Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus

Regulatory T (TREG) cells play an important role in maintaining immune tolerance and avoiding autoimmunity. We analyzed the expression of membrane molecules in TREG and effector T cells in systemic lupus erythematosus (SLE). TREG and effector T cells were analyzed for the expression of CTLA-4, PD1, CD28, CD95, GITR, HLA-DR, OX40, CD40L, and CD45RO in 26 patients with active disease, 31 with inactive disease, and 26 healthy controls. TREG cells were defined as CD25^+/highCD127^Ø/lowFoxP3⁺, and effector T cells were defined as CD25⁺CD127⁺FoxP3^Ø. The ratio of TREG to effector T cells expressing GITR, PD1, HLA-DR, OX40, CD40L, and CD45RO was determined in the three groups. The frequency of TREG cells was similar in patients with SLE and controls. However, SLE patients had a decreased frequency of CTLA-4⁺TREG and CD28⁺TREG cells and an increased frequency of CD40L⁺TREG cells. There was a decrease in the TREG/effector-T ratio for GITR⁺, HLA-DR⁺, OX40⁺, and CD45RO⁺ cells, and an increased ratio of TREG/effector-T CD40L⁺ cells in patients with SLE. In addition, CD40L⁺TREG cell frequency correlated with the SLE disease activity index (P=0.0163). In conclusion, our findings showed several abnormalities in the expression of functionally critical surface molecules in TREG and effector T cells in SLE that may be relevant to the pathogenesis of this disease.     

茯苓多糖对系统性红斑狼疮患者Th17/Treg平衡的影响

目的:研究茯苓多糖对系统性红斑狼疮(SLE)患者外周血辅助性T细胞17(Th17)/调节性T细胞(Treg)平衡的免疫调节作用。方法:选取45例SLE患者和35例健康对照者,应用磁珠分选法分离外周血CD4~+ T细胞,流式细胞术检测CD4~+ T细胞中Th17和Treg细胞的比例。用茯苓多糖分别处理健康对照者及患者的CD4~+ T细胞,MTT法检测细胞活力以测定茯苓多糖毒性,ELISA检测细胞中白细胞介素17(IL-17)、IL-6、IL-10及转化生长因子β(TGF-β)的含量,RT-q PCR和Western blot法分别测定维甲酸相关孤儿受体γt(RORγt)与叉头框蛋白P3(Foxp3)的mRNA和蛋白表达水平。结果:与健康对照组相比,SLE患者的Th17细胞比例显著升高,Treg细胞比例明显降低(P0.05)。用100μg/L的茯苓多糖处理SLE患者CD4~+ T细胞,与空白对照组相比,IL-17和IL-6的含量显著降低,IL-10和TGF-β的含量明显上升(P0.05);RORγt的mRNA和蛋白表达显著下降,同时Foxp3的表达在mRNA和蛋白水平上明显增加(P0.05);并且Th17/Treg的比值降低(P0.05)。结论:茯苓多糖可以通过升高Treg并降低Th17细胞的比例,对SLE起到一定的治疗作用。     

Regulatory T cells in systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune disease, develops when immunologic self‐tolerance fails. Treg cells are a subset of CD4⁺ T cells that maintain self‐tolerance by suppressing autoreactive lymphocytes. Defects in Treg cells are therefore considered to be an aspect of SLE pathogenesis. Nevertheless, reports on the numbers and function of Treg cells in SLE are contradictory and the definitive role of Treg cells in SLE remains unclear. In this review, we summarize findings from murine models and ex vivo experiments, which provide insights into the mechanisms that result in the breakdown of tolerance. We also include recent findings about Treg‐cell subsets and their markers in human SLE. The identification of unique markers to identify bona fide Treg cells, as well as therapies to reconstitute the balance between Treg cells and autoreactive T cells in SLE, are the future challenges for SLE research.     

Ets-1在系统性红斑狼疮中的研究进展

系统性红斑狼疮(SCE)是一种典型的系统性自身免疫性疾病,其发病机制尚未明确,其中T、B细胞功能异常起着重要作用.转录因子Ets-1作为SLE的易感基因之一在淋巴细胞分化与细胞因子调节上起重要作用.Ets-1除影响B细胞分化和功能外,对T细胞的生存、增殖、发育和功能起重要作用.虽然Ets-1在SLE发病中的确切机制仍尚未明确,但越来越多的研究表明Ets-1在SLE的发生发展中起着重要作用.     

系统性红斑狼疮患者外周血CD4+CD25high Tr和 CD4+CD25low T细胞PD-1表达的分析和意义

目的 探讨PD-1(programmed death-1)在系统性红斑狼疮(systemic lupus erythematosus,SLE)患者外周血CD4+ CD25high调节性T细胞(regulatory T cell,Tr)和CD4+ CD25lowT细胞上的表达及临床意义.方法 应用流式细胞仪检测51例SLE患者和38例健康对照者外周血CD4+ CD25high Tr和CD4+ CD25lowT细胞表面PD-1表达水平,同时收集SLE患者临床表现、实验室检查数据,比较SLE稳定组、活动组和健康对照组以及狼疮肾炎组和无狼疮肾炎组之间CD4+ CD25 high Tr和CD4+CD25lowT细胞表PD-1表达的百分比,并分析其与临床表现及实验室检查数据的相关性.结果 (1)SLE活动组和稳定组外周血CD4+ CD25 high Tr和CD4+ CD25lowT细胞的百分率均低于对照组.(2)SLE活动组和稳定组外周血CD4+ CD25 highTr表达PD-1的百分率均高于对照组.SLE稳定组和对照组外周血CD4+ CD25lowT细胞表达PD-1的百分率均高于活动组.(3)狼疮肾炎患者外周血CD4+CD25highTr表达PD-1的百分率高于无狼疮肾炎患者.而狼疮肾炎患者CD4+ CD25lowT细胞表达PD-1的百分率低于无狼疮肾炎患者.(4) CD4+CD25high PD-1+T细胞百分率与SLEDAI评分呈正相关;CD4+ CD25high Tr、CD4+CD25lowPD-1+T细胞百分率与SLEDAI评分呈负相关.结论 SLE患者外周血中CD4+ CD25high Tr、CD4+ CD25lowT细胞以及它们表面PD-1表达异常,并且与疾病活动性相关,PD-1/PD-L1信号通路可能对CD4+CD25highTr、CD4+CD25lowT细胞的数量和功能有影响.     

T cells in the pathogenesis of systemic lupus erythematosus

Recent studies in patients with systemic lupus erythematosus (SLE) have demonstrated that autoantigen-reactive T cells can be isolated from peripheral blood and that such cells can support autoantibody production ex vivo, suggesting that they may have a central role in the pathogenesis of disease. In addition, recent work has identified and characterized signaling abnormalities in T cells from SLE that may be fundamental to the disease. This review will examine the role of T cells in the pathogenesis of SLE and it will consider pathogenic mechanisms by which T cells escape normal of immunological tolerance. The focus will be on recent studies characterizing autoantigen-reactive human T cells and signaling abnormalities identified in T cells from patients with SLE.     

HLA class II haplotypes in Mexican systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is an autoimmune disease in which polymorphisms within the human leukocyte antigen (HLA) region have been associated to its etiology. For this study, HLA-DQB1, DQA1, and DRB1 genes were typed by polymerase chain reaction–sequence-specific primer in 237 individuals, taken from 74 families, who had a member with SLE, and who had their residence in the western region of Mexico; as well as in 159 ethnically matched healthy volunteers taken from 32 families. Genotype and allele frequency analysis was performed in 74 SLE patients and 54 unrelated controls. Precise three-loci identification of independent haplotypes was performed in 48 patients and 54 controls by familial segregation. Genotype distribution at each loci was concordant with Hardy-Weinberg’s equilibrium in the control group. In general, no genotype effect was observed in SLE patients. Allele distribution comparison showed in the SLE group a significant increase of HLA-DQA1*0102, DQB1*0402, and DRB1*15; whereas alleles HLA-DQB1*0303 and *0501 were significantly decreased. SLE patients showed haplotype DQB1*0602-DQA1-*0102-DRB1*15 increased. As expected, patients with SLE have a reduced haplotype genetic diversity. The associations found in this study are related to an ancestral haplotype that has been observed in SLE populations of different origins.     

Curcumin: A natural modulator of immune cells in systemic lupus erythematosus

Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE.     

系统性红斑狼疮的分子遗传学研究

系统性红斑狼疮（systemiclupuserythematosus,SLE）是一种复合性多基因的自身免疫性疾病。遗传因素在SLE易感性方面起重要的作用。该文介绍目前已知几个与SLE的易感性有关的遗传基因。通过对这些基因研究,有利于阐明SLE的发病机制,进一步为SLE的预防、诊断和治疗提供重要的依据。     

Current and novel therapeutics in the treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant clinical heterogeneity. Recent advances in our understanding of the genetic, molecular, and cellular bases of autoimmune diseases and especially SLE have led to the application of novel and targeted treatments. Although many treatment modalities are effective in lupus-prone mice, the situation is more complex in human subjects. This article reviews the general approach to the therapy of SLE, focusing on current approved therapies and novel approaches that might be used in the future.     

Abnormalities of B cell subsets in patients with systemic lupus erythematosus

The prototypic autoimmune disease, SLE, is known to be associated with polyclonal B cell hyperreactivity. Developing an understanding of the complex nature of human B cell differentiation, largely through the application of multiparameter flow cytometry to an analysis of circulating B cells has permitted an assessment of whether specific stages of B cell maturation are affected by the tendency for polyclonal B cell activation. Moreover, the analysis of perturbations of the specific stages of B cell maturation has generated new information on whether abnormalities in B cell differentiation are primarily involved in autoimmune disease immunopathology or, rather, are secondary to the inflammatory environment characteristic of subjects with this autoimmune disease. Multivariant analysis has begun to document abnormalities in B cell maturation that are primarily associated with lupus, or, alternatively related to disease duration, disease activity and concomitant medication. Together, these analyses have provided new insights on the role of B cell over-reactivity in SLE.     

系统性红斑狼疮自身抗体研究进展

经化学修饰的组织抗原,与正常组织成分有交叉反应的外来抗原、隔绝的体内自身成分及低分化的组织抗原等在一定条件下可刺激机体组织产生自身抗体.某些自身抗体因对系统性红斑狼疮(SLE)的判断具有高度特异性,已成为诊断SLE的血清指标或特异性抗体,有些自身抗体与疾病的活动性有相关性.因此,测定自身抗体有助于SLE的诊断,并对疾病的活动程度,观察治疗效果,指导临床用药具有重要的临床意义.     

钙调神经磷酸酶-活化T细胞核因子与系统性红斑狼疮

系统性红斑狼疮是一种以多种自身抗体产生为特点的侵犯多系统多脏器的自身免疫性疾病,其发病机制尚未明确,目前认为T淋巴细胞异常是SLE的发病的关键.钙调神经磷酸酶-活化T细胞核因子信号通路作为T细胞内重要的生物信号转导通路,在T细胞活化中起到调节枢纽的作用,了解CaN/NFAT信号途径在SLE中的作用及目前相关主要治疗药物的研究现状可为SLE的基础研究及临床治疗提供依据.     

Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus

Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.     

DNaseI in pathogenesis of systemic lupus erythematosus

The aberrant activation of lymphocytes causes autoimmune diseases. Although there are many candidate molecules that are involved in the pathogenesis of autoimmune diseases, it still remains unclear how immunological tolerance is disturbed in each autoimmune disease. Recently, we discovered two patients suffering from systemic lupus erythematosus (SLE) with a defect in the DNaseI gene locus. According to immunological and genetic analysis, we hypothesize that defective antigen clearance, especially accumulation of nucleosomal antigens, is responsible for the development of SLE. In this article, we review the pathogenesis of SLE from the view of defective self-antigen clearance due to low DNaseI activity.     

HLA and systemic lupus erythematosus in Chinese

Seventy-five unrelated Chinese SLE patients were HLA typed and subdivided into mild and severe disease The HLA-B13 was associated with mild disease Fourteen of 30 (46.7%) mild disease patients had B13 compared to 63/330 (19.1%) normal subjects (p < 0 0005, corrected p < 0 013, RR = 3 7) The HLA-B17 on the other hand was observed in 29% of 45 severe disease patients compared to 13 9% of 330 normal subjects (p < 0 01, RR = 2.5). The frequency of HLA-B17 in 11 patients who died was even higher (45 5%).     

B-cell-targeted therapies in systemic lupus erythematosus

Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of harmful auto-antibodies (auto-Abs), B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator (BLyS) in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells.     

系统性红斑狼疮中内皮细胞相关自身抗原的鉴定

目的在内皮细胞中筛选与系统性红斑狼疮(systemic lupus erythematosus,SLE)疾病相关的自身抗原。方法用免疫沉淀法以SLE病人血清中自身抗体捕获人脐带内皮细胞(human umbilical vein endothelial cell,HUVEC)相关抗原,并用双向电泳法分离免疫沉淀产物,然后用LC-MS-MS串联质谱鉴定与SLE病人血清反应的蛋白点。最后用Western blot法验证部分鉴定蛋白。结果相对于正常人血清对照,SLE病人血清捕获了多个内皮细胞相关蛋白,质谱鉴定结果显示:通过免疫沉淀与双向电泳结合的方法成功鉴定了包括GAPDH等已知SLE自身抗原在内的一系列蛋白,其中钙/钙调蛋白依赖性丝氨酸蛋白激酶(calcium/calmodulin-dependent serine protein kinase,CASK)为新发现SLE候选自身抗原。并以重组人CASK蛋白证实SLE病人血清中CASK抗体水平显著高于正常人对照。结论内皮细胞蛋白CASK可能作为一个新的SLE相关自身抗原。