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T輔助細(xì)胞亞群在系統(tǒng)性紅斑狼瘡?fù)庵苎谋磉_及臨床意義

發(fā)布時間:2018-08-16 08:04
【摘要】:研究背景:系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus,SLE)是一種由多因素引起的以多臟器受累為特征的自身免疫性疾病,狼瘡腎炎(lupus nephritis,LN)是SLE最嚴(yán)重和常見的并發(fā)癥之一。T淋巴細(xì)胞的異常、B淋巴細(xì)胞的過度活化最終導(dǎo)致免疫系統(tǒng)的異常免疫應(yīng)答是其主要發(fā)病機制。研究表明SLE患者T輔助淋巴細(xì)胞(Th)的數(shù)量及功能失衡是T淋巴細(xì)胞免疫功能異常的重要方面。根據(jù)分泌細(xì)胞因子的不同,Th細(xì)胞又分為Th1細(xì)胞、Th2細(xì)胞、Th17細(xì)胞和調(diào)節(jié)性T細(xì)胞(regulatory T cell,Treg).既往研究多關(guān)注于Th1/Th2的失衡與SLE的發(fā)病關(guān)系,顯示二者的平衡狀態(tài)在SLE中起著決定性的作用:“Th2優(yōu)勢”、“Th1優(yōu)勢”等多種免疫紊亂狀態(tài)均在SLE患者體內(nèi)被證實。但進一步的研究發(fā)現(xiàn)很多SLE臨床表現(xiàn)和實驗室特點并不能用已知的Th1/Th2失衡模式來解釋。近年來,Treg細(xì)胞和Th17細(xì)胞在機體的免疫調(diào)節(jié)和免疫應(yīng)答中的作用越來越受到重視。有研究顯示,SLE患者外周血Th17細(xì)胞升高與Treg細(xì)胞減少可能共同參與了其異常免疫應(yīng)答過程,Th17細(xì)胞和Treg細(xì)胞可能與SLE的發(fā)病相關(guān)。因此同時研究這4種Th細(xì)胞在SLE患者中的變化對了解SLE的發(fā)病機制有著非常重要的意義。本文通過檢測外周血Thl細(xì)胞、Th2細(xì)胞、Th17細(xì)胞、Treg細(xì)胞百分?jǐn)?shù),探討它們及其比值在SLE.LN發(fā)生和發(fā)展中的作用。目的:探討Thl細(xì)胞、Th2細(xì)胞、Th17細(xì)胞、Treg細(xì)胞百分比及其比值在系統(tǒng)性紅斑狼瘡(SLE)、狼瘡腎炎(LN)發(fā)生和發(fā)展中的作用,以期尋找病情評估的新型生物學(xué)標(biāo)志物。方法:選取SLE患者103例及23例健康體檢者,其中LN患者40例,新診斷、未治療的SLE患者42例。SLE患者非活動組(SLEDAI 0~4分)患者16例、輕度活動組(SLEDAI 5~9分)患者29例、中度活動組(SLEDAI 10~14分)患者26例、重度活動組(SLEDAI≥15分)患者32例。用四色分選流式細(xì)胞儀檢測外周血CD4+IFN-r+Th1細(xì)胞、CD4+IL-4+Th2細(xì)胞、CD4+IL-17+Th17細(xì)胞和CD4+CD25+FOXP3+Treg細(xì)胞百分?jǐn)?shù),分析其與疾病活動性(SLEDAI評分)、補體C3、C4和腎臟受累的關(guān)系,并作統(tǒng)計學(xué)分析。結(jié)果:(1)SLE輕、中、重度活動組Th17細(xì)胞百分?jǐn)?shù)均高于健康對照組(P=0.0000、0.0000、0.0000)和非活動組(P=0.0001.0.0000.0.0000), SLE中、重度活動組Th17細(xì)胞百分?jǐn)?shù)均高于輕度活動組(P=0.0173、0.0009);LN組Th17細(xì)胞百分?jǐn)?shù)高于非LN組(P=0.0008);新發(fā)SLE活動期Th17細(xì)胞百分?jǐn)?shù)高于健康對照組(P=0.0000)和穩(wěn)定期(P=0.0004);復(fù)發(fā)SLE活動期Th17細(xì)胞百分?jǐn)?shù)高于穩(wěn)定期(P=0.0002);新發(fā)、復(fù)發(fā)SLE患者Th17細(xì)胞百分?jǐn)?shù)無明顯差異(P=0.2419);20例SLE活動期患者治療1月后Th17細(xì)胞百分?jǐn)?shù)低于治療前(P=0.0297);補體降低組SLE患者Th17細(xì)胞高于補體正常組(P=0.0000)及健康對照組(P=0.0000);Th17細(xì)胞百分?jǐn)?shù)與SLEDAI評分呈正相關(guān)。(2)SLE重度活動組Treg細(xì)胞低于健康對照組(P=0.0027)、非活動組(P=0.0103)及輕度活動組(P=0.0446);LN組Treg細(xì)胞百分?jǐn)?shù)與非LN組比較,無明顯差異(P=0.2568);新發(fā)SLE活動期Treg細(xì)胞百分?jǐn)?shù)低于健康對照組(P=0.0076)和穩(wěn)定期(P=0.0019);復(fù)發(fā)SLE活動期Treg細(xì)胞百分?jǐn)?shù)低于健康對照組(P=0.0261),與SLE穩(wěn)定期無明顯差異(P=0.1991);新發(fā)、復(fù)發(fā)SLE患者Treg細(xì)胞百分?jǐn)?shù)比較,無明顯差異(P=0.8351);20例SLE活動期患者治療1月后Treg細(xì)胞百分?jǐn)?shù)與治療前無明顯差異(P=0.6046);補體降低組SLE患者Treg細(xì)胞百分?jǐn)?shù)低于健康對照組(P=0.0415),與補體正常組無明顯差異(P=0.1500);Treg細(xì)胞百分?jǐn)?shù)與SLEDAI評分無相關(guān)性。(3)SLE輕、中、重度活動組Th17/Treg比值均顯著高于健康對照組(P=0.0044.0.0006、0.0000), SLE中、重度活動組Th17/Treg比值均高于非活動組(P=-0.0075、0.0002)和輕度活動組(P=0.0417、0.0044);LN組及非LN組Th17/Treg比值均高于健康對照組(P=0.0000、0.0000),LN組Th17/Treg高于非LN組(P=0.0429);新發(fā)SLE活動期Th17/Treg細(xì)胞比值高于健康對照組(P=0.0000)和穩(wěn)定期(P=0.0000);復(fù)發(fā)SLE活動期Th17/Treg高于穩(wěn)定期(P=0.0150);新發(fā)、復(fù)發(fā)SLE患者Th17/Treg細(xì)胞比值比較,無明顯差異(P=0.9397);20例SLE活動期患者治療1月后Th17/Treg比值低于治療前(P=0.0363);補體降低組SLE患者Th17/Treg比值高于補體正常組(P=0.0020)及健康對照組(P=0.0000);Th17/Treg比值與SLEDAI評分呈正相關(guān)。(4)SLE患者及非活動組、輕、中、重度活動組Thl細(xì)胞百分?jǐn)?shù)均高于健康對照組(P= 0.0000.0.0008.0.0004.0.0000), SLE患者輕、中、重及非活動組間無明顯差異(P0.05);LN及非LN組Thl細(xì)胞百分?jǐn)?shù)均高于健康對照組(P=0.0000、0.0000),二者之間無明顯差異(P=0.2749);新發(fā)SLE患者Thl細(xì)胞百分?jǐn)?shù)高于健康對照組(P=0.0005);補體降低SLE患者Thl細(xì)胞百分?jǐn)?shù)高于健康對照組(P=0.0000)。Thl細(xì)胞百分?jǐn)?shù)與SLEDAI評分、尿蛋白無相關(guān)性。(5)SLE患者及非活動組、輕、中、重度活動組Th2細(xì)胞百分?jǐn)?shù)均高于健康對照組(P=0.0212、0.0205、0.0339、0.0247), SLE患者輕、中、重及非活動組問無明顯差異(P0.05);LN及非LN患者Th2細(xì)胞百分?jǐn)?shù)均高于健康對照組(P=0.0016、0.0202),二者之間無明顯差異(P=0.1831);新發(fā)SLE患者與健康對照組Th2細(xì)胞百分?jǐn)?shù)無明顯差異(P=0.0806);補體降低SLE患者Th2細(xì)胞百分?jǐn)?shù)高于健康對照組(P=0.0037);Th2細(xì)胞百分?jǐn)?shù)與SLEDAI評分、尿蛋白無相關(guān)性。(6)SLE患者及非活動組、中、重度活動組Th1/Th2比值均高于健康對照組(P=0.0002、0.0012、0.0019);LN及非LN患者Th1/Th2匕值均高于健康對照組(P=0.0023、0.0004),二者之間無明顯差異(P=0.9192);新發(fā)SLE患者Th1/Th2比值高于健康對照組(P=0.0032);補體降低SLE患者Th1/Th2比值高于健康對照組(P=0.0006); Th1/Th2比值與SLEDAI評分、尿蛋白無相關(guān)性。結(jié)論:活動性SLE患者外周血Thl7細(xì)胞升高、Treg細(xì)胞下降,Th17/Treg細(xì)胞比值與疾病活動呈正相關(guān),提示SLE發(fā)病不僅僅存在Th17細(xì)胞升高或Treg細(xì)胞下降,還與二者相互作用導(dǎo)致免疫失衡有關(guān);顒有許LE患者外周血Th1細(xì)胞升高、Th1/Th2升高、Thl7細(xì)胞升高、Treg細(xì)胞下降、Th17/Treg比值升高,且Th17/Treg細(xì)胞比值與疾病活動呈正相關(guān),提示這4種T輔助細(xì)胞在SLE發(fā)生和發(fā)展中起重要作用,同時Thl及Th2, Th17及Treg的失衡狀態(tài)可能導(dǎo)致SLE患者細(xì)胞功能紊亂。SLE發(fā)病可能是Th1/Th2、Th17/Treg相互作用導(dǎo)致免疫失衡所致,故應(yīng)將Th1/Th2、Th17/Treg作為一個觀察整體,從而比單純研究某類細(xì)胞的變化來推斷SLE疾病狀態(tài)更加科學(xué)系統(tǒng),為SLE的發(fā)病機制和治療提供新的思路。
[Abstract]:Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement caused by multiple factors. Lupus nephritis (LN) is one of the most serious and common complications of SLE. T lymphocyte abnormalities and excessive B lymphocyte activation eventually lead to the immune system. Studies have shown that the number and dysfunction of T helper lymphocytes (Th) in SLE patients is an important aspect of T lymphocyte immune dysfunction. Th cells are divided into Th1 cells, Th2 cells, Th17 cells and regulatory T cells (Treg) according to the secretion of cytokines. Studies have focused on the relationship between Th1/Th2 imbalance and SLE, showing that the balance between the two plays a decisive role in SLE: "Th2 advantage", "Th1 advantage" and other immune disorders have been confirmed in SLE patients. However, further studies have found that many SLE clinical manifestations and laboratory characteristics can not be used with the known Th1/Th1 advantage. In recent years, Treg cells and Th17 cells play a more and more important role in immune regulation and immune response. Studies have shown that the increase of Th17 cells and the decrease of Treg cells in peripheral blood of SLE patients may be involved in the abnormal immune response. Th17 cells and Treg cells may be related to the pathogenesis of SLE. Therefore, it is very important to study the changes of the four Th cells in SLE patients at the same time to understand the pathogenesis of SLE. The role of reg cell percentage and its ratio in the occurrence and development of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in order to find new biomarkers for disease evaluation. Methods: 103 SLE patients and 23 healthy persons were selected, including 40 LN patients, 42 newly diagnosed and untreated SLE patients. Sixteen patients, 29 patients with SLEDAI (5-9 points), 26 patients with SLEDAI (10-14 points) and 32 patients with SLEDAI (15 points) were enrolled in the study. The percentage of CD4+IFN-r+Th1 cells, CD4+IL-4+Th2 cells, CD4+IL-17+Th17 cells and CD4+CD25+FOXP3+Treg cells in peripheral blood were detected by four-color sorting flow cytometry. Results: (1) The percentage of Th17 cells in SLE mild, moderate and severe active group was higher than that in healthy control group (P = 0.0000, 0.0000, 0.0000) and non-active group (P = 0.0001.0.0000). Th17 cell percentage in active SLE group was higher than that in non-LN group (P = 0.0008); Th17 cell percentage in active SLE group was higher than that in healthy control group (P = 0.0000) and stable SLE group (P = 0.0004); Th17 cell percentage in active SLE group was higher than that in stable SLE group (P = 0.0002); Th17 cell percentage in recurrent SLE group was no significant difference (P = 0.0002). The percentage of Th17 cells in active SLE group was lower than that before treatment (P = 0.0297), the percentage of Th17 cells in SLE group was higher than that in normal complement group (P = 0.0000) and healthy control group (P = 0.0000), and the percentage of Th17 cells was positively correlated with SLEDAI score. (2) Treg cells in severe active SLE group were lower than that in healthy control group (P = 0.0027). The percentage of Treg cells in the active phase of SLE was lower than that in the healthy control group (P = 0.0076) and the stable phase (P = 0.0019); the percentage of Treg cells in the active phase of relapsed SLE was lower than that in the healthy control group (P = 0.0261), and was stable with SLE. There was no significant difference in the percentage of Treg cells (P = 0.1991), no significant difference in the percentage of Treg cells (P = 0.8351) in newly diagnosed and relapsed SLE patients, no significant difference in the percentage of Treg cells (P = 0.6046) in 20 active SLE patients after 1 month of treatment, and no significant difference in the percentage of Treg cells (P = 0.0415) in SLE patients with reduced complement compared with healthy control group (P = 0.0415) and normal complement group (P = 0.0415). There was no correlation between the percentage of Treg cells and SLEDAI score. Th17/Treg ratio in LN group was higher than that in non-LN group (P = 0.0000, 0.0000), Th17/Treg ratio in active phase of new onset SLE was higher than that in healthy control group (P = 0.0000) and stable phase (P = 0.0000), Th17/Treg ratio in active phase of relapse SLE was higher than that in stable phase (P = 0.0150), Th17/Treg ratio in New onset and relapse SLE was higher than that in non-LN group (P = 0.0429). There was no significant difference (P = 0.9397); Th17/Treg ratio was lower in 20 SLE active patients than before treatment (P = 0.0363); Th17/Treg ratio in SLE patients with reduced complement was higher than that in normal complement group (P = 0.0020) and healthy control group (P = 0.0000); Th17/Treg ratio was positively correlated with SLEDAI score. (4) SLE patients and inactive group, mild, moderate and severe. The percentage of Thl cells in active group was higher than that in healthy control group (P = 0.0000.0008.0.0004.0 000 0), and there was no significant difference among light, medium, heavy and inactive SLE patients (P 0.05); the percentage of Thl cells in LN and non-LN groups was higher than that in healthy control group (P = 0.0000, 0.0000), and there was no significant difference between them (P = 0.2749); the percentage of Thl cells in new SLE patients was higher than that in healthy control group (P = 0.2749). In the healthy control group (P = 0.0005), the percentage of Thl cells in SLE patients was higher than that in the healthy control group (P = 0.0000). There was no correlation between the percentage of Thl cells and SLEDAI score and urinary protein. Th2 cell percentage in LN and non-LN patients was higher than that in healthy control group (P = 0.0016, 0.0202), and there was no significant difference between them (P = 0.1831); Th2 cell percentage in new-onset SLE patients and healthy control group had no significant difference (P = 0.0806); Th2 cell percentage in complement-reduced SLE patients was higher than that in healthy control group (P = 0.0016, 0.0202). Th2 cell percentage was not correlated with SLEDAI score and urinary protein. (6) Th1/Th2 ratio in SLE patients and inactive group was higher than that in healthy control group (P = 0.0002,0.0012,0.0019); Th1/Th2 dagger value in LN and non-LN patients was higher than that in healthy control group (P = 0.0023,0.0004), and there was no significant difference between them (P = 0.9192). Th1/Th2 ratio in new-onset SLE patients was higher than that in healthy control group (P = 0.0032); Th1/Th2 ratio in complement-reduced SLE patients was higher than that in healthy control group (P = 0.0006); Th1/Th2 ratio had no correlation with SLEDAI score and urinary protein. It is suggested that the increase of Th17 cells or Treg cells is not only associated with the onset of SLE, but also with the imbalance of immunity caused by the interaction between them.The increase of Th1 cells, Th1/Th2, Thl7 cells, Treg cells and Th17/Treg ratio in peripheral blood of active SLE patients are positively correlated with disease activity. Synergids play an important role in the occurrence and development of SLE, and the imbalance of Thl and Th2, Th17 and Treg may lead to cell dysfunction in SLE patients. The pathogenesis of SLE may be due to the imbalance of immunity caused by the interaction of Th1/Th2 and Th17/Treg. Therefore, Th1/Th2 and Th17/Treg should be considered as a whole, so as to study the changes of certain kinds of cells more than simply studying the changes of cells. To infer a more scientific system of SLE disease, and to provide new ideas for the pathogenesis and treatment of SLE.
【學(xué)位授予單位】:中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】:碩士
【學(xué)位授予年份】:2015
【分類號】:R593.241

【參考文獻】

相關(guān)期刊論文 前1條

1 黃華;陳勇;樓燕如;黃嫻倩;忻霞菲;周麗;王庭輝;覃文;;Th17/Treg在系統(tǒng)性紅斑狼瘡患者中的探討[J];現(xiàn)代實用醫(yī)學(xué);2014年09期

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