，參與免疫應(yīng)答和免疫調(diào)節(jié)，其在輔助性T細(xì)胞增殖和分化中的作用受到關(guān)注。本研究通過觀察LFA-1基因敲除對實驗性自身免疫性腦脊髓炎（experimental autoimmuneencephalomyelitis, EAE）小鼠關(guān)節(jié)局部引流淋巴結(jié)T細(xì)胞活性的影響，并檢測CD4+T細(xì)胞產(chǎn)生細(xì)胞因子的情況，探討LFA-1調(diào)控T細(xì)胞活性在EAE發(fā)病中的作用。目的： 觀察LFA-1基因敲除鼠的EAE發(fā)病情況，并探討LFA-1基因缺失對EAE發(fā)病時的T細(xì)胞影響。方法： 采用MOG35-55多肽免疫法誘導(dǎo)野生型小鼠及LFA-1基因敲除小鼠EAE模型，觀察兩組EAE模型小鼠的發(fā)病情況、體重、臨床癥狀及神經(jīng)損害情況，BrdU法檢測LFA-1基因敲除小鼠及野生型小鼠引流淋巴結(jié)T細(xì)胞增殖，流式細(xì)胞術(shù)檢測CD4+T細(xì)胞產(chǎn)生細(xì)胞因子情況。結(jié)果： 研究顯示MOG誘導(dǎo)后，與野生型小鼠相比，LFA-1基因敲除組小鼠的EAE發(fā)病率降低、潛伏期延長，差異具有統(tǒng)計學(xué)意義（P0.01）。且發(fā)病癥狀較輕，發(fā)病時間較晚，神經(jīng)功能損害評分較低，在發(fā)病初期，，二者的評分差異有顯著性（P0.01）。與LFA-1基因敲除鼠相比，野生型小鼠的體重下降出現(xiàn)的時間較早，下降的幅度更大。組織學(xué)檢查發(fā)現(xiàn)，野生型小鼠脊髓出現(xiàn)明顯的脫髓鞘病理變化，而LFA-1基因敲除小鼠脊髓無明顯脫髓鞘改變；進一步研究表明在疾病早期7天時LFA-1基因敲除可以減少淋巴細(xì)胞向引流淋巴結(jié)聚集，降低MOG體外刺激T細(xì)胞增殖能力，產(chǎn)生IFN-γ及IL-17的T細(xì)胞比例也較野生型小鼠組明顯降低。而在疾病緩解期21天時LFA-1基因敲除鼠淋巴細(xì)胞聚集及T細(xì)胞增殖能力與對照組幾乎沒有差別。 結(jié)論：1、LFA-1基因敲除鼠的EAE發(fā)病率低、潛伏期長、臨床癥狀及神經(jīng)損害較 野生型小鼠輕；2、LFA-1基因敲除可通過減少淋巴細(xì)胞向引流淋巴結(jié)聚集，降低T淋巴細(xì)胞增殖能力，并通過調(diào)節(jié)Th1細(xì)胞分泌IFN-γ及Th17細(xì)胞分泌IL-17等機制影 響EAE的發(fā)生發(fā)展；3、在EAE疾病發(fā)生早期，LFA-1可能起到了關(guān)鍵性的作用，因此LFA-1有可能成為EAE治療的重要分子靶點。
[Abstract]:Multiple sclerosis (MS) is a typical autoimmune disease characterized by demyelination of the central nervous system.High incidence of disease deterioration and disability. The incidence of MS is the result of multiple factors, in which T lymphocytes play an important role in the pathogenesis of MS and the biological process of disease progression.Lymphocyte function-associated antigen (1(lymphocytefunction-associated antigen-1) is involved in the development and differentiation of immune cells, immune response and immune regulation, and its role in the proliferation and differentiation of helper T cells has attracted much attention.To investigate the role of LFA-1 in the regulation of T cell activity in the pathogenesis of EAE.Objective:Methods:The EAE model of wild-type mice and LFA-1 knockout mice was induced by MOG35-55 polypeptide immunization. The incidence and body weight of the two groups of EAE model mice were observed.LFA-1 gene knockout mice and wild-type mice were detected for T cell proliferation in draining lymph nodes by BrdU method and cytokines produced by CD4 T cells were detected by flow cytometry.Results:The results showed that compared with wild type mice, the incidence of EAE was decreased and the latent period was prolonged after induction of MOG, and the difference was statistically significant (P 0.01).The symptoms were mild, the onset time was late, and the neurological impairment score was lower. At the beginning of the disease, there was a significant difference between the two groups (P 0.01).Compared with LFA-1 knockout mice, the body weight loss of wild type mice appeared earlier and the decline was larger than that of LFA-1 knockout mice.Histological examination showed that there were obvious demyelinating pathological changes in the spinal cord of wild type mice, but there was no obvious demyelinating change in the spinal cord of LFA-1 gene knockout mice.Further studies showed that LFA-1 gene knockout could reduce the aggregation of lymphocytes to drainage lymph nodes, reduce the proliferation of T cells stimulated by MOG in vitro, and reduce the proportion of T cells producing IFN- 緯 and IL-17 in wild type mice.The ability of lymphocyte aggregation and T cell proliferation of LFA-1 knockout mice was almost the same as that of the control group at 21 days after remission.Conclusion the incidence of EAE was lower, the incubation period was longer, and the clinical symptoms and nerve damage were higher in the knockout mice with the LFA-1 gene knockout.LFA-1 knockout of wild-type mice can reduce lymphocyte aggregation to draining lymph nodes, reduce T lymphocyte proliferation, and regulate the secretion of IFN- 緯 by Th1 cells and IL-17 secretion by Th17 cells.The pathogenesis and development of EAE may play a key role in the early stage of EAE disease, so LFA-1 may be an important molecular target for EAE therapy.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R744

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