雷公藤对系统性红斑狼疮治疗作用的研究进展

传统的中医药底蕴丰富,是前人在实践与认识过程中逐渐积累起来的,中药毒副作用小,疗效明显,所以是许多科研和医务工作者研究重点及热点之一.系统性红斑狼疮(SLE)是非器官特异性自身免疫性疾病,现已证明雷公藤具有抗炎和免疫抑制作用,它对SLE患者的多个免疫环节均起作用,目前在SLE的治疗中广泛应用,已经取得满意的疗效.     

调节性T细胞治疗系统性红斑狼疮的研究进展

系统性红斑狼疮(SLE)作为一种典型的自身免疫性疾病,SLE患者体内免疫稳态被打破:T、B细胞功能紊乱,促炎因子过度释放,导致全身自身免疫反应的发生。然而调节T细胞(Treg)是一类具有免疫抑制和维持免疫稳态功能的细胞群,已被用于肿瘤、感染、炎症性疾病和1型糖尿病的治疗中。本文以Foxp3+Treg为代表,阐述了Treg的分类、免疫抑制机制及其可塑性研究和调控机制,总结了Treg体内诱导的进展及培养扩增纯化技术,以期探索基于调节细胞的疗法(regulatory cell-based therapy)重建免疫耐受的治疗策略,达到治疗或治愈SLE的目的。     

免疫检查点抑制剂在肿瘤治疗中的应用进展

免疫检查点是人类进化出的控制免疫反应强度和持续时间、最大限度减少过度活跃的免疫应答导致的过度炎症反应和自身免疫性疾病的一种机制.相比于放疗、化疗等传统治疗手段,免疫疗法因其对正常细胞毒副作用小而在肿瘤治疗中日渐兴起.该疗法种类繁多,其中免疫检查点抑制疗法通过解除肿瘤免疫耐受、激活机体自身免疫系统进而清除肿瘤细胞,治疗手段极具潜力,成为肿瘤治疗中的研究热点.针对肿瘤免疫效应机制和逃逸机制进行了阐述,综述了抗细胞毒T淋巴细胞相关抗原4和程序性细胞死亡受体1两个免疫检查点抑制剂的作用机制和临床应用,对免疫检查点抑制剂的应用前景进行了展望.     

老药新用在系统性红斑狼疮中的研究进展

系统性红斑狼疮(systemic lupus erythematosus, SLE)是一种慢性自身免疫性疾病, 确切机制尚未完全阐明。治疗上除糖皮质激素、免疫抑制剂外, 生物制剂、小分子靶向药也逐步用于临床。虽然以上药物提高了疾病缓解率, 但仍有部分患者治疗效果不满意, 且因药物副作用或价格昂贵不能长期用药。近年来, 老药新用在SLE的治疗中发挥了重要作用。文章就目前研究较多的老药在SLE治疗中作用机制及安全性做一综述, 以期为SLE的发病机制及治疗提供新策略。     

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。     

系统性红斑狼疮患者miRNA异常在TLR7/9-IFN通路中的作用机制

系统性红斑狼疮（SLE）是一种复杂的以自身抗体大量产生为特点的慢性系统性自身免疫性疾病,发病机制尚未明确。近年来研究发现miRNA可通过多种方式参与SLE发病机制。本文重点阐述SLE患者miRNA异常对TLR7/9-IFN通路的影响,以利于进一步探讨SLE发病机制,为寻找新型靶向治疗药物提供思路。     

骁悉对系统性红斑狼疮患者免疫功能的影响

系统性红斑狼疮（systemiclupuserythematosus,SLE）是一种累及多系统、多脏器的自身免疫性疾病。其发病机制复杂,治疗难度大。传统的治疗方法通常是采用皮质类固醇与环磷酰胺和硫唑嘌呤等免疫抑制剂联合。虽然对病情的控制有一定的作用,但增加了感染、骨髓抑制和发生恶性肿瘤等的危险性。为探索治疗SLE的新途径,我们应用新型免疫抑制剂骁悉（cellcept）治疗了３０例SLE患者,并观察了骁悉对SLE患者免疫功能的影响。１材料和方法１．１对象按１９８２年美国风湿病学会制定的SLE分类标准,选择了３０例住我院的SLE患者,其中女性…     

滤泡辅助T(Tfh)细胞在系统性红斑狼疮发病机制中的作用

系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病,其特异性B细胞功能亢进而产生的抗核抗体似乎是发病机制的基础。因此,控制SLE患者自身抗体的异常分泌可能成为治疗SLE的关键步骤,一些可以影响B细胞分泌抗体的分子和细胞因子可作为新的治疗靶点。滤泡辅助性T(Tfh)细胞是近些年描述的辅助性T(Th)细胞新亚群。Tfh细胞是生发中心和长期血清学记忆生成所必需的,并在B细胞分化为浆细胞分泌免疫球蛋白过程中发挥关键作用。无论是在SLE小鼠模型中,还是SLE患者体内,都可以观察到Tfh细胞的异常扩增。以Tfh细胞为新的治疗靶点可能成为治疗包括SLE在内的自身免疫性疾病的重要方法。因此,我们总结了SLE动物模型以及SLE患者方面Tfh细胞与SLE之间的相关关系,并强调了Tfh细胞作为新靶点在SLE治疗上的巨大潜力。     

流式细胞术检测SLE患者甲强龙冲击前、后淋巴细胞亚群的变化

系统性红斑狼疮(SLE)是一种自身免疫性疾病,累及多器官系统,临床表现复杂,病程迁延反复,已证实SLE患者存在免疫功能紊乱.应用大剂量甲基强的松龙(甲强龙)冲击治疗SLE获得较理想效果[1].本文应用流式细胞仪(FCM)观察SLE患者使用甲强龙冲击前及冲击后第3天、第10天外周血淋巴细胞表型,了解其T淋巴细胞、B淋巴细胞及NK细胞的变化.探讨冲击疗法对SLE患者免疫细胞及免疫功能的影响.     

造血干细胞移植后免疫重建

造血干细胞移植（HSCT）已广泛应用于临床,是治疗血液系统疾患、实体瘤、基因缺陷及自身免疫性疾病的重要手段干细胞移植伴随着严重的免疫缺陷,这一时期,患者有合并严重感染的风险固有免疫恢复迅速．NK细胞、树突状细胞移植后数周内即可恢复。而适应性免疫系统恢复缓慢,T细胞和B细胞移植后数月才可恢复正常,而T细胞功能恢复需要数年的时间：研究造血系统各细胞存移植后数量、功能上的恢复规律,对如何加快免疫重建,降低移植死亡率有重要意义.     

B-Cell-Targeted Therapy for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by a myriad of immune system aberrations, most likely resulting from pathogenic autoantibody production, immune complex deposition, and subsequent end-organ damage. B cells play a key role in the pathogenesis; therefore, B-cell-targeted therapies, including B-cell depletion and blockage of B-cell survival factors such as B-lymphocyte stimulator (BLyS), are potential therapeutic targets for SLE. In uncontrolled clinical trials from approximately 20 studies, rituximab--a mouse-human chimeric anti-CD20 monoclonal antibody that effectively depletes B cells--has been demonstrated to reduce disease activity and decrease serum autoantibodies, with a clinical response of 86% in a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide. Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially depletes B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE. Randomized controlled phase I/II trials in patients with active SLE have documented that belimumab, a humanized anti-BLyS monoclonal antibody, reduces B-cell numbers, inhibits disease activity and decreases anti-double-stranded DNA autoantibody in SLE patients. All these therapies are well tolerated, but accompanying infectious complications have been observed. Other B-cell-targeted therapies such as 'humanized' monoclonal antibodies to CD20 (e.g. ocrelizumab) and agents that interrupt B-cell/T-cell interactions also have potential, and the efficacy of these, along with rituximab, belimumab and epratuzumab, needs to be determined by randomized controlled trials.     

Emerging roles for the interferon-inducible p200-family proteins in sex bias in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple organs. The disease is characterized by the production of pathogenic autoantibodies to DNA and certain nuclear antigens, chronic inflammation, and immune dysregulation. Genetic studies involving SLE patients and mouse models have indicated that multiple lupus susceptible genes contribute to the disease phenotype. Notably, the development of SLE in patients and in certain mouse models exhibits a strong sex bias. In addition, several lines of evidence indicates that activation of interferon-α (IFN-α) signaling in immune cells and alterations in the expression of certain immunomodulatory cytokines contribute to lupus pathogenesis. Studies have implicated factors, such as the X chromosomal gene dosage effect and the sex hormones, in gender bias in SLE. However, the molecular mechanisms remain unclear. Additionally, it remains unclear whether these factors influence the "IFN-signature," which is associated with SLE. In this regard, a mutually positive regulatory feedback loop between IFNs and estrogen receptor-α (ERα) has been identified in immune cells. Moreover, studies indicate that the expression of certain IFN-inducible p200-family proteins that act as innate immune sensors for cytosolic DNA is differentially regulated by sex hormones. In this review, we discuss how the modulation of the expression of the p200-family proteins in immune cells by sex hormones and IFNs contributes to sex bias in SLE. An improved understanding of the regulation and roles of the p200-family proteins in immune cells is critical to understand lupus pathogenesis as well as response (or the lack of it) to various therapies.     

Novel Approaches to Therapy for SLE

Systemic lupus erythermatosus (SLE) is an autoimmune disease manifested by multi-organ involvement and elevated titers of anti-DNA antibodies. Current therapies for SLE are broadspectrum, and include steroids and immunosuppresive cytotoxic agents that are counterbalanced by the toxicity and side effects of the medications. One of the goals is to target thrapeies by altering specific known mechanisms of inflammation and autoimmunity. Although the inciting antigen is still unknown in SLE, it may be possible to alter the regulation of the immune response by targeted molecular therapy. Methods under investigation, which may be beneficial, are manipulation of second-signal stimulation of the immune response (anti-CD40L) manipulation of cytokines (monoclonal anti-IL-10), inducing tolerance by administration of blocking peptides (LJP394), and the manipulation of idiotypes (IVIg). In this article, we also discuss modalities that are steroid-sparing (MTX), and selective immunosuppression (stem-cell restoration and MMF). We review the ongoing literature from 2000–2002, utilizing the MEDLINE search. Controlled trials, open trials, and trials in phase I and II have been included, and anecdotal reports were excluded. The major advances have been with mycophenolate mofetil (MMF) and LJP 394     

The curiously suspicious: infectious disease may ameliorate an ongoing autoimmune destruction in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, which can arise from a combination of genetic and environmental factors. In the past, infections (Epstein Barr virus, parvovirus B-19) have been indicated to play a causative role in the development of autoimmune diseases, such as SLE. On the other hand, with the emergence of the "hygiene hypothesis" infections have also shown to play a protective role in autoimmune diseases. Two case studies are presented which provide clinical evidence of SLE patients with severe, long-term disease, despite immunosuppresive therapy. The course of both diseases changed remarkably after they experienced infections with multiple microbes (bacterial, viral and fungal). Surprisingly, their clinical and laboratory signs of SLE normalized and they are now symptom-free after 5 and 3year follow-ups. The second patient has even had a normal pregnancy, which was a trigger factor for disease flare in the past. The infections presumably changed the host immune systems and the mechanisms of their protective effects are most likely multifactorial. Our cases illustrate that infections could be beneficial in SLE patients and re-directing research toward novel innate-based SLE therapy should be explored.     

Unmet Needs in the Pathogenesis and Treatment of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with a prevalence of approximately 1 in 1000. Over the last 30 years, advances in treatment such as use of corticosteroids and immunosuppressants have improved life expectancy and quality of life for patients with lupus and the key unmet needs have therefore changed. With the reduced mortality from disease activity, development of cardiovascular disease (CVD) has become an increasingly important cause of death in patients with SLE. The increased CVD risk in these patients is partly, but not fully explained by standard risk factors, and abnormalities in the immune response to lipids may play a role. Invariant natural killer T cells, which are triggered specifically by lipid antigens, may protect against progression of subclinical atherosclerosis. However, currently our recommendation is that clinicians should focus on optimal management of standard CVD risk factors such as smoking, blood pressure and lipid levels. Fatigue is one of the most common and most limiting symptoms suffered by patients with SLE. The cause of fatigue is multifactorial and disease activity does not explain this symptom. Consequently, therapies directed towards reducing inflammation and disease activity do not reliably reduce fatigue and new approaches are needed. Currently, we recommend asking about sleep pattern, optimising pain relief and excluding other causes of fatigue such as anaemia and metabolic disturbances. For the subgroup of patients whose disease activity is not fully controlled by standard treatment regimes, a range of different biologic agents have been proposed and subjected to clinical trials. Many of these trials have given disappointing results, though belimumab, which targets B lymphocytes, did meet its primary endpoint. New biologics targeting B cells, T cells or cytokines (especially interferon) are still going through trials raising the hope that novel therapies for patients with refractory SLE may be available soon.     

Gene expression profiling in the study of the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex pathogenesis involving multiple genetic and environmental contributions. DNA microarray technology has recently been applied to unravel some of this complexity through genomewide profiling. Early studies using microarray analysis of peripheral blood mononuclear cells (PBMCs) from SLE patients revealed dysregulation of inflammatory cytokines, chemokines, and immune response-related genes, as well as genes involved in apoptosis, signal transduction, and the cell cycle. More recently, using arrays containing many more genes, 4 independent research groups have found that interferon (IFN)-regulated genes are highly overexpressed in the peripheral blood and kidney glomeruli of SLE patients, supporting a crucial role for interferon in SLE. Future studies focusing on target tissues or organs in lupus, including the kidney, may further contribute to our understanding of lupus pathogenesis while providing new targets for therapy.     

Emerging therapies for systemic lupus erythematosus--focus on targeting interferon-alpha

Current therapies for systemic lupus erythematosus (SLE), a debilitating, potentially lethal, multifactorial systemic autoimmune disease, are limited to suppressing disease activity and are associated with multiple adverse effects. Recent advances in basic and translational sciences have elucidated a crucial role for the interferon-alpha (IFNα) pathway in the pathogenesis of this enigmatic disease. The so-called "type I interferon signature" has emerged as a major risk factor for disease activity of SLE. Multiple genes encoding for molecules within the type I interferon pathway have been associated with SLE in genome wide association studies. In addition, innate immune receptors are thought to be triggered by either endogenous and/or exogenous stimuli that lead to hypersecretion of IFNα. We review the multiple emerging treatment strategies targeting IFNα-related pathways. These include monoclonal antibodies against IFNα, anti-IFNα antibody-inducing vaccines, and inhibitors of Toll-like receptors. We also summarize the current status of these pharmaceutical agents in early clinical trials.     

Autoimmune disease: is it a disorder of the microenvironment?

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that involves several vital organs including the cardiovascular system, joints, and kidneys. The pathology is characterized by accumulation of autoreactive lymphocytes that attack the patients' own tissues, secretion of autoantibodies and deposition of immune complexes in vital organs. Chronic widespread inflammation is the hallmark of SLE and the target of current therapy. According to recent theories, intonating immune circuits of inflammatory cytokines and immune cells constitute highly specialized targets for SLE therapy, which nonetheless consists for the most part of anti-inflammatory medications and cytotoxic drugs. For advanced autoimmune disorders, cell therapy aiming at introducing "healthy" stem cells has been promising, keeping in mind that in its current state, stem cell therapy is reserved for the most advanced diseases refractory to traditional therapy. Ongoing studies in our laboratories examined the role of the bone marrow microenvironment, in particular, mesenchymal stem cells (MSCs) in the etiopathogenesis of SLE. Specifically, we are testing the hypothesis that, in human SLE mouse model, marrow MSCs are defective structurally and functionally. Preliminary data indicate that structural and functional defects in MSC population from an autoimmune mouse model for human SLE may contribute to this pathology and consequently present a target for cell therapy.     

Aberrant B Cell Selection and Activation in Systemic Lupus Erythematosus

The detrimental role of B lymphocytes in systemic lupus erythematosus (SLE) is evident from the high levels of pathogenic antinuclear autoantibodies (ANAs) found in SLE patients. Affirming this causative role, additional antibody-independent roles of B cells in SLE were appreciated. In recent years, many defects in B cell selection and activation have been identified in murine lupus models and SLE patients that explain the increased emergence and persistence of autoreactive B cells and their lowered activation threshold. Therefore, clinical trials with B cell depletion regimens in SLE patients were initiated but disappointingly the efficacy of B cell depleting agents proved to be limited. Remarkably however, a major breakthrough in SLE therapy was accomplished by blocking B cell survival factors rather then eliminating B cells. This surprising finding indicates that although SLE is a B cell-driven disease, the amplifying crosstalk between B cells and other cells of the immune system likely evokes the observed tolerance breakdown in B cells. Moreover, this implies that intelligent interception of pro-inflammatory loops rather then selectively silencing B cells will be key to the development of new SLE therapies. In this review, we will not only highlight the intrinsic B cell defects that facilitate the persistence of autoreactive B cells and their activation, but in addition we will focus on B cell extrinsic signals derived from T cells and innate immune cells that lower the activation threshold for B cells.     

Immunotherapy of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a remarkably heterogeneous multisystem autoimmune disease. Improved understanding of the immunopathogenesis of this disorder over the past two decades is now being applied to therapy, with treatment being directed at specific immunological targets. This review will focus on both new uses for established therapies as well as on the introduction of novel agents. It is premature to claim that any one agent has superior efficacy to current therapies. However, the willingness of investigators supported by the pharmaceutical and biotechnology industries to evaluate the efficacy and safety of new products in controlled clinical trials may provide answers.