T辅助细胞亚群在系统性红斑狼疮外周血的表达及临床意义
发布时间：2018-08-16 08:04
【摘要】：研究背景：系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种由多因素引起的以多脏器受累为特征的自身免疫性疾病,狼疮肾炎(lupus nephritis,LN)是SLE最严重和常见的并发症之一。T淋巴细胞的异常、B淋巴细胞的过度活化最终导致免疫系统的异常免疫应答是其主要发病机制。研究表明SLE患者T辅助淋巴细胞(Th)的数量及功能失衡是T淋巴细胞免疫功能异常的重要方面。根据分泌细胞因子的不同,Th细胞又分为Th1细胞、Th2细胞、Th17细胞和调节性T细胞(regulatory T cell,Treg).既往研究多关注于Th1/Th2的失衡与SLE的发病关系,显示二者的平衡状态在SLE中起着决定性的作用：“Th2优势”、“Th1优势”等多种免疫紊乱状态均在SLE患者体内被证实。但进一步的研究发现很多SLE临床表现和实验室特点并不能用已知的Th1/Th2失衡模式来解释。近年来,Treg细胞和Th17细胞在机体的免疫调节和免疫应答中的作用越来越受到重视。有研究显示,SLE患者外周血Th17细胞升高与Treg细胞减少可能共同参与了其异常免疫应答过程,Th17细胞和Treg细胞可能与SLE的发病相关。因此同时研究这4种Th细胞在SLE患者中的变化对了解SLE的发病机制有着非常重要的意义。本文通过检测外周血Thl细胞、Th2细胞、Th17细胞、Treg细胞百分数,探讨它们及其比值在SLE.LN发生和发展中的作用。目的：探讨Thl细胞、Th2细胞、Th17细胞、Treg细胞百分比及其比值在系统性红斑狼疮(SLE)、狼疮肾炎(LN)发生和发展中的作用,以期寻找病情评估的新型生物学标志物。方法：选取SLE患者103例及23例健康体检者,其中LN患者40例,新诊断、未治疗的SLE患者42例。SLE患者非活动组(SLEDAI 0～4分)患者16例、轻度活动组(SLEDAI 5～9分)患者29例、中度活动组(SLEDAI 10～14分)患者26例、重度活动组(SLEDAI≥15分)患者32例。用四色分选流式细胞仪检测外周血CD4+IFN-r+Th1细胞、CD4+IL-4+Th2细胞、CD4+IL-17+Th17细胞和CD4+CD25+FOXP3+Treg细胞百分数,分析其与疾病活动性(SLEDAI评分)、补体C3、C4和肾脏受累的关系,并作统计学分析。结果：(1)SLE轻、中、重度活动组Th17细胞百分数均高于健康对照组(P=0.0000、0.0000、0.0000)和非活动组(P=0.0001.0.0000.0.0000), SLE中、重度活动组Th17细胞百分数均高于轻度活动组(P=0.0173、0.0009)；LN组Th17细胞百分数高于非LN组(P=0.0008)；新发SLE活动期Th17细胞百分数高于健康对照组(P=0.0000)和稳定期(P=0.0004)；复发SLE活动期Th17细胞百分数高于稳定期(P=0.0002)；新发、复发SLE患者Th17细胞百分数无明显差异(P=0.2419)；20例SLE活动期患者治疗1月后Th17细胞百分数低于治疗前(P=0.0297)；补体降低组SLE患者Th17细胞高于补体正常组(P=0.0000)及健康对照组(P=0.0000)；Th17细胞百分数与SLEDAI评分呈正相关。(2)SLE重度活动组Treg细胞低于健康对照组(P=0.0027)、非活动组(P=0.0103)及轻度活动组(P=0.0446)；LN组Treg细胞百分数与非LN组比较,无明显差异(P=0.2568)；新发SLE活动期Treg细胞百分数低于健康对照组(P=0.0076)和稳定期(P=0.0019)；复发SLE活动期Treg细胞百分数低于健康对照组(P=0.0261),与SLE稳定期无明显差异(P=0.1991)；新发、复发SLE患者Treg细胞百分数比较,无明显差异(P=0.8351)；20例SLE活动期患者治疗1月后Treg细胞百分数与治疗前无明显差异(P=0.6046)；补体降低组SLE患者Treg细胞百分数低于健康对照组(P=0.0415),与补体正常组无明显差异(P=0.1500)；Treg细胞百分数与SLEDAI评分无相关性。(3)SLE轻、中、重度活动组Th17/Treg比值均显著高于健康对照组(P=0.0044.0.0006、0.0000), SLE中、重度活动组Th17/Treg比值均高于非活动组(P=-0.0075、0.0002)和轻度活动组(P=0.0417、0.0044)；LN组及非LN组Th17/Treg比值均高于健康对照组(P=0.0000、0.0000),LN组Th17/Treg高于非LN组(P=0.0429)；新发SLE活动期Th17/Treg细胞比值高于健康对照组(P=0.0000)和稳定期(P=0.0000)；复发SLE活动期Th17/Treg高于稳定期(P=0.0150)；新发、复发SLE患者Th17/Treg细胞比值比较,无明显差异(P=0.9397)；20例SLE活动期患者治疗1月后Th17/Treg比值低于治疗前(P=0.0363)；补体降低组SLE患者Th17/Treg比值高于补体正常组(P=0.0020)及健康对照组(P=0.0000)；Th17/Treg比值与SLEDAI评分呈正相关。(4)SLE患者及非活动组、轻、中、重度活动组Thl细胞百分数均高于健康对照组(P= 0.0000.0.0008.0.0004.0.0000), SLE患者轻、中、重及非活动组间无明显差异(P0.05)；LN及非LN组Thl细胞百分数均高于健康对照组(P=0.0000、0.0000),二者之间无明显差异(P=0.2749)；新发SLE患者Thl细胞百分数高于健康对照组(P=0.0005)；补体降低SLE患者Thl细胞百分数高于健康对照组(P=0.0000)。Thl细胞百分数与SLEDAI评分、尿蛋白无相关性。(5)SLE患者及非活动组、轻、中、重度活动组Th2细胞百分数均高于健康对照组(P=0.0212、0.0205、0.0339、0.0247), SLE患者轻、中、重及非活动组问无明显差异(P0.05)；LN及非LN患者Th2细胞百分数均高于健康对照组(P=0.0016、0.0202),二者之间无明显差异(P=0.1831)；新发SLE患者与健康对照组Th2细胞百分数无明显差异(P=0.0806)；补体降低SLE患者Th2细胞百分数高于健康对照组(P=0.0037)；Th2细胞百分数与SLEDAI评分、尿蛋白无相关性。(6)SLE患者及非活动组、中、重度活动组Th1/Th2比值均高于健康对照组(P=0.0002、0.0012、0.0019)；LN及非LN患者Th1/Th2匕值均高于健康对照组(P=0.0023、0.0004),二者之间无明显差异(P=0.9192)；新发SLE患者Th1/Th2比值高于健康对照组(P=0.0032)；补体降低SLE患者Th1/Th2比值高于健康对照组(P=0.0006); Th1/Th2比值与SLEDAI评分、尿蛋白无相关性。结论：活动性SLE患者外周血Thl7细胞升高、Treg细胞下降,Th17/Treg细胞比值与疾病活动呈正相关,提示SLE发病不仅仅存在Th17细胞升高或Treg细胞下降,还与二者相互作用导致免疫失衡有关。活动性SLE患者外周血Th1细胞升高、Th1/Th2升高、Thl7细胞升高、Treg细胞下降、Th17/Treg比值升高,且Th17/Treg细胞比值与疾病活动呈正相关,提示这4种T辅助细胞在SLE发生和发展中起重要作用,同时Thl及Th2, Th17及Treg的失衡状态可能导致SLE患者细胞功能紊乱。SLE发病可能是Th1/Th2、Th17/Treg相互作用导致免疫失衡所致,故应将Th1/Th2、Th17/Treg作为一个观察整体,从而比单纯研究某类细胞的变化来推断SLE疾病状态更加科学系统,为SLE的发病机制和治疗提供新的思路。
[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.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R593.241
本文编号：2185395
[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.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R593.241
【参考文献】
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1 黄华;陈勇;楼燕如;黄娴倩;忻霞菲;周丽;王庭辉;覃文;;Th17/Treg在系统性红斑狼疮患者中的探讨[J];现代实用医学;2014年09期
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