Th17/Treg免疫平衡在特发性膜性肾病发病中的作用及环孢素A对其影响
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摘要
背景和目的
特发性膜性肾病(IMN)是成人肾病综合征(NS)的常见病因之一。IMN的发病机制目前尚不完全清楚。来自人类和Heymann'肾炎的研究表明,它是一种B细胞活化、抗原抗体介导的器官特异的自身免疫疾病。动物实验证实,CD4+T细胞在Heymann1肾炎的发病中起到重要作用。CD4+辅助性T细胞(Th)是一类重要的免疫调节细胞,它对维持机体的免疫平衡发挥重要作用。传统观念将CD4+Th细胞分为Thl和Th2两类细胞亚群。近年来,人们发现另外两类新的Th细胞亚群,即调节性T细胞(Treg)和辅助T细胞17(Th17)。Treg和Th17细胞都来源于初始T细胞,两者的功能和分化过程相互对抗,它们在维持机体免疫平衡方面发挥重要作用,是对Thl/Th2免疫平衡理论的重要补充。Th17/Treg免疫失衡在炎症、感染、肿瘤、自身免疫性疾病等多种疾病状态中的报道已有不少,但在NS中的研究尚属少见。此外,环孢素A(CsA)是治疗IMN有效的药物。目前已有报道CsA治疗自身免疫性疾病和器官移植术后对Th17/Treg免疫平衡产生影响,并与临床疗效相关,但尚无CsA治疗IMN对Th17/Treg免疫平衡影响的相关报道。因此,本研究的目的就是要观察IMN患者Th17/Treg免疫平衡的变化,及CsA治疗IMN对Th17/Treg平衡的影响,探讨其与IMN发病机制及治疗反应和预后间的关系。
方法
选择49例临床和病理确诊为IMN,排除各种继发性肾脏疾病的患者为研究对象。28例性别、年龄匹配的健康人为对照组。以流式细胞仪检测外周血辅助T细胞亚群(Treg/Th17/Th1/Th2)、B细胞、T细胞亚群(CD3+、CD4+、CD8+)的计数和／或百分率。流式方法检测Treg表面CD127, CD39和CD73的表达率以Real-time RT-PCR方法检测外周血单个核细胞(PBMC)核转录因子Foxp3和RORyt的表达量。采用ELISA方法检测血浆中细胞因子的水平。体外共培养实验检测IMN患者和正常人外周血CD4+CD25+T细胞的抑制功能。分析Th细胞亚群与相关细胞因子、临床指标间的相关性。免疫组化方法检测肾组织Treg浸润和IL-17的表达。观察19例入组IMN患者经CsA联合糖皮质激素(简称激素)治疗后外周血Treg和Th17细胞及其他T、B淋巴细胞亚群百分率的变化。体外实验观察不同浓度CsA和甲基强的松龙(MP)及二者联合对正常人Treg和Th17细胞的作用。
结果
(1)IMN患者外周血Treg细胞百分率和血浆TGF-β1水平较正常对照显著降低,而Th2、Th17及B细胞百分率、血浆IL-23和IL-17水平显著升高(p<0.05)。核转录因子Foxp3和RORyt在PBMC中的表达量与Treg和Th17的百分率变化趋势相同。
(2)IMN患者血浆TGF-β1与Treg百分率呈明显正相关(r=0.311,p=0.029),而IL-23与Th17百分率也呈明显正相关(r=0.347,p=0.014)
(3)IMN患者外周血Treg表型改变特点：表面功能分子CD39表达率较正常对照显著降低(p<0.05)。但仍然保持CD25高表达和CD127低表达的特点,与对照组无差别。
(4)与正常对照组比较,IMN患者外周血CD4+CD25+T细胞体外抑制CD4+CD25-效应T细胞增殖的能力减低,并且CD4+CD25+T细胞抑制B细胞分泌IgG的能力降低。
(5)IMN患者外周血Th17/Treg比值与尿蛋白呈明显正相关(r=0.294,p=0.036)而与血清白蛋白呈明显负相关(r=-0.323,p=0.024)
(6)根据患者随访6个月时尿蛋白是否达到部分缓解(小于3.5g/24h)将入选病例分为有效组和无效组两组比较,发现无效组治疗前尿蛋白水平、CD4/CD8比值、Th17/Treg比值显著高于有效组(p<0.05)
(7)IMN患者肾组织弥漫表达IL-17,较正常肾组织明显升高(p<0.05)。正常肾组织内未观察到Foxp3+Treg浸润,而部分IMN患者肾间质灶状单个核细胞浸润的部位同时可见Foxp3+Treg细胞浸润,并且伴有肾间质Foxp3+Treg浸润的患者经治疗后绝大部分获得临床缓解。
(8)CsA联合激素治疗IMN随着病情好转,外周血Th17/Treg比值和血浆TGF-β1水平逐渐恢复正常,B细胞和Th2百分率均显著降低。
(9)体外CsA抑制TGF-β诱导Treg的分化和Th17的表达,并随剂量的增加作用增强。甲基强的松龙(MP)与CsA联合作用后,能增强CsA对Th17的抑制,而减轻其对Treg的抑制。
结论
IMN患者体内存在Th17/Treg免疫平衡异常,主要表现为外周血Treg细胞百分率和功能的降低,而Th17细胞的百分率和肾脏局部表达增高。IMN中Th2细胞辅助B细胞过度活化的过程中,Treg细胞的功能缺陷也可能起到一定作用。肾脏局部Treg细胞浸润与预后的关系值得进一步探讨。CsA治疗IMN随着病情好转,外周血Th17/Treg免疫失衡逐渐恢复。体外实验结果显示,激素联合CsA用药更有利于纠正Th17/Treg免疫失衡,但其具体机制尚需进一步探讨。
Background and Objective
Idiopathic membranous nephropathy (IMN) is the leading cause of nephrotic syndrome in adults. However,the precise mechanisms involved in IMN have not been clear.Data from studies in human and Heymann nephritis indicated that, MN is a conceptually simple organ-specific autoimmune disease,which involve T and B lymphocytes dysfunction.CD4+T helper(Th) cells play important roles in regulation of autoimmunity in vivo. Traditionally, CD 4+Th cells had been divided into two types of subsets:type 1 and type2. Recently, regulatory T cells (Treg) cells and Thl7 cells have been described as two distinct subsets from Thl and Th2 cells.Treg and Th17 cells,both of which gerated from naive CD4+T cells, play opposite roles and restrain each other.The balance between Th17 and Treg may be important in the development/prevention of autoimmunity. It has been reported that Th17/Treg imbalance exists in inflammation, infection, tumour and autoimmue diseases.However, it is not clare wether it exisits in nephrotic syndrome,especial membranous nephropathy. In addition, cyclosporine A (CsA) is considered as an effective treatment with IMN.Several studies had been focused on the influence of immunosuppressive drugs on Th17/Treg balance in posttraplant patients, and the influence in IMN has not been investigated. So, the objective of this study was to evaluate whether the Th17/Treg balance was broken in IMN patients, and how CsA impacts the Thl7/Treg balance during treating IMN.
Methods
Fourty-nine patients, diagnosted IMN by renal biopsy and exluded potential secondary factors, were enrolled in this study.Twenty-eight age-and sex-matched healthy volunteers served as healthy controls(HC).The frequencies of peripheral Th cell subsets(Treg/Thl7/Thl/Th2),B cells and T cell subsets(CD3+,CD4+,CD8+)were evaluated in IMN patients and HC by flow cytometry.The expression of CD127,CD39 and CD73 were also evaluated by flow cytometry.The peripheral relative mRNA
expression of key transcription factors for Treg and Th17, Foxp3 and RORyt,were determined by real-time RT-PCR assay. The concentrations of plasma cytokines were evaluated by ELISA. Proliferation assay were performed on isolated CD4+CD25+T cells and/or target lymphocytes.Correlations between CD4+Th subpopulations and plasma cytokines or clinical manifestations in IMN patients were analized.The infiltration of Treg cells and expression of IL-17 in renal tissue from HC and IMN patients were determined by immunohistochemical staining. Nineteen patients with IMN who received CsA plus corticosteroids treatment were evaluated the changes of peripheral Treg, Th17 and T, B subpopulations over six months. In addition, we observed the influence of diferent concentrations of CsA or/and Methylprednisolone (MP) on Treg and Thl7 cells in vitro.
Results
(1) Compared with healthy controls, the frequency of peripheral Treg cells and plasma TGF-β1 level decreased,while the frequencies of Th2,Th17, B lymphocytes and plasma IL-23, IL-17 levels increased significantly in IMN patients(p<0.05).The key transcription factors of Treg and Th17, Foxp3 and RORyt, had similar alterations in HC and IMN patients.
(2) TGF-β1 concentrations were positively correlated with peripheral blood frequencies of Treg (r=0.311,p=0.029) and IL-23 concentrations were positively correlated with peripheral blood frequencies of Th17 (r=0.347,P=0.014) in IMN patients.
(3) Alterations of Treg cell surface markers in IMN patients:the frequency of CD39 markly decreased, while the expression of CD25 and CD127 had no difference with controls.
(4) The peripheral CD4+CD25+Treg cells from IMN patients exhibited a decreased inhibition of CD4+CD25-effect T cells proliferation and B cells secretion of IgG.
(5) The Th17/Treg ratios increased along with increased proteinuria(r=0.294,P=0.036) and decreased albumin levels (r=-0.323,p=0.024) in patients with IMN.
(6) Patients were divided into two groups based on the response to therapy after 6 months. Data showed that patients who have no response to treatment had a higher proteinuria level, CD4/CD8 ratio and Th17/Treg ratio than those who had good response to treatment.
(7) IL-17 protein expression in the renal tissue of IMN patients increased significantly compared with that in control subjects (p<0.05). Infiltration of Treg cells was also detected in the renal tissue of IMN patients, while rare Treg cells had been seen in normal renal tissue. Treg cells allways located in renal interstitium along with other type of lymphocytes in IMN potients. The infiltration of Treg cells in renal interstitium also related to a higher clinical remmision in IMN patients.
(8) IMN patients receiving CsA plus corticosteroids therapy showed a significant decrease of Th17/Treg ratio, peripheral frequencies of B cells and Th2 cells, as well as obvious increase of plasma TGF-β1 level along with the decrease of proteinuria level.
(9) CsA inhibited the differentiation of Treg cells induced by TGF-β, as well as the IL-17 expressing T cells in vitro. In addition, MP could enhance the inhibition of Thl7 cells, and alleviate the inhibition of Treg cell differentiation by CsA.
Conclusions
Th17/Treg imbalance, charactered by enhanced peripheral and local Th17 function and weakened Treg function, existed in IMN patients. Altered function of Treg cells may contributed to activating of B cells by Th2 cytokines. The clinical meaning of infiltration of Treg cells in renal tissue deserved further studies in IMN patients. With the decrease of proteinuria, the peripheral Th17/Treg imbalance recovered after effective CsA plus corticosteroids therapy in IMN patients. MP plus CsA had more benefit to maintain Th17/Treg balance in vitro experiment of which the exact mechanisms need further explorations.
特发性膜性肾病(IMN)是成人肾病综合征(NS)的常见病因之一。IMN的发病机制目前尚不完全清楚。来自人类和Heymann'肾炎的研究表明,它是一种B细胞活化、抗原抗体介导的器官特异的自身免疫疾病。动物实验证实,CD4+T细胞在Heymann1肾炎的发病中起到重要作用。CD4+辅助性T细胞(Th)是一类重要的免疫调节细胞,它对维持机体的免疫平衡发挥重要作用。传统观念将CD4+Th细胞分为Thl和Th2两类细胞亚群。近年来,人们发现另外两类新的Th细胞亚群,即调节性T细胞(Treg)和辅助T细胞17(Th17)。Treg和Th17细胞都来源于初始T细胞,两者的功能和分化过程相互对抗,它们在维持机体免疫平衡方面发挥重要作用,是对Thl/Th2免疫平衡理论的重要补充。Th17/Treg免疫失衡在炎症、感染、肿瘤、自身免疫性疾病等多种疾病状态中的报道已有不少,但在NS中的研究尚属少见。此外,环孢素A(CsA)是治疗IMN有效的药物。目前已有报道CsA治疗自身免疫性疾病和器官移植术后对Th17/Treg免疫平衡产生影响,并与临床疗效相关,但尚无CsA治疗IMN对Th17/Treg免疫平衡影响的相关报道。因此,本研究的目的就是要观察IMN患者Th17/Treg免疫平衡的变化,及CsA治疗IMN对Th17/Treg平衡的影响,探讨其与IMN发病机制及治疗反应和预后间的关系。
方法
选择49例临床和病理确诊为IMN,排除各种继发性肾脏疾病的患者为研究对象。28例性别、年龄匹配的健康人为对照组。以流式细胞仪检测外周血辅助T细胞亚群(Treg/Th17/Th1/Th2)、B细胞、T细胞亚群(CD3+、CD4+、CD8+)的计数和／或百分率。流式方法检测Treg表面CD127, CD39和CD73的表达率以Real-time RT-PCR方法检测外周血单个核细胞(PBMC)核转录因子Foxp3和RORyt的表达量。采用ELISA方法检测血浆中细胞因子的水平。体外共培养实验检测IMN患者和正常人外周血CD4+CD25+T细胞的抑制功能。分析Th细胞亚群与相关细胞因子、临床指标间的相关性。免疫组化方法检测肾组织Treg浸润和IL-17的表达。观察19例入组IMN患者经CsA联合糖皮质激素(简称激素)治疗后外周血Treg和Th17细胞及其他T、B淋巴细胞亚群百分率的变化。体外实验观察不同浓度CsA和甲基强的松龙(MP)及二者联合对正常人Treg和Th17细胞的作用。
结果
(1)IMN患者外周血Treg细胞百分率和血浆TGF-β1水平较正常对照显著降低,而Th2、Th17及B细胞百分率、血浆IL-23和IL-17水平显著升高(p<0.05)。核转录因子Foxp3和RORyt在PBMC中的表达量与Treg和Th17的百分率变化趋势相同。
(2)IMN患者血浆TGF-β1与Treg百分率呈明显正相关(r=0.311,p=0.029),而IL-23与Th17百分率也呈明显正相关(r=0.347,p=0.014)
(3)IMN患者外周血Treg表型改变特点：表面功能分子CD39表达率较正常对照显著降低(p<0.05)。但仍然保持CD25高表达和CD127低表达的特点,与对照组无差别。
(4)与正常对照组比较,IMN患者外周血CD4+CD25+T细胞体外抑制CD4+CD25-效应T细胞增殖的能力减低,并且CD4+CD25+T细胞抑制B细胞分泌IgG的能力降低。
(5)IMN患者外周血Th17/Treg比值与尿蛋白呈明显正相关(r=0.294,p=0.036)而与血清白蛋白呈明显负相关(r=-0.323,p=0.024)
(6)根据患者随访6个月时尿蛋白是否达到部分缓解(小于3.5g/24h)将入选病例分为有效组和无效组两组比较,发现无效组治疗前尿蛋白水平、CD4/CD8比值、Th17/Treg比值显著高于有效组(p<0.05)
(7)IMN患者肾组织弥漫表达IL-17,较正常肾组织明显升高(p<0.05)。正常肾组织内未观察到Foxp3+Treg浸润,而部分IMN患者肾间质灶状单个核细胞浸润的部位同时可见Foxp3+Treg细胞浸润,并且伴有肾间质Foxp3+Treg浸润的患者经治疗后绝大部分获得临床缓解。
(8)CsA联合激素治疗IMN随着病情好转,外周血Th17/Treg比值和血浆TGF-β1水平逐渐恢复正常,B细胞和Th2百分率均显著降低。
(9)体外CsA抑制TGF-β诱导Treg的分化和Th17的表达,并随剂量的增加作用增强。甲基强的松龙(MP)与CsA联合作用后,能增强CsA对Th17的抑制,而减轻其对Treg的抑制。
结论
IMN患者体内存在Th17/Treg免疫平衡异常,主要表现为外周血Treg细胞百分率和功能的降低,而Th17细胞的百分率和肾脏局部表达增高。IMN中Th2细胞辅助B细胞过度活化的过程中,Treg细胞的功能缺陷也可能起到一定作用。肾脏局部Treg细胞浸润与预后的关系值得进一步探讨。CsA治疗IMN随着病情好转,外周血Th17/Treg免疫失衡逐渐恢复。体外实验结果显示,激素联合CsA用药更有利于纠正Th17/Treg免疫失衡,但其具体机制尚需进一步探讨。
Background and Objective
Idiopathic membranous nephropathy (IMN) is the leading cause of nephrotic syndrome in adults. However,the precise mechanisms involved in IMN have not been clear.Data from studies in human and Heymann nephritis indicated that, MN is a conceptually simple organ-specific autoimmune disease,which involve T and B lymphocytes dysfunction.CD4+T helper(Th) cells play important roles in regulation of autoimmunity in vivo. Traditionally, CD 4+Th cells had been divided into two types of subsets:type 1 and type2. Recently, regulatory T cells (Treg) cells and Thl7 cells have been described as two distinct subsets from Thl and Th2 cells.Treg and Th17 cells,both of which gerated from naive CD4+T cells, play opposite roles and restrain each other.The balance between Th17 and Treg may be important in the development/prevention of autoimmunity. It has been reported that Th17/Treg imbalance exists in inflammation, infection, tumour and autoimmue diseases.However, it is not clare wether it exisits in nephrotic syndrome,especial membranous nephropathy. In addition, cyclosporine A (CsA) is considered as an effective treatment with IMN.Several studies had been focused on the influence of immunosuppressive drugs on Th17/Treg balance in posttraplant patients, and the influence in IMN has not been investigated. So, the objective of this study was to evaluate whether the Th17/Treg balance was broken in IMN patients, and how CsA impacts the Thl7/Treg balance during treating IMN.
Methods
Fourty-nine patients, diagnosted IMN by renal biopsy and exluded potential secondary factors, were enrolled in this study.Twenty-eight age-and sex-matched healthy volunteers served as healthy controls(HC).The frequencies of peripheral Th cell subsets(Treg/Thl7/Thl/Th2),B cells and T cell subsets(CD3+,CD4+,CD8+)were evaluated in IMN patients and HC by flow cytometry.The expression of CD127,CD39 and CD73 were also evaluated by flow cytometry.The peripheral relative mRNA
expression of key transcription factors for Treg and Th17, Foxp3 and RORyt,were determined by real-time RT-PCR assay. The concentrations of plasma cytokines were evaluated by ELISA. Proliferation assay were performed on isolated CD4+CD25+T cells and/or target lymphocytes.Correlations between CD4+Th subpopulations and plasma cytokines or clinical manifestations in IMN patients were analized.The infiltration of Treg cells and expression of IL-17 in renal tissue from HC and IMN patients were determined by immunohistochemical staining. Nineteen patients with IMN who received CsA plus corticosteroids treatment were evaluated the changes of peripheral Treg, Th17 and T, B subpopulations over six months. In addition, we observed the influence of diferent concentrations of CsA or/and Methylprednisolone (MP) on Treg and Thl7 cells in vitro.
Results
(1) Compared with healthy controls, the frequency of peripheral Treg cells and plasma TGF-β1 level decreased,while the frequencies of Th2,Th17, B lymphocytes and plasma IL-23, IL-17 levels increased significantly in IMN patients(p<0.05).The key transcription factors of Treg and Th17, Foxp3 and RORyt, had similar alterations in HC and IMN patients.
(2) TGF-β1 concentrations were positively correlated with peripheral blood frequencies of Treg (r=0.311,p=0.029) and IL-23 concentrations were positively correlated with peripheral blood frequencies of Th17 (r=0.347,P=0.014) in IMN patients.
(3) Alterations of Treg cell surface markers in IMN patients:the frequency of CD39 markly decreased, while the expression of CD25 and CD127 had no difference with controls.
(4) The peripheral CD4+CD25+Treg cells from IMN patients exhibited a decreased inhibition of CD4+CD25-effect T cells proliferation and B cells secretion of IgG.
(5) The Th17/Treg ratios increased along with increased proteinuria(r=0.294,P=0.036) and decreased albumin levels (r=-0.323,p=0.024) in patients with IMN.
(6) Patients were divided into two groups based on the response to therapy after 6 months. Data showed that patients who have no response to treatment had a higher proteinuria level, CD4/CD8 ratio and Th17/Treg ratio than those who had good response to treatment.
(7) IL-17 protein expression in the renal tissue of IMN patients increased significantly compared with that in control subjects (p<0.05). Infiltration of Treg cells was also detected in the renal tissue of IMN patients, while rare Treg cells had been seen in normal renal tissue. Treg cells allways located in renal interstitium along with other type of lymphocytes in IMN potients. The infiltration of Treg cells in renal interstitium also related to a higher clinical remmision in IMN patients.
(8) IMN patients receiving CsA plus corticosteroids therapy showed a significant decrease of Th17/Treg ratio, peripheral frequencies of B cells and Th2 cells, as well as obvious increase of plasma TGF-β1 level along with the decrease of proteinuria level.
(9) CsA inhibited the differentiation of Treg cells induced by TGF-β, as well as the IL-17 expressing T cells in vitro. In addition, MP could enhance the inhibition of Thl7 cells, and alleviate the inhibition of Treg cell differentiation by CsA.
Conclusions
Th17/Treg imbalance, charactered by enhanced peripheral and local Th17 function and weakened Treg function, existed in IMN patients. Altered function of Treg cells may contributed to activating of B cells by Th2 cytokines. The clinical meaning of infiltration of Treg cells in renal tissue deserved further studies in IMN patients. With the decrease of proteinuria, the peripheral Th17/Treg imbalance recovered after effective CsA plus corticosteroids therapy in IMN patients. MP plus CsA had more benefit to maintain Th17/Treg balance in vitro experiment of which the exact mechanisms need further explorations.
引文
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