本文選題：結(jié)節(jié)病 + 白介素35��； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：背景和目的:我們先前研究已經(jīng)發(fā)現(xiàn),Treg/Th17失衡及Treg細(xì)胞免疫抑制功能缺陷是結(jié)節(jié)病發(fā)病的重要原因之一。IL-35作為Treg細(xì)胞免疫抑制功能的執(zhí)行者,通過促進(jìn)Treg細(xì)胞增殖,抑制Th17分化并誘導(dǎo)iTr35細(xì)胞(分泌IL-35的Treg細(xì)胞亞群)生成發(fā)揮免疫抑制作用。我們推測(cè)結(jié)節(jié)病中Treg細(xì)胞的抑制功能缺陷和Treg/Th17失衡可能與IL-35分泌減少或其在細(xì)胞內(nèi)信號(hào)傳導(dǎo)途徑異常有關(guān)。因此本研究將在先前研究基礎(chǔ)上明確結(jié)節(jié)病中合成和釋放IL-35的細(xì)胞來源及其表達(dá)情況;探討IL-35在結(jié)節(jié)病的發(fā)病機(jī)制中可能發(fā)揮的生物學(xué)效應(yīng),此研究旨在探尋結(jié)節(jié)病的發(fā)病機(jī)制和尋找潛在的治療靶點(diǎn)。方法:ELISA檢測(cè)結(jié)節(jié)病組(n=98)和正常對(duì)照組(n=98)血漿中IL-35的水平,Real-time PCR檢測(cè)結(jié)節(jié)病組和正常對(duì)照組IL-35兩個(gè)亞基EBI3和p35的表達(dá)水平,以及Treg細(xì)胞轉(zhuǎn)錄因子Foxp3的表達(dá)水平。Pearson相關(guān)分析結(jié)節(jié)病患者血漿中IL-35的水平與臨床參數(shù)的相關(guān)性。選取初治結(jié)節(jié)病患者10例,健康對(duì)照者10例,采用流式細(xì)胞術(shù)檢測(cè)外周血中Treg細(xì)胞占CD4+T細(xì)胞的比例,IL-35在CD4+T細(xì)胞、CD8+T細(xì)胞、Treg細(xì)胞上的表達(dá)情況。結(jié)果:結(jié)節(jié)病組血漿中IL-35的水平(43.56±11.77pg/mL)明顯低于正常對(duì)照組(55.18± 11.53 pg/mL),差異具有統(tǒng)計(jì)學(xué)意義(P0.001)。結(jié)節(jié)病治療組(n=57)較未治療組(n=41)血漿中IL-35的水平明顯升高(47.38±12.02pg/mL vs 40.82± 10.89 pg/mL;P=0.0059),結(jié)節(jié)病患者血漿中IL-35水平與DLCO占預(yù)測(cè)值%成正相關(guān)(r=0.76,P0.001),而與其他臨床參數(shù)未發(fā)現(xiàn)明顯相關(guān)性。結(jié)節(jié)病組EBI3和Foxp3基因mRNA的表達(dá)水平均明顯低于正常對(duì)照組(分別為 P=0.0016,P=0.0391),而p35基因mRNA的表達(dá)水平在兩組間無明顯差別(P =0.5816),結(jié)節(jié)病組和正常對(duì)照組EBI3基因相對(duì)表達(dá)量與Foxp3基因相對(duì)表達(dá)量均成明顯正相關(guān)(分別為 r =0.786,P0.001;r =0.730,P0.001),p35 與 Foxp3 基因相對(duì)表達(dá)量在結(jié)節(jié)病組成低度正相關(guān)(r =0.383,P =0.037),而在正常對(duì)照組兩基因表達(dá)無明顯相關(guān)性(r=0.208,P =0.271)。流式細(xì)胞術(shù)檢測(cè)發(fā)現(xiàn),10例結(jié)節(jié)病患者外周血中Treg/CD4+T細(xì)胞的平均比例(5.82±0.51%)與健康對(duì)照者(5.71 ±0.90%)相比無顯著差異(P=0.7413),在CD4+T細(xì)胞、CD8+T細(xì)胞和Treg細(xì)胞中均未發(fā)現(xiàn)表達(dá)IL-35的細(xì)胞。結(jié)論:結(jié)節(jié)病患者血漿中IL-35水平較正常健康者明顯減低,且經(jīng)激素和或免疫抑制劑治療后水平升高,提示IL-35可能參與了結(jié)節(jié)病的炎癥過程,在其發(fā)病過程中具有重要作用。結(jié)節(jié)病患者血漿中IL-35水平與DLCO占預(yù)測(cè)值%成正相關(guān),提示其有可能作為預(yù)測(cè)結(jié)節(jié)病肺部病變進(jìn)展的生物學(xué)指標(biāo)。IL-35的一個(gè)亞基EBI3和Treg細(xì)胞轉(zhuǎn)錄因子Foxp3的mRNA表達(dá)水平均明顯低于正常對(duì)照組,且EBI3、p35基因與Foxp3基因相對(duì)表達(dá)量成正相關(guān),提示結(jié)節(jié)病患者外周血中Treg細(xì)胞數(shù)量的減少可能導(dǎo)致了 EBI3、p35基因生成減少,以至于EBI3與p35形成的異源二聚體減少,最終合成IL-35減少。而本研究采用流式細(xì)胞術(shù)檢測(cè)人類T淋巴細(xì)胞亞群并未發(fā)現(xiàn)IL-35表達(dá)陽性的細(xì)胞,可能與人T淋巴細(xì)胞亞群中分泌IL-35的細(xì)胞數(shù)量太少有關(guān),抑或IL-35可能主要由其它細(xì)胞亞群所分泌。
[Abstract]:Background and purpose: our previous studies have found that the Treg/Th17 imbalance and Treg cell immunosuppressive function defects are one of the important causes of sarcoidosis,.IL-35 as the executor of the immunosuppressive function of Treg cells, by promoting the proliferation of Treg cells, inhibiting the differentiation of Th17 and inducing the generation of iTr35 cells (the Treg cell subgroup of IL-35) to produce hair. We speculate that the inhibitory functional defects of Treg cells and Treg/Th17 imbalance in sarcoidosis may be related to the decrease of IL-35 secretion or the abnormal signal transduction pathway in the cells. Therefore, this study will make clear the synthesis and release of IL-35 cells and their expression in sarcoidosis based on previous studies, and discuss IL-35 in the study. The biological effects may be played in the pathogenesis of sarcoidosis. This study aims to explore the pathogenesis of sarcoidosis and to find potential therapeutic targets. Methods: ELISA detection of IL-35 levels in plasma of sarcoidosis group (n=98) and normal control group (n=98), Real-time PCR to detect EBI3 and p35 of IL-35 two subunits in nodal disease group and normal control group. The level of expression and the expression level of Treg cell transcription factor Foxp3 were correlated with the correlation between the level of IL-35 in the plasma of sarcoidosis patients and the correlation of clinical parameters. 10 patients with primary sarcoidosis and 10 healthy controls were selected, and the proportion of Treg cells to CD4+T cells in peripheral blood was detected by flow cytometry, and IL-35 in CD4+T cells, CD8+T. Result: the level of IL-35 in the plasma of the sarcoidosis group (43.56 + 11.77pg/mL) was significantly lower than that of the normal control group (55.18 + 11.53 pg/mL), and the difference was statistically significant (P0.001). The level of IL-35 in the plasma of sarcoidosis group (n=57) was significantly higher than that in the untreated group (n=41) (47.38 + 12.02pg/mL vs 40.82 + 10.89 P. G/mL; P=0.0059), the level of IL-35 in the plasma of sarcoidosis patients was positively correlated with the predicted value of DLCO (r=0.76, P0.001), but not significantly correlated with other clinical parameters. The expression level of EBI3 and Foxp3 gene mRNA in sarcoidosis group was significantly lower than that of normal control group (P= 0.0016, P=0.0391), while the expression level of p35 gene was between the two groups. There was no significant difference (P =0.5816). The relative expression of EBI3 gene in the sarcoidosis group and the normal control group was positively correlated with the relative expression of the Foxp3 gene (R =0.786, P0.001; R =0.730, P0.001), and the relative expression of p35 and Foxp3 genes in the low degree of sarcoidosis, but in the normal control group two gene table. There was no significant correlation (r=0.208, P =0.271). Flow cytometry showed that the average proportion of Treg/CD4+T cells in peripheral blood of 10 sarcoidosis patients (5.82 + 0.51%) was not significantly different from that of healthy controls (5.71 + 0.90%) (P=0.7413). No IL-35 cells were found in CD4+T cells, CD8+T fine cells and Treg cells. Conclusion: Sarcoidosis The level of IL-35 in the patient's plasma is significantly lower than that of the normal health, and the level of IL-35 may be involved in the inflammatory process of sarcoidosis, which may play an important role in the pathogenesis of sarcoidosis. The level of IL-35 in the plasma of sarcoidosis patients is positively correlated with the predictive value of DLCO, suggesting that it may be a precondition. The biological index of the progression of sarcoidosis pulmonary disease.IL-35, the mRNA expression level of a subunit EBI3 and Treg cell transcription factor Foxp3 was significantly lower than that of the normal control group, and the EBI3, p35 gene was positively correlated with the relative expression of Foxp3 gene, suggesting that the decrease of Treg cell in the peripheral blood of sarcoidosis patients may lead to EBI3, p35 basis. As a result of the reduction of the formation of the heterogenous two polymer formed by EBI3 and p35, the final synthesis of IL-35 decreased. In this study, the use of flow cytometry to detect human T lymphocyte subsets did not find IL-35 positive cells. It may be related to the small number of cells secreting IL-35 in human T lymphocyte subsets, or IL-35 may be mainly caused by others. Secreted by cell subgroups.

【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】：2017
【分類號(hào)】：R593.9

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