BAFF、CD200、调节T细胞与Th17细胞在系统性红斑狼疮发病机制中的意义初探
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摘要
背景和目的
系统性红斑狼疮(systemic lupus erythematosus, SLE)是经典的、慢性、多系统受累的自身免疫病,B细胞的异常活化及分化是SLE的特征之一。B细胞通过产生自身抗体介导组织损伤,递呈抗原给自身反应性T细胞,以及产生可溶性介质触发和维持炎症反应等参与SLE发病机制的多个环节。
B细胞的发育、分化和功能受到B细胞活化因子(B cell activating factor belonging to TNF family, BAFF)这一TNF超家族成员的调节。BAFF通过与其受体结合,提供B细胞生存信号、促进Ig类别转换,并促使B细胞向ISC (immunoglobulin secreting cells)分化。BAFF过表达可使自身反应性B细胞有可能克服自身抗原触发的强死亡信号,促使异常的ICS长期存活免于凋亡,从而参与SLE的发病和维持。APRIL作为BAFF(?)的同源分子与其共享某些生物功能。
已有多篇报道对自身免疫病中BAFF的表达情况进行了探索,但这一领域内研究结果存在较多分歧。造成分歧的一个可能原因是分析时未对患者在入组前是否已接受治疗加以考虑。
在本研究中,我们试图分析BAFF、APRIL及其受体BR3 (BAFF receptor, BAFF-R, BR3)、BCMA (B cell maturation antigen)和TACI (transmembrane activater of and calcium modulator and cyclophilin ligand interactor)在SLE患者不同组群中的表达差异及其与临床特征的相关性,探索BAFF及其受体在SLE临床谱中的表达规律,深化我们对BAFF在SLE发病机制中作用和地位的认识,并为BAFF拮抗剂的靶向性治疗提供更多依据。
研究方法
明确诊断为SLE的患者73人,同期选取年龄性别匹配的健康对照28人,采集抗凝外周静脉血分离单个核细胞。
流式细胞术检测外周血PBMC中BR3、TACI和BCMA在B细胞及其各亚群中的表达。
ELISA法检测血浆BAFF和APRIL的水平。
荧光定量PCR法检测BR3、TACI和BCMA的mRNA水平。
外源性BAFF共培养测定BAFF对BR3、TACI和BCMA表达的影响。
收集患者临床资料,按照SLEDAI 2000评分体系评价患者疾病活动度,按照初治vs.经治、活动vs.稳定、治疗前vs.治疗后以及脏器受累情况分组评价。
结果
1. SLE患者血浆BAFF水平较健康对照显著增高(2111.59±220.08pg/ml vs. 914.84±43.66pg/ml, p0.001),在初治活动性狼疮患者中BAFF的增高最为明显(3403.89±640.65pg/ml,p<0.001)。BAFF水平与SLEDAI评分正相关(p=0.018),治疗反应佳者治疗后BAFF水平下降(p=0.026)。
2. SLE患者外周血B细胞上可检测到的BR3受体表达水平较健康对照显著下调(p<0.001),且与血浆BAFF水平负相关(p=0.022)。可检测到的BR3表达在B细胞各亚群包括初始B细胞(CD19+IgD+CD27-)、类别转换前记忆B细胞(CD19+IgD+CD27+)和类别转换后记忆B细胞(CD19+IgD-CD27+)中均等下调。BR3的下调在活动性狼疮患者较不活动狼疮患者更明显(p=O.013),经治狼疮较初治狼疮更明显(p=0.018),有肾脏受累者较无肾脏受累者更明显(p=0.002)。在未经治疗的初治患者中B细胞上BR3的表达率与SLEDAI评分负相关(p=0.002),与C3水平正相关(p=0.028)。
3.有肾脏受累的SLE患者外周血B细胞表达TACI的比例增高,高于健康对照和无肾脏受累者(p<0.05),特别是有肾脏受累的初治患者尤为明显(p=0.001),狼疮肾炎患者免疫治疗后TACI表达下降(p=0.007)。
4. BCMA在外周血的表达少或无,但SLE患者B细胞中BCMA的表达有上调趋势(p=0.032)。有肾脏受累的患者反而有所减少。CD19+BCMA+细胞比例与SLE患者抗dsDNA抗体滴度和SLEDAI评分有负相关趋势(p=0.035和p=0.019)。
5. SLE患者BR3 mRNA和BCMA mRNA水平与健康对照相比无显著差异(p均>0.05),TACI mRNA上调(p=0.023)。
6.高水平的BAFF可导致健康对照外周血B细胞上可检测到的BR3下调。
结论
SLE患者血浆BAFF水平明显增高和B细胞上BR3表达下调,可作为病情活动的标志物。BR3是外周血B细胞上表达的最主要的BAFF受体。PBMC中BR3mRNA的水平SLE患者与健康对照并无差异,高表达BR3的健康对照PBMC在与BAFF孵育后出现BR3下调,推测SLE患者外周血B细胞上BR3的实际表达水平与健康对照可能并无差异,而由于高水平BAFF占据其结合位点导致可检测到的BR3蛋白水平下调,提示BAFF/BR3通路在SLE患者中存在过度激活,这种BAFF/BR3通路的过度激活在活动性狼疮患者和肾脏受累的狼疮患者中更为显著。而TACI的表达上调与狼疮肾炎密切相关。初治活动特别是有肾脏受累的狼疮患者有可能从BAFF拮抗剂的靶向治疗中获益最大。
背景和目的
T辅助细胞功能异常在SLE多重免疫紊乱中占有重要地位,近年来对T辅助细胞亚群成员的认识拓展至Th1、Th2、Treg和Th17,几个亚群的Th细胞在发育和功能上既相互联系,又相互牵制,其分泌的细胞因子构成调控免疫的细胞网络和细胞因子网络：Thl分泌IFNγ、IL-2、TNF-α、IL-12等细胞因子,参与巨噬细胞活化,刺激细胞毒T细胞的增殖和分化,参与细胞免疫；Th2能分泌IL-4、IL-5、IL-10、IL-13等细胞因子,促进B细胞的增殖、分化和抗体生成,参与体液免疫；Treg细胞能分泌TGF-β和IL-10,具有增殖无能的特点并能够通过细胞间接触抑制效应T细胞增殖而具有免疫调节作用。Th17则能分泌IL-17、IL-22等,参与抗感染免疫,促进炎症,参与组织损伤和炎症性骨破坏,Th17在类风湿关节炎、炎症性肠病和多发性硬化等疾病中的作用逐渐为人们所认识。SLE中Treg和Th17的研究也是近年来研究的热点,本研究通过胞内核转录因子Foxp3和胞内细胞因子(IFNγ、IL-4、IL-17)染色进行流式细胞仪检测初步分析T辅助细胞比例失衡与SLE临床疾病谱的相关性。
研究方法
明确诊断为SLE的患者46人,同期选取年龄性别匹配的健康对照29人,采集抗凝外周静脉血分离单个核细胞PBMC。
PBMC进行CD4和CD25表面染色和胞内Foxp3染色,流式细胞仪检测。
PBMC在RPMI 1640完全培养基中与PMA、Ionomycin共培养,刺激胞内细胞因子分泌,并加入Golgiplug阻断细胞因子释放,进行胞内细胞因子IFNγ、IL-4.IL-17染色及膜表面CD4染色,流式细胞仪检测。
收集患者临床资料,按照SLEDAI 2000评分体系评价患者疾病活动度,并按疾病活动性及脏器受累情况分组评价。
结果
1.活动性狼疮患者Thl细胞在T辅助亚群中的比例显著高于健康对照(15.20±1.62%vs.10.85±1.05%,p=0.041)。未发现不同脏器受累者之间存在差异。
2. SLE患者T辅助细胞亚群中Th2细胞的比例较健康对照显著增高(3.20±0.62%vs.1.01±0.19%,p=0.021),但不与抗dsDNA抗体滴度、C3、IgG相关,也未发现病情活动与不活动者之间及不同脏器受累者之间有统计学差异。短期随访(n=7)未发现与治疗前后有显著差异(p=0.398)。
3.活动性狼疮患者T辅助细胞中Th17比例高于健康对照组和不活动狼疮组(2.20±0.21 vs.1.53±O.16%和1.32±0.19%,p=0.011和p=0.010)；初发SLE患者高于经治SLE患者(2.29±0.26vs.1.58±0.18%,p=0.019)；合并狼疮肾炎的患者高于无狼疮肾炎的患者(2.56±0.34%vs.1.59±0.14%,p=0.002)；合并NPSLE患者也可观察到CD4+T中Th17的比例高于健康对照(p=0.026),但与无NPSLE的患者相比差异不显著(p=0.122)。
4.Th17在CD4+T细胞中所占的比例与SLEDAI评分和抗dsDNA抗体滴度正相关(p=0.008和p<0.001),而与C3水平负相关(p=0.005)；
5. SLE患者CD4+T细胞中Treg的比例与健康对照相比无显著差异(p=0.058),合并NPSLE的SLE患者Treg占CD4的比例较健康对照增高(5.42±1.14%vs.3.1±0.28%,p=0.02),CD4+CD25-Foxp3+细胞所占CD4+T细胞的比例显著高于健康对照(P<0.001),各个亚组之间无显著差异。
6. SLE患者中Th17/Treg比例与C3水平负相关(p=0.038),而与抗dsDNA水平正相关(p=O.012)。
结论
SLE患者存在T辅助亚群比例失调,Th2细胞比例增高,可能是B细胞过度活化和自身抗体的持续产生的机制之一。活动性SLE患者伴有Th1和Th17细胞比例增高,T辅助细胞中Th17的比例与病情活动度和肾脏受累相关,提示Th17在SLE发病机制和脏器受累中发挥重要作用。尽管合并脑病的SLE患者出现调节性T细胞比例增高,但SLE患者整体的Treg水平与健康对照无显著差异,合并脑病的患者中的增高可能是一种保护机制。SLE患者中CD4+CD25-Foxp3+T细胞增多,该群细胞性质未明,可能是效应性T细胞。
背景和目的
CD200是表达于多种免疫和炎症相关细胞类型上的I型膜糖蛋白。CD200可表达于树突细胞、内皮细胞、活化T细胞等,与其受体CD200R结合可传递免疫调节信号,在实验动物中可参与调节免疫应答阈值和细胞因子产生极向,参与维持免疫稳态,防止移植排斥和自身免疫疾病。目前对CD200/CD200R轴的研究多局限于动物,主要集中在CIA、EAE等自身免疫病模型以及对肥大细胞和巨噬细胞功能影响方面研究。对其人体内的生物学功能的认知还十分有限,在SLE中的作用罕有报道。在本实验室的前期工作中发现CD200 mRNA和CD200R mRNA在SLE患者表达降低,表达CD200的PBMC比例增高,为探讨CD200蛋白在SLE中增高的意义进行本研究。本研究就CD200信号是否对T辅助亚群的比例平衡产生调节和影响以及CD200信号通路对PBMC增殖的影响进行了探讨。
方法
SLE患者和健康对照PBMC与CD200Fc、CD200R1 Fc和anti-CD200R1共培养48小时,胞内细胞染色流式细胞术测定T辅助亚群中Th1、Th2、Th17和Treg的比例变化；ELISA法测定培养上清中IL-17的水平。
PBMC经CFSE标染后分别给予CD200 Fc、CD200R1 Fc或anti-CD200R1共培养96小时,或给予PHA、抗CD3/CD28刺激增殖,同时加入CD200 Fc、CD200R1Fc或anti-CD200R1共培养96小时激活或阻断CD200信号通路,流式细胞术检测增殖情况。
结果
1. SLE患者血清游离CD200水平较健康对照增高(306.60±72.63pg/ml vs. 109.48±23.39pg/ml, p=0.001),经免疫抑制治疗后下降至正常(140.32±31.58pg/ml,与治疗前相比p<0.001)。
2. CD200信号对于健康对照T辅助细胞的比例平衡影响较小,但大剂量CD200R1 Fc可使Thl细胞比例增加(p=0.043),而CD200 Fc可使SLE患者Th17细胞比例减低(p=0.046)。
3. PBMC与CD200 Fc、CD200R1 Fc和anti-CD200R1共培养后培养上清的IL-17水平无明显改变。
4. CD200 Fc或CD200R1 Fc对PBMC自发增殖和PHA或抗CD3/CD28刺激下的增殖无明显影响。但在SLE患者中可观察到anti-CD200R1增强抗CD3/CD28刺激PBMC增殖作用的现象。
结论
SLE患者血清中游离的CD200增高,经过激素和免疫抑制药物治疗后下降至正常。CD200 Fc、CD200R Fc和antiCD200R1对健康对照外周血T辅助细胞亚群的比例调节作用较小,而在SLE患者中,CD200通路活化可使Th17细胞比例减低,阻断CD200信号通路则可使Thl细胞比例增高,CD200信号通路参与SLE患者T辅助细胞亚群的比例调节。体外增殖实验中,anti-CD200R1阻断CD200R信号可对抗CD3/CD28刺激的PBMC增殖起到促进作用。CD200信号通路在SLE患者中的增高具有一定保护意义。
Background
SLE (systemic lupus erythematosus) is a chronic, multisystem-involved typical autoimmune disease in which abnormally activated and differentiated B cells act as one of the important characteristics of SLE. B cells not only function as effector cells by producing autoantibodies and secreting inflammatory mediators to trigger, sustain and expand immune response, but also act as antigen presenting cells to activate T cells, so B cells contribute a great deal to the pathogenesis of SLE.
BAFF (B cell activating factor belonging to TNF family), also known as BLys (B-lymphocyte stimulator), was discovered in 1999 as a new member of TNF (tumor necrosis factor) superfamily of ligands. Through binding to its receptors, BAFF exerts potent stimulation to B cells, regulates the differentiation and maturation of B cells, promotes isotype switch, supports the survival of B cells and spares plasma cells from apoptosis. Over-expression of BAFF may help auto-reactive B effector cells overcome "death signal" triggered by autoantigen which may be involved in the onset and development of SLE. APRIL shares some functions with BAFF.
Although several literatures have reported the status of BAFF expression in autoimmune disease, the results are divergent and controversial. One possible reason for the discrepancy might be that patients had received immunosuppressive treatment before being recruited, and this was not considered as an influential.factor.
In this research, we tried to analyze the differences in BAFF, APRIL as well as their receptors BR3 (BAFF receptor, BAFF-R, BR3), BCMA(B cell maturation antigen) and TACI (transmembrane activater of and calcium modulator and cyclophilin ligand interactor) in different subgroups of SLE patients. We also analyzed the correlations of these items with clinical manifestations, hoping to expand our knowledge about BAFF and its role in the pathogenesis of SLE and provide some evidence for selecting candidates for BAFF-targeting therapy.
Method
Seventy-three patients diagnosed of SLE were recuited. Twenty-eight sex and age matched health volunteers were accepted as health controls (HC). Anti-coagulated peripheral blood was collected and mononuclear cells were isolated.
Expression of BR3, TACI and BCMA on peripheral B cells were detected by flow cytometer.
Plasma BAFF levels and APRIL levels were detected by ELISA.
BR3 mRNA, TACI mRNA and BCMA mRNA were measured and quantified by real-time polymerase chain reaction.
Coculture of health PBMC with exogenous recombinant human BAFF was processed to investigate the influence of elevated BAFF on expressions of its recetpors.
Clinical data was collected and disease activity was evaluated according to SLEDAI 2000 system. Patients were classified into subgroups according to organ involvement and/or status of medical treatment and/or SLEDAI scores。
Results
1. SLE patients had higher BAFF levels in their plasma than health controls. (2111.59±220.08pg/ml vs.914.84±43.66pg/ml, p<0.001). And in new-onse patients with active disease, BAFF was especially high (3403.89±640.65pg/ml, p<0.001). BAFF levels correlated positively with SLEDAI scores (p=0.018) and reduced after effective treatment (p=0.026).
2. Detectable BR3 protein on peripheral B cells was significantly down-regulated in SLE patients compared to HC (p<0.001) and correlated negatively with plasma BAFF levels (p=0.022). The down-regulation of detectable BR3 was parallel among CD19+IgD+CD27- naive B cells, CD19+IgD+CD27+pre-switch memory B cells and CD19+IgD-CD27+ post-switch B cells and was more distinguished in patients with active disease than those with inactive disease (p=0.013). Post-therapeutic patients had less detectable BR3 than new-onset patient (p=0.018), so did patients with lupus nephritis (LN) than those without (p=0.002). For new-onset patients, expression of BR3 on B cells correlated negatively with SLEDAI (p=0.002) and positively with C3 level (p=0.028).
3. Patients with LN had higher expression rate of TACI on peripheral B cells than HC and those patients without LN (p<0.05). TACI expression rate was expecially high in those new-onset patheints with LN (p=0.001) and reduced after immunosuppressive therapy (p=0.007).
4. Only low levels of BCMA on developing B lymphocytes had been demonstrated in our study. But a trendency of up-regulation of BCMA expression on B cells in patients can be observed (p=0.032). And the percentage of CD 19+BCMA+ cells tended to correlate with the titers of anti-dsDNA and SLEDAI scores (p=0.035 and p=0.019). What's more, those without lupus nephritis had higher percentage of this group of cells.
5. No significant differences of BR3 mRNA and BCMA mRNA level were found between SLE patients and HC. But SLE patients had higher TACI mRNA expression than HC (p=0.023).
6. Eleavated BAFF may result more binding with BR3 which in turn caused down-regulation of detectable BR3 protein on B cell surface.
Conclusions
Higher levels of BAFF and less expression of BR3 were prominent in SLE patients, and they could act as biomarkers for active disease. BR3 was the fundamental receptor of BAFF which was expressed exclusively on B cells. The actual BR3 expression may not differ between SLE patients and health controls and the down-regulation of detected BR3 may due to prior occupation by elevated BAFF. BAFF/BR3 axis may be over-activated in SLE patients since lower BR3 detection means more binding of BAFF with BR3 which was more distinguished in patients with active disease and patients with lupus nephritis. Up-regulation of TACI in SLE patients was significant in patients with LN. New-onset SLE patients with active disease especially those with nephritis may benefit the most from BAFF-targeting therapy.
Background
Malfunction of T helper cells plays a central role in the immunological disorders in Systemic lupus erythematosus. Except for well-known Thl and Th2 cells, two new members have joined T helper family, which are T regulatory cell and T helper 17 cells. These four subgroups not only connect with each other on their origin, but also restrict with each other on their development and function. Cytokines secreted by them constitute a network:Thl can secret IFNγ、IL-2、TNF-α、IL-12, induce the activation of macrophage and stimulate the development and proliferation of cytotoxic T cells, thus participate in cellular immunity; Th2 can secret IL-、IL-5、IL-10、IL-13, stimulte B cells to proliferate and produce antibody, thus paticipate in humoral immuity; Treg possesses anergic property and is capable of suppressing the proliferation of T effector cells by cell contact. But Treg is also capable of secreting cytokines like TGF-βand IL-10 to enhance immunoregulation. Thl7 cells were named for its capability of secreting IL-17. IL-17 and other cytokines secreted by Th17 like IL-22 are pro-inflammatory cytokines that are involved in anti-infections immunity, tissue damage and inflammatory osteocalsia. Now the pathogenetic role of Th17 in rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis was recognized. But its role in SLE is rather ambiguous. In this research, through intracellure cytokines staining, T helper subgroups were identified and their correlations with clinical manifestations were analyzed.
Method
Forty-six patients diagnosed of SLE were recuited. Twenty-nine sex and age matched health volunteers were accepted as health controls (HC). Anti-coagulated peripheral blood was collected and peripheral blood mononuclear cells (PBMC) were isolated.
Surface staining of CD4 and CD25 as well as intracellular Foxp3 were used to indentify Treg cells.
PBMC was cultured in RPMI 1640 complete culture medium with PMA and Ionomycin to stimulate the expression of intracellular cytokines in the presence of protein transport inhibitor-Golgiplug. Thl, Th2 and Th17 cells were identified by the expression of surface CD4 and intracellular cytokine IFNy, IL-4 and IL-17 respectively.
Clinical data was collected, organ involvement was assessed and SLEDAI score was evaluated according to SLEDAI 2000 system.
Results
1. SLE patients with active disease had higher percentage of Thl cells among CD4+T cells than HC (15.20±1.62%vs.10.85±1.05%, p=0.041). No significant difference was found between patients with organ involvement and those without.
2. Percentage of Th2 cells among CD4+T cells increased in SLE patients (3.20±0.62% vs.1.01±0.19%, p=0.021), but did not correlated with the titters of anti-dsDNA antibody, C3 or IgG level. And no difference between patients with active disease and inactive disease was found. And patients with organ involvement did not differ from those without. Short-term follow-up (n=7) showed no significant change ocurred (p=0.398).
3. Patients with active disease had higher percentage of Thl7 cells among CD4+T cells compared with HC and those with inactive disease (2.20±0.21 vs.1.53±0.16% and 1.32±0.19%, p=0.011and p=0.010); Thl7 percentage in CD4+ T cells was higher in new-onset patients than post-therapeutic patients (2.29±0.26% vs. 1.58±0.18%, p=0.019), and higher in those with lupus nephritis than those without (2.56±0.34% vs.1.59±0.14%, p=0.002). Although patients with NPSLE had higher percentage of Th17 cells than HC (p=0.026), they did not differ from those without NPSLE (p=0.122).
4. Percentage of Th17 cells among CD4+T correlated positively with SLEDAI scores and titers of anti-dsDNA (p=0.008 and p<0.001) and correlated negatively with C3 level (p=0.005).
5. No significant difference of Treg percentage was found between SLE patients and HC (p=0.058), although patients with NPSLE tended to have higher percentage of Treg than HC (5.42±1.14% vs.3.1±0.28%, p=0.02). CD4+CD25-Foxp3+ cells significantly increased in SLE patients no matter they were with active disease or not, or with organs involvement or not (P<0.001).
6. The ratio of Th17/Treg correlated negatively with C3 level (p=0.038), while positively with titters of anti-dsDNA antibody (p=0.012).
Conclusion
Imbalance of T helper subgroups exists in SLE patients. SLE patients had higher percentage of Th2 cells, which indicates one of the mechanisms of overactivation of B cells and continuous production of autoantigen. Patients with active disease had higher percentage of Thl and Th17 cells, and increased Th17 cells percentage correlating positively with disease activity and nephritis, indicating the possible pathogenetic role of Thl7 in SLE and organ involvement. Althogh patients with NPSLE tended to have a higher percentage of Treg cells than HC, no significant difference was found between HC and SLE patients as a whole. The increase of Treg in patients with NPSLE may be protective. The significantly increased CD4+CD25-Foxp3+T cells deserved more study to investigate its property.
Background
CD200 is a type I membrane glycoprotein which is expressed on a number of cell types uniquely relevant to the inflammatory and immune cascade including dendritic cells, endothelial cells and activated T cells. Previous studies have shown that CD200 could regulate the activation threshold of inflammatory immune responses, polarize cytokine production and maintain the immune homeostasis. Therefore it plays an important role in prevention of graft rejection, autoimmune diseases and spontaneous abortion. Till now most researches about CD200 have been operated in animal models such as collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). And the studies of CD200/CD200R1 axis have focused on regulating the function of macrophage and mast cells. The knowledge of CD200/CD200R axis in human especially in SLE patients was very limited and lack of report. In the previous study of our lab, CD200 mRNA and CD200R mRNA decreased in SLE patients, yet the percentage of cells in PBMC expressing CD200 increased, indicating an abnormality in CD200 signal. In this research we try to investigate the possible effect of CD200 signal on the proportion of Th cells and on the proliferation of PBMC.
Method
PBMC from SLE patients and health controls were cocultured with CD200Fc、CD200R1 Fc and anti-CD200R1 separately for 48 hours. Intracellular staining was processed and flow cytometry detection was analyzed to determine the change of Thl, Th2, Treg and Th17 cells. The concentration of IL-17 in the supernatant was measured by ELISA.
Certain amount of PBMC were also stained with CFSE under sterile conditions and cocultured with CD200 Fc, CD200R1 Fc or anti-CD200R1 in the presence or absence of stimulator (PHA or anti-CD3/CD28) for 96 hours. The status of proliferation was detected by flow cytometer.
Results
1. Soluble CD200 increased in SLE sera compared with HC (306.60±72.63pg/ml vs. 109.48±23.39pg/ml, p=0.001), but reduced to normal after immunosuppressive therapy (140.32±31.58pg/ml, p<0.001 as compared to before treatment).
2. The effect of CD200 Fc on the balance of T helper cells in health controls was rather negligible. But in SLE patients, CD200R1 Fc could increase the percentage of Thl cells which CD200 Fc could reduce the percentage of Th17 cells.
3. IL-17 levels in culture supernatant did not differ among the groups cocultured with or without CD200 Fc, CD200R1 Fc or anti-CD200R1.
4. Both CD200 Fc and CD200R1 Fc have little influence on the auto-proliferation of PBMC, nor did they have an effect on the proliferation of PBMC under PHA or anti-CD3/CD28 stimulation. But SLE patients may respond to antiCD3/CD28 stimulation more actively in the presence of anti-CD200R1.
Conclusion
SLE patients had higher soluable CD200 in their sera which decreased to normal after immunosuppressive therapy. CD200 Fc, CD200R Fc and anti-CD200R1 had little effect on the proportion of T helper cell subgroups in HC. But in SLE patients, CD200R1 which blocks CD200 could increase the propotion of Thl cells while CD200 Fc could reduce the percentage of Th17 cells although IL-17 levels in culture supernatant were not altered. CD200 signal may take a part in the regulation of T helper cell subgroups. As shown by the proliferation experiment in vitro, anti-CD200R1 may promote the proliferation of PBMC under the stimulation of anti-CD3/CD28. CD200/CD200R1 axis may exert protective function in SLE patients.
系统性红斑狼疮(systemic lupus erythematosus, SLE)是经典的、慢性、多系统受累的自身免疫病,B细胞的异常活化及分化是SLE的特征之一。B细胞通过产生自身抗体介导组织损伤,递呈抗原给自身反应性T细胞,以及产生可溶性介质触发和维持炎症反应等参与SLE发病机制的多个环节。
B细胞的发育、分化和功能受到B细胞活化因子(B cell activating factor belonging to TNF family, BAFF)这一TNF超家族成员的调节。BAFF通过与其受体结合,提供B细胞生存信号、促进Ig类别转换,并促使B细胞向ISC (immunoglobulin secreting cells)分化。BAFF过表达可使自身反应性B细胞有可能克服自身抗原触发的强死亡信号,促使异常的ICS长期存活免于凋亡,从而参与SLE的发病和维持。APRIL作为BAFF(?)的同源分子与其共享某些生物功能。
已有多篇报道对自身免疫病中BAFF的表达情况进行了探索,但这一领域内研究结果存在较多分歧。造成分歧的一个可能原因是分析时未对患者在入组前是否已接受治疗加以考虑。
在本研究中,我们试图分析BAFF、APRIL及其受体BR3 (BAFF receptor, BAFF-R, BR3)、BCMA (B cell maturation antigen)和TACI (transmembrane activater of and calcium modulator and cyclophilin ligand interactor)在SLE患者不同组群中的表达差异及其与临床特征的相关性,探索BAFF及其受体在SLE临床谱中的表达规律,深化我们对BAFF在SLE发病机制中作用和地位的认识,并为BAFF拮抗剂的靶向性治疗提供更多依据。
研究方法
明确诊断为SLE的患者73人,同期选取年龄性别匹配的健康对照28人,采集抗凝外周静脉血分离单个核细胞。
流式细胞术检测外周血PBMC中BR3、TACI和BCMA在B细胞及其各亚群中的表达。
ELISA法检测血浆BAFF和APRIL的水平。
荧光定量PCR法检测BR3、TACI和BCMA的mRNA水平。
外源性BAFF共培养测定BAFF对BR3、TACI和BCMA表达的影响。
收集患者临床资料,按照SLEDAI 2000评分体系评价患者疾病活动度,按照初治vs.经治、活动vs.稳定、治疗前vs.治疗后以及脏器受累情况分组评价。
结果
1. SLE患者血浆BAFF水平较健康对照显著增高(2111.59±220.08pg/ml vs. 914.84±43.66pg/ml, p0.001),在初治活动性狼疮患者中BAFF的增高最为明显(3403.89±640.65pg/ml,p<0.001)。BAFF水平与SLEDAI评分正相关(p=0.018),治疗反应佳者治疗后BAFF水平下降(p=0.026)。
2. SLE患者外周血B细胞上可检测到的BR3受体表达水平较健康对照显著下调(p<0.001),且与血浆BAFF水平负相关(p=0.022)。可检测到的BR3表达在B细胞各亚群包括初始B细胞(CD19+IgD+CD27-)、类别转换前记忆B细胞(CD19+IgD+CD27+)和类别转换后记忆B细胞(CD19+IgD-CD27+)中均等下调。BR3的下调在活动性狼疮患者较不活动狼疮患者更明显(p=O.013),经治狼疮较初治狼疮更明显(p=0.018),有肾脏受累者较无肾脏受累者更明显(p=0.002)。在未经治疗的初治患者中B细胞上BR3的表达率与SLEDAI评分负相关(p=0.002),与C3水平正相关(p=0.028)。
3.有肾脏受累的SLE患者外周血B细胞表达TACI的比例增高,高于健康对照和无肾脏受累者(p<0.05),特别是有肾脏受累的初治患者尤为明显(p=0.001),狼疮肾炎患者免疫治疗后TACI表达下降(p=0.007)。
4. BCMA在外周血的表达少或无,但SLE患者B细胞中BCMA的表达有上调趋势(p=0.032)。有肾脏受累的患者反而有所减少。CD19+BCMA+细胞比例与SLE患者抗dsDNA抗体滴度和SLEDAI评分有负相关趋势(p=0.035和p=0.019)。
5. SLE患者BR3 mRNA和BCMA mRNA水平与健康对照相比无显著差异(p均>0.05),TACI mRNA上调(p=0.023)。
6.高水平的BAFF可导致健康对照外周血B细胞上可检测到的BR3下调。
结论
SLE患者血浆BAFF水平明显增高和B细胞上BR3表达下调,可作为病情活动的标志物。BR3是外周血B细胞上表达的最主要的BAFF受体。PBMC中BR3mRNA的水平SLE患者与健康对照并无差异,高表达BR3的健康对照PBMC在与BAFF孵育后出现BR3下调,推测SLE患者外周血B细胞上BR3的实际表达水平与健康对照可能并无差异,而由于高水平BAFF占据其结合位点导致可检测到的BR3蛋白水平下调,提示BAFF/BR3通路在SLE患者中存在过度激活,这种BAFF/BR3通路的过度激活在活动性狼疮患者和肾脏受累的狼疮患者中更为显著。而TACI的表达上调与狼疮肾炎密切相关。初治活动特别是有肾脏受累的狼疮患者有可能从BAFF拮抗剂的靶向治疗中获益最大。
背景和目的
T辅助细胞功能异常在SLE多重免疫紊乱中占有重要地位,近年来对T辅助细胞亚群成员的认识拓展至Th1、Th2、Treg和Th17,几个亚群的Th细胞在发育和功能上既相互联系,又相互牵制,其分泌的细胞因子构成调控免疫的细胞网络和细胞因子网络：Thl分泌IFNγ、IL-2、TNF-α、IL-12等细胞因子,参与巨噬细胞活化,刺激细胞毒T细胞的增殖和分化,参与细胞免疫；Th2能分泌IL-4、IL-5、IL-10、IL-13等细胞因子,促进B细胞的增殖、分化和抗体生成,参与体液免疫；Treg细胞能分泌TGF-β和IL-10,具有增殖无能的特点并能够通过细胞间接触抑制效应T细胞增殖而具有免疫调节作用。Th17则能分泌IL-17、IL-22等,参与抗感染免疫,促进炎症,参与组织损伤和炎症性骨破坏,Th17在类风湿关节炎、炎症性肠病和多发性硬化等疾病中的作用逐渐为人们所认识。SLE中Treg和Th17的研究也是近年来研究的热点,本研究通过胞内核转录因子Foxp3和胞内细胞因子(IFNγ、IL-4、IL-17)染色进行流式细胞仪检测初步分析T辅助细胞比例失衡与SLE临床疾病谱的相关性。
研究方法
明确诊断为SLE的患者46人,同期选取年龄性别匹配的健康对照29人,采集抗凝外周静脉血分离单个核细胞PBMC。
PBMC进行CD4和CD25表面染色和胞内Foxp3染色,流式细胞仪检测。
PBMC在RPMI 1640完全培养基中与PMA、Ionomycin共培养,刺激胞内细胞因子分泌,并加入Golgiplug阻断细胞因子释放,进行胞内细胞因子IFNγ、IL-4.IL-17染色及膜表面CD4染色,流式细胞仪检测。
收集患者临床资料,按照SLEDAI 2000评分体系评价患者疾病活动度,并按疾病活动性及脏器受累情况分组评价。
结果
1.活动性狼疮患者Thl细胞在T辅助亚群中的比例显著高于健康对照(15.20±1.62%vs.10.85±1.05%,p=0.041)。未发现不同脏器受累者之间存在差异。
2. SLE患者T辅助细胞亚群中Th2细胞的比例较健康对照显著增高(3.20±0.62%vs.1.01±0.19%,p=0.021),但不与抗dsDNA抗体滴度、C3、IgG相关,也未发现病情活动与不活动者之间及不同脏器受累者之间有统计学差异。短期随访(n=7)未发现与治疗前后有显著差异(p=0.398)。
3.活动性狼疮患者T辅助细胞中Th17比例高于健康对照组和不活动狼疮组(2.20±0.21 vs.1.53±O.16%和1.32±0.19%,p=0.011和p=0.010)；初发SLE患者高于经治SLE患者(2.29±0.26vs.1.58±0.18%,p=0.019)；合并狼疮肾炎的患者高于无狼疮肾炎的患者(2.56±0.34%vs.1.59±0.14%,p=0.002)；合并NPSLE患者也可观察到CD4+T中Th17的比例高于健康对照(p=0.026),但与无NPSLE的患者相比差异不显著(p=0.122)。
4.Th17在CD4+T细胞中所占的比例与SLEDAI评分和抗dsDNA抗体滴度正相关(p=0.008和p<0.001),而与C3水平负相关(p=0.005)；
5. SLE患者CD4+T细胞中Treg的比例与健康对照相比无显著差异(p=0.058),合并NPSLE的SLE患者Treg占CD4的比例较健康对照增高(5.42±1.14%vs.3.1±0.28%,p=0.02),CD4+CD25-Foxp3+细胞所占CD4+T细胞的比例显著高于健康对照(P<0.001),各个亚组之间无显著差异。
6. SLE患者中Th17/Treg比例与C3水平负相关(p=0.038),而与抗dsDNA水平正相关(p=O.012)。
结论
SLE患者存在T辅助亚群比例失调,Th2细胞比例增高,可能是B细胞过度活化和自身抗体的持续产生的机制之一。活动性SLE患者伴有Th1和Th17细胞比例增高,T辅助细胞中Th17的比例与病情活动度和肾脏受累相关,提示Th17在SLE发病机制和脏器受累中发挥重要作用。尽管合并脑病的SLE患者出现调节性T细胞比例增高,但SLE患者整体的Treg水平与健康对照无显著差异,合并脑病的患者中的增高可能是一种保护机制。SLE患者中CD4+CD25-Foxp3+T细胞增多,该群细胞性质未明,可能是效应性T细胞。
背景和目的
CD200是表达于多种免疫和炎症相关细胞类型上的I型膜糖蛋白。CD200可表达于树突细胞、内皮细胞、活化T细胞等,与其受体CD200R结合可传递免疫调节信号,在实验动物中可参与调节免疫应答阈值和细胞因子产生极向,参与维持免疫稳态,防止移植排斥和自身免疫疾病。目前对CD200/CD200R轴的研究多局限于动物,主要集中在CIA、EAE等自身免疫病模型以及对肥大细胞和巨噬细胞功能影响方面研究。对其人体内的生物学功能的认知还十分有限,在SLE中的作用罕有报道。在本实验室的前期工作中发现CD200 mRNA和CD200R mRNA在SLE患者表达降低,表达CD200的PBMC比例增高,为探讨CD200蛋白在SLE中增高的意义进行本研究。本研究就CD200信号是否对T辅助亚群的比例平衡产生调节和影响以及CD200信号通路对PBMC增殖的影响进行了探讨。
方法
SLE患者和健康对照PBMC与CD200Fc、CD200R1 Fc和anti-CD200R1共培养48小时,胞内细胞染色流式细胞术测定T辅助亚群中Th1、Th2、Th17和Treg的比例变化；ELISA法测定培养上清中IL-17的水平。
PBMC经CFSE标染后分别给予CD200 Fc、CD200R1 Fc或anti-CD200R1共培养96小时,或给予PHA、抗CD3/CD28刺激增殖,同时加入CD200 Fc、CD200R1Fc或anti-CD200R1共培养96小时激活或阻断CD200信号通路,流式细胞术检测增殖情况。
结果
1. SLE患者血清游离CD200水平较健康对照增高(306.60±72.63pg/ml vs. 109.48±23.39pg/ml, p=0.001),经免疫抑制治疗后下降至正常(140.32±31.58pg/ml,与治疗前相比p<0.001)。
2. CD200信号对于健康对照T辅助细胞的比例平衡影响较小,但大剂量CD200R1 Fc可使Thl细胞比例增加(p=0.043),而CD200 Fc可使SLE患者Th17细胞比例减低(p=0.046)。
3. PBMC与CD200 Fc、CD200R1 Fc和anti-CD200R1共培养后培养上清的IL-17水平无明显改变。
4. CD200 Fc或CD200R1 Fc对PBMC自发增殖和PHA或抗CD3/CD28刺激下的增殖无明显影响。但在SLE患者中可观察到anti-CD200R1增强抗CD3/CD28刺激PBMC增殖作用的现象。
结论
SLE患者血清中游离的CD200增高,经过激素和免疫抑制药物治疗后下降至正常。CD200 Fc、CD200R Fc和antiCD200R1对健康对照外周血T辅助细胞亚群的比例调节作用较小,而在SLE患者中,CD200通路活化可使Th17细胞比例减低,阻断CD200信号通路则可使Thl细胞比例增高,CD200信号通路参与SLE患者T辅助细胞亚群的比例调节。体外增殖实验中,anti-CD200R1阻断CD200R信号可对抗CD3/CD28刺激的PBMC增殖起到促进作用。CD200信号通路在SLE患者中的增高具有一定保护意义。
Background
SLE (systemic lupus erythematosus) is a chronic, multisystem-involved typical autoimmune disease in which abnormally activated and differentiated B cells act as one of the important characteristics of SLE. B cells not only function as effector cells by producing autoantibodies and secreting inflammatory mediators to trigger, sustain and expand immune response, but also act as antigen presenting cells to activate T cells, so B cells contribute a great deal to the pathogenesis of SLE.
BAFF (B cell activating factor belonging to TNF family), also known as BLys (B-lymphocyte stimulator), was discovered in 1999 as a new member of TNF (tumor necrosis factor) superfamily of ligands. Through binding to its receptors, BAFF exerts potent stimulation to B cells, regulates the differentiation and maturation of B cells, promotes isotype switch, supports the survival of B cells and spares plasma cells from apoptosis. Over-expression of BAFF may help auto-reactive B effector cells overcome "death signal" triggered by autoantigen which may be involved in the onset and development of SLE. APRIL shares some functions with BAFF.
Although several literatures have reported the status of BAFF expression in autoimmune disease, the results are divergent and controversial. One possible reason for the discrepancy might be that patients had received immunosuppressive treatment before being recruited, and this was not considered as an influential.factor.
In this research, we tried to analyze the differences in BAFF, APRIL as well as their receptors BR3 (BAFF receptor, BAFF-R, BR3), BCMA(B cell maturation antigen) and TACI (transmembrane activater of and calcium modulator and cyclophilin ligand interactor) in different subgroups of SLE patients. We also analyzed the correlations of these items with clinical manifestations, hoping to expand our knowledge about BAFF and its role in the pathogenesis of SLE and provide some evidence for selecting candidates for BAFF-targeting therapy.
Method
Seventy-three patients diagnosed of SLE were recuited. Twenty-eight sex and age matched health volunteers were accepted as health controls (HC). Anti-coagulated peripheral blood was collected and mononuclear cells were isolated.
Expression of BR3, TACI and BCMA on peripheral B cells were detected by flow cytometer.
Plasma BAFF levels and APRIL levels were detected by ELISA.
BR3 mRNA, TACI mRNA and BCMA mRNA were measured and quantified by real-time polymerase chain reaction.
Coculture of health PBMC with exogenous recombinant human BAFF was processed to investigate the influence of elevated BAFF on expressions of its recetpors.
Clinical data was collected and disease activity was evaluated according to SLEDAI 2000 system. Patients were classified into subgroups according to organ involvement and/or status of medical treatment and/or SLEDAI scores。
Results
1. SLE patients had higher BAFF levels in their plasma than health controls. (2111.59±220.08pg/ml vs.914.84±43.66pg/ml, p<0.001). And in new-onse patients with active disease, BAFF was especially high (3403.89±640.65pg/ml, p<0.001). BAFF levels correlated positively with SLEDAI scores (p=0.018) and reduced after effective treatment (p=0.026).
2. Detectable BR3 protein on peripheral B cells was significantly down-regulated in SLE patients compared to HC (p<0.001) and correlated negatively with plasma BAFF levels (p=0.022). The down-regulation of detectable BR3 was parallel among CD19+IgD+CD27- naive B cells, CD19+IgD+CD27+pre-switch memory B cells and CD19+IgD-CD27+ post-switch B cells and was more distinguished in patients with active disease than those with inactive disease (p=0.013). Post-therapeutic patients had less detectable BR3 than new-onset patient (p=0.018), so did patients with lupus nephritis (LN) than those without (p=0.002). For new-onset patients, expression of BR3 on B cells correlated negatively with SLEDAI (p=0.002) and positively with C3 level (p=0.028).
3. Patients with LN had higher expression rate of TACI on peripheral B cells than HC and those patients without LN (p<0.05). TACI expression rate was expecially high in those new-onset patheints with LN (p=0.001) and reduced after immunosuppressive therapy (p=0.007).
4. Only low levels of BCMA on developing B lymphocytes had been demonstrated in our study. But a trendency of up-regulation of BCMA expression on B cells in patients can be observed (p=0.032). And the percentage of CD 19+BCMA+ cells tended to correlate with the titers of anti-dsDNA and SLEDAI scores (p=0.035 and p=0.019). What's more, those without lupus nephritis had higher percentage of this group of cells.
5. No significant differences of BR3 mRNA and BCMA mRNA level were found between SLE patients and HC. But SLE patients had higher TACI mRNA expression than HC (p=0.023).
6. Eleavated BAFF may result more binding with BR3 which in turn caused down-regulation of detectable BR3 protein on B cell surface.
Conclusions
Higher levels of BAFF and less expression of BR3 were prominent in SLE patients, and they could act as biomarkers for active disease. BR3 was the fundamental receptor of BAFF which was expressed exclusively on B cells. The actual BR3 expression may not differ between SLE patients and health controls and the down-regulation of detected BR3 may due to prior occupation by elevated BAFF. BAFF/BR3 axis may be over-activated in SLE patients since lower BR3 detection means more binding of BAFF with BR3 which was more distinguished in patients with active disease and patients with lupus nephritis. Up-regulation of TACI in SLE patients was significant in patients with LN. New-onset SLE patients with active disease especially those with nephritis may benefit the most from BAFF-targeting therapy.
Background
Malfunction of T helper cells plays a central role in the immunological disorders in Systemic lupus erythematosus. Except for well-known Thl and Th2 cells, two new members have joined T helper family, which are T regulatory cell and T helper 17 cells. These four subgroups not only connect with each other on their origin, but also restrict with each other on their development and function. Cytokines secreted by them constitute a network:Thl can secret IFNγ、IL-2、TNF-α、IL-12, induce the activation of macrophage and stimulate the development and proliferation of cytotoxic T cells, thus participate in cellular immunity; Th2 can secret IL-、IL-5、IL-10、IL-13, stimulte B cells to proliferate and produce antibody, thus paticipate in humoral immuity; Treg possesses anergic property and is capable of suppressing the proliferation of T effector cells by cell contact. But Treg is also capable of secreting cytokines like TGF-βand IL-10 to enhance immunoregulation. Thl7 cells were named for its capability of secreting IL-17. IL-17 and other cytokines secreted by Th17 like IL-22 are pro-inflammatory cytokines that are involved in anti-infections immunity, tissue damage and inflammatory osteocalsia. Now the pathogenetic role of Th17 in rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis was recognized. But its role in SLE is rather ambiguous. In this research, through intracellure cytokines staining, T helper subgroups were identified and their correlations with clinical manifestations were analyzed.
Method
Forty-six patients diagnosed of SLE were recuited. Twenty-nine sex and age matched health volunteers were accepted as health controls (HC). Anti-coagulated peripheral blood was collected and peripheral blood mononuclear cells (PBMC) were isolated.
Surface staining of CD4 and CD25 as well as intracellular Foxp3 were used to indentify Treg cells.
PBMC was cultured in RPMI 1640 complete culture medium with PMA and Ionomycin to stimulate the expression of intracellular cytokines in the presence of protein transport inhibitor-Golgiplug. Thl, Th2 and Th17 cells were identified by the expression of surface CD4 and intracellular cytokine IFNy, IL-4 and IL-17 respectively.
Clinical data was collected, organ involvement was assessed and SLEDAI score was evaluated according to SLEDAI 2000 system.
Results
1. SLE patients with active disease had higher percentage of Thl cells among CD4+T cells than HC (15.20±1.62%vs.10.85±1.05%, p=0.041). No significant difference was found between patients with organ involvement and those without.
2. Percentage of Th2 cells among CD4+T cells increased in SLE patients (3.20±0.62% vs.1.01±0.19%, p=0.021), but did not correlated with the titters of anti-dsDNA antibody, C3 or IgG level. And no difference between patients with active disease and inactive disease was found. And patients with organ involvement did not differ from those without. Short-term follow-up (n=7) showed no significant change ocurred (p=0.398).
3. Patients with active disease had higher percentage of Thl7 cells among CD4+T cells compared with HC and those with inactive disease (2.20±0.21 vs.1.53±0.16% and 1.32±0.19%, p=0.011and p=0.010); Thl7 percentage in CD4+ T cells was higher in new-onset patients than post-therapeutic patients (2.29±0.26% vs. 1.58±0.18%, p=0.019), and higher in those with lupus nephritis than those without (2.56±0.34% vs.1.59±0.14%, p=0.002). Although patients with NPSLE had higher percentage of Th17 cells than HC (p=0.026), they did not differ from those without NPSLE (p=0.122).
4. Percentage of Th17 cells among CD4+T correlated positively with SLEDAI scores and titers of anti-dsDNA (p=0.008 and p<0.001) and correlated negatively with C3 level (p=0.005).
5. No significant difference of Treg percentage was found between SLE patients and HC (p=0.058), although patients with NPSLE tended to have higher percentage of Treg than HC (5.42±1.14% vs.3.1±0.28%, p=0.02). CD4+CD25-Foxp3+ cells significantly increased in SLE patients no matter they were with active disease or not, or with organs involvement or not (P<0.001).
6. The ratio of Th17/Treg correlated negatively with C3 level (p=0.038), while positively with titters of anti-dsDNA antibody (p=0.012).
Conclusion
Imbalance of T helper subgroups exists in SLE patients. SLE patients had higher percentage of Th2 cells, which indicates one of the mechanisms of overactivation of B cells and continuous production of autoantigen. Patients with active disease had higher percentage of Thl and Th17 cells, and increased Th17 cells percentage correlating positively with disease activity and nephritis, indicating the possible pathogenetic role of Thl7 in SLE and organ involvement. Althogh patients with NPSLE tended to have a higher percentage of Treg cells than HC, no significant difference was found between HC and SLE patients as a whole. The increase of Treg in patients with NPSLE may be protective. The significantly increased CD4+CD25-Foxp3+T cells deserved more study to investigate its property.
Background
CD200 is a type I membrane glycoprotein which is expressed on a number of cell types uniquely relevant to the inflammatory and immune cascade including dendritic cells, endothelial cells and activated T cells. Previous studies have shown that CD200 could regulate the activation threshold of inflammatory immune responses, polarize cytokine production and maintain the immune homeostasis. Therefore it plays an important role in prevention of graft rejection, autoimmune diseases and spontaneous abortion. Till now most researches about CD200 have been operated in animal models such as collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). And the studies of CD200/CD200R1 axis have focused on regulating the function of macrophage and mast cells. The knowledge of CD200/CD200R axis in human especially in SLE patients was very limited and lack of report. In the previous study of our lab, CD200 mRNA and CD200R mRNA decreased in SLE patients, yet the percentage of cells in PBMC expressing CD200 increased, indicating an abnormality in CD200 signal. In this research we try to investigate the possible effect of CD200 signal on the proportion of Th cells and on the proliferation of PBMC.
Method
PBMC from SLE patients and health controls were cocultured with CD200Fc、CD200R1 Fc and anti-CD200R1 separately for 48 hours. Intracellular staining was processed and flow cytometry detection was analyzed to determine the change of Thl, Th2, Treg and Th17 cells. The concentration of IL-17 in the supernatant was measured by ELISA.
Certain amount of PBMC were also stained with CFSE under sterile conditions and cocultured with CD200 Fc, CD200R1 Fc or anti-CD200R1 in the presence or absence of stimulator (PHA or anti-CD3/CD28) for 96 hours. The status of proliferation was detected by flow cytometer.
Results
1. Soluble CD200 increased in SLE sera compared with HC (306.60±72.63pg/ml vs. 109.48±23.39pg/ml, p=0.001), but reduced to normal after immunosuppressive therapy (140.32±31.58pg/ml, p<0.001 as compared to before treatment).
2. The effect of CD200 Fc on the balance of T helper cells in health controls was rather negligible. But in SLE patients, CD200R1 Fc could increase the percentage of Thl cells which CD200 Fc could reduce the percentage of Th17 cells.
3. IL-17 levels in culture supernatant did not differ among the groups cocultured with or without CD200 Fc, CD200R1 Fc or anti-CD200R1.
4. Both CD200 Fc and CD200R1 Fc have little influence on the auto-proliferation of PBMC, nor did they have an effect on the proliferation of PBMC under PHA or anti-CD3/CD28 stimulation. But SLE patients may respond to antiCD3/CD28 stimulation more actively in the presence of anti-CD200R1.
Conclusion
SLE patients had higher soluable CD200 in their sera which decreased to normal after immunosuppressive therapy. CD200 Fc, CD200R Fc and anti-CD200R1 had little effect on the proportion of T helper cell subgroups in HC. But in SLE patients, CD200R1 which blocks CD200 could increase the propotion of Thl cells while CD200 Fc could reduce the percentage of Th17 cells although IL-17 levels in culture supernatant were not altered. CD200 signal may take a part in the regulation of T helper cell subgroups. As shown by the proliferation experiment in vitro, anti-CD200R1 may promote the proliferation of PBMC under the stimulation of anti-CD3/CD28. CD200/CD200R1 axis may exert protective function in SLE patients.
引文
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