本文選題：抗N-甲基-D-天冬氨酸受體腦炎　切入點(diǎn)：細(xì)胞因子　出處：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文　論文類型：學(xué)位論文

【摘要】：研究目的：抗N-甲基-D-天冬氨酸受體腦炎(抗NMDAR腦炎)是最常見的一類自身免疫性腦炎。其臨床表現(xiàn)復(fù)雜多樣,多起病急驟、進(jìn)展較快,病情嚴(yán)重程度復(fù)雜不一。近年來對(duì)于抗NMDAR腦炎的發(fā)病機(jī)制研究,提示體內(nèi)產(chǎn)生特異性的抗GluN1抗體是致病的直接原因；但抗體上游的免疫機(jī)制尚不清楚。目前臨床上診斷依賴腦脊液特異性的抗GluN1抗體陽(yáng)性。臨床病情評(píng)估方式主要包括臨床癥狀、改良Rankin評(píng)分、腦脊液抗體滴度和鞘內(nèi)IgG合成率等。我們檢測(cè)了抗NMDAR腦炎患者腦脊液與血清的細(xì)胞因子水平,分析其對(duì)抗NMDAR腦炎的臨床意義。研究方法：收集52例明確抗NMDAR腦炎、13例炎性對(duì)照組、6例非炎性對(duì)照組患者的腦脊液與血清標(biāo)本,用酶聯(lián)免疫分析(ELISA)法檢測(cè)其中CXCL13、BAFF、 APRIL、IL-6和CXCL10等5種細(xì)胞因子水平。使用SPSS IBM 20.0軟件對(duì)實(shí)驗(yàn)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,對(duì)比不同疾病組間、急性期與緩解期細(xì)胞因子的均值差異,及影響急性期腦脊液細(xì)胞因子水平的可能因素。研究結(jié)果：(1)血清APRIL在實(shí)驗(yàn)組與非炎性對(duì)照組之間的分布存在顯著差異(Sidak事后檢驗(yàn)：P=0.004)。腦脊液細(xì)胞因子水平對(duì)照組比較具有升高趨勢(shì),未見統(tǒng)計(jì)學(xué)差異,可能與對(duì)照組例數(shù)不足有關(guān)。(2) CXCL13、BAFF和IL-6在急性期與緩解期患者腦脊液之間的分布存在顯著差異(分別P=0.050；P=0.014；P=0.041)；BAFF在急性期與緩解期患者血清之間的分布存在顯著差異(P=0.022)。(3)患者年齡與腦脊液CXCL13水平相關(guān)；腦脊液淋巴細(xì)胞炎癥影響IL-6水平；腦脊液CXCL10與患者年齡、mRS相關(guān),治療與否亦影響水平；腦脊液BAFF、APRIL水平與患者臨床特征不相關(guān)。(4)2例周期性鞘注病例的腦脊液BAFF、IL-6、CXCL10的水平,與腦脊液抗GluN1抗體滴度的變化趨勢(shì)基本符合；急性期(免疫治療)后腦脊液CXCL13迅速回落到正常水平。結(jié)論：以B細(xì)胞為核心、Th17輔助的鞘內(nèi)體液免疫反應(yīng)可能是抗NMDAR腦炎主要的免疫機(jī)制；除鞘內(nèi)的免疫反應(yīng)外,還存在全身體液免疫激活。抗NMDAR腦炎患者的腦脊液CXCL13、BAFF、IL-6,以及血清BAFF是病情評(píng)價(jià)和觀察治療反應(yīng)潛在的生物標(biāo)志物。腦脊液淋巴細(xì)胞炎癥與腦脊液IL-6水平相關(guān),年齡可能影響CXCL13的水平。多種細(xì)胞因子與抗體滴度的變化趨勢(shì)相一致。
[Abstract]:Objective: Anti-N- methyl-Daspartic acid receptor encephalitis (NMDAR encephalitis) is the most common type of autoimmune encephalitis. Recent studies on the pathogenesis of anti NMDAR encephalitis suggest that the production of specific anti GluN1 antibodies in vivo is the direct cause of the disease. However, the immunological mechanism of the upstream antibody is not clear. At present, the clinical diagnosis of GluN1 antibody is dependent on cerebrospinal fluid (CSF). The main clinical evaluation methods include clinical symptoms, modified Rankin score, The levels of cytokines in cerebrospinal fluid and serum of patients with anti NMDAR encephalitis were measured. The clinical significance of NMDAR encephalitis was analyzed. Methods: the cerebrospinal fluid (CSF) and serum samples were collected from 13 patients with anti NMDAR encephalitis and 6 patients with non-inflammatory control group. The levels of five cytokines, BAFF, APRILILILIL-6 and CXCL10, were detected by Elisa. The experimental data were statistically analyzed by SPSS IBM 20.0 software, and the mean values of cytokines in different disease groups, acute phase and remission stage were compared. The distribution of serum APRIL between the experimental group and the non-inflammatory control group was significantly different. After Sidak test, the levels of cytokines in cerebrospinal fluid (CSF) were higher than those in control group. With an upward trend, There was no statistical difference, The distribution of CXCL13 BAFF and IL-6 in cerebrospinal fluid (CSF) was significantly different between acute and remission patients (P0. 050, P0. 014, P0. 041). There was a significant difference in the distribution of BAFF and IL-6 between acute and remission patients. Age was correlated with cerebrospinal fluid (CXCL13) level. Cerebrospinal fluid (CSF) lymphocyte inflammation affected the level of IL-6, cerebrospinal fluid (CSF) CXCL10 was correlated with patients' age and mRS, and the level of CSF APRIL was not correlated with the clinical characteristics of patients. The level of cerebrospinal fluid BAFFFU IL-6 (CXCL10) was not correlated with the clinical characteristics of the patients. The titer of anti GluN1 antibody in cerebrospinal fluid was basically consistent with that of cerebrospinal fluid. In acute phase (immunotherapy), cerebrospinal fluid (CSF) CXCL13 rapidly returned to normal level. Conclusion: the intrathecal humoral immune response assisted by B cells may be the main immune mechanism against NMDAR encephalitis, except the intrathecal immune response. There was also systemic humoral immune activation. The cerebrospinal fluid (CSF) CXCL13, BAFF, IL-6 and serum BAFF were potential biomarkers for evaluating and observing the response to treatment in patients with NMDAR encephalitis. The level of cerebrospinal fluid (CSF) IL-6 was correlated with lymphocytic inflammation in cerebrospinal fluid (CSF). Age may affect the level of CXCL13.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R742.9

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