T细胞对B细胞的旁路激活及其与系统性红斑狼疮的关系

<正>系统性红斑狼疮(SLE)是典型的抗体介导的自身免疫性疾病。其主要免疫学特征是患者血液中含有大量的抗核(如核心蛋白,DNA等)抗体及抗其它自身抗原(如红细胞表面抗原等)的抗体,抗原抗体复合物在肾小球基底膜等处沉积造成病理损伤。目前,我们对SLE患者体内多克隆自身免疫性B细胞被激活的机理知之甚少,因而也缺少有效的药物或方法用於治疗。实际上健康人的外周血中也有许多能够合成自身抗体的B细胞,但绝大多数处于未活化状态而不能产生自身抗体。笔者认为,SLE可能是自身免疫性B细胞表面MHC分子的变化引起T-B细胞间旁路激活的结果。本文探讨T-B细胞相互作用之经典途径与旁路途径的主要特点和区别,以及旁路激活在SLE发病过程中的作用。     

调节性B细胞在系统性红斑狼疮中的作用机制研究进展

SLE是一种累及多系统的自身免疫病。近年来,调节性B细胞在SLE中的作用受到广泛的关注。调节性B细胞主要通过分泌IL-10等细胞因子发挥负向调节作用而参与免疫耐受,抑制炎症反应,影响SLE的病程发展。本文主要综述调节性B细胞亚群在SLE中的数量和功能及其与Tfh、Treg细胞的相互作用。     

B细胞免疫耐受缺陷与系统性红斑狼疮的最新研究进展

系统性红斑狼疮(SLE)是一种全身多器官受累的自身免疫性疾病.致病性自身抗体是该病的一个标志性特征,并且在引发SLE患者临床表现中发挥重要作用,这些自身抗体导致免疫复合物沉积在内脏器官而引起炎症及机体损伤.尽管SLE存在多种分子途径异常以及多种细胞类型调节异常,但B细胞在该疾病中发挥中心作用.最近研究认为,调节自身反应性B细胞存活、分化及活化的中枢与外周耐受机制在SLE患者中存在缺陷.因此了解B细胞免疫耐受缺陷与SLE的最新研究进展十分必要.     

系统性红斑狼疮患者B细胞亚群谱系分析

目的检测系统性红斑狼疮(systemic lupus erythematosus,SLE)患者外周血B细胞各亚群比例、分析B细胞分化及其临床意义,进一步探讨SLE患者B细胞功能分化在疾病中的作用。方法收取ds-DNA阳性、经过正规疗程激素及免疫抑制剂治疗后,临床治疗仍未达标的21例SLE患者简称难治性SLE患者,同时选取16例健康体检者作为正常对照组。采用流式细胞术检测健康对照及SLE患者外周血淋巴细胞中B细胞亚群比例的变化情况,并与患者的临床指标进行相关性分析。结果与健康人相比,高抗体滴度的SLE患者外周血双阴性记忆B细胞(CD19⁺CD27^-IgD^-)比例明显增多,浆母细胞(CD19⁺CD27⁺CD38⁺)比例明显增多,而非类型转换的记忆B细胞(CD19⁺CD27⁺IgD⁺)比例明显下降。类型转换记忆B细胞(CD19⁺CD27⁺IgD^...     

细胞凋亡与系统性红斑狼疮

系统性红斑狼疮是典型的自身免疫性疾病，发病机制不清，细胞凋亡是细胞生理性死亡的过程，在免疫系统中具有重要意义，系统性红斑狼疮病人凋亡的淋巴细胞数增多，循环中核小体增加，与抗ＤＮＡ抗体等自身抗体的产生有关，抗核小体抗体参与狼疮肾的发生。     

外周血CD19+B细胞PD-L1的表达与系统性红斑狼疮发病的相关性分析

目的:探讨程序性死亡配体1(Programmed death ligand-1,PD-L1)在系统性红斑狼疮(Systemic lupus erythema-tosus,SLE)患者外周血B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CD19+B细胞表面PD-L1的表达水平,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CD19+B细胞表面PD-L1表达阳性细胞的百分比,并分析其与临床表现及实验室检查数据的相关性。结果:SLE活动组和稳定组CD19+PD-L1+B细胞百分率均低于健康对照组,活动组又低于稳定组,差异均有统计学意义(均P<0.05)。狼疮肾炎患者CD19+PD-L1+B细胞百分率低于无狼疮肾炎患者(P<0.05)。SLE患者CD19+PD-L1+B细胞百分率与SLEDAI评分、尿蛋白定量、呈负相关,与C3呈正相关。SLE患者中抗dsDNA抗体、抗Sm抗体、抗U1snRNP抗体、抗核小体抗体阳性组外周血B细胞PD-L1表达水平均低于对应阴性组,且均有统计学意义(均P<0.05)。结论:SLE患者外周血CD19+B细胞表达PD-L1下降,与病情活动性和抗体产生有很好的相关性。     

系统性红斑狼疮中的树突状细胞相关研究进展

系统性红斑狼疮中T细胞的过度活化可能与树突状细胞功能失调有关。发现其前体单核细胞和浆细胞样细胞功能紊乱，SLE的血清中含有IFN-α的诱导物，可以促进正常单核细胞向树突状细胞的分化，髓样和淋巴样树突状细胞有异常迁移行为。树突状细胞的异常已经成为SLE中研究的一个新课题。     

雷公藤碱戊对系统性红斑狼疮患者B细胞免疫功能的体外实验 …

目的：探讨雷公藤碱戊的免疫药理作用。方法：采用系统性红斑狼疮（ＳＬＥ）病人外周血单个核细胞（ＰＢＭＣ）体外培养观察雷公藤碱戊对ＳＬＥ病人ＰＢＭＣ的Ｂ细胞功能的影响及时效关系。结果：雷公藤碱戊能抑制ＳＬＥ的ＰＢＭＣ自发性增殖反应以及正常人和ＳＬＥ病人ＰＢＭＣ对ＳＡＣ刺激后的增殖反应。同时在培养的７２前加入雷公藤碱戊均能对正常人ＰＢＭＣ在ＰＷＭ诱导下的ＩｇＧ产生呈现抑制效应。结论：雷公藤碱戊对Ｂ细胞均     

系统性红斑狼疮中的树突状细胞相关研究进展

系统性红斑狼疮中T细胞的过度活化可能与树突状细胞功能失调有关。发现其前体单核细胞和浆细胞样细胞功能紊乱 ,SLE的血清中含有IFN α的诱导物 ,可以促进正常单核细胞向树突状细胞的分化 ,髓样和淋巴样树突状细胞有异常迁移行为。树突状细胞的异常已经成为SLE中研究的一个新课题     

099 系统性红斑狼疮中的树突状细胞相关研究进展

系统性红斑狼疮中T细胞的过度活化可能与树突状细胞功能失调有关.发现其前体单核细胞和浆细胞样细胞功能紊乱,SLE的血清中含有IFN-α的诱导物,可以促进正常单核细胞向树突状细胞的分化,髓样和淋巴样树突状细胞有异常迁移行为.树突状细胞的异常已经成为SLE中研究的一个新课题.     

Associations of B cell‐activating factor (BAFF) and anti‐BAFF autoantibodies with disease activity in multi‐ethnic Asian systemic lupus erythematosus patients in Singapore

To measure the levels of B cell‐activating factor (BAFF) and endogenous anti‐BAFF autoantibodies in a cohort of multi‐ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age‐ and sex‐matched healthy controls were assayed for BAFF and anti‐BAFF immunoglobulin (Ig)G antibody levels by enzyme‐linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti‐BAFF‐IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti‐BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM‐R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti‐dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM‐R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti‐BAFF IgG, which were correlated negatively with disease activity (r = –0·436, P < 0·01), levels of anti‐dsDNA antibody (r = –0·347, P < 0·02) and BAFF (r = –0·459, P < 0·01). The majority of patients in this multi‐ethnic Asian SLE cohort had elevated levels of BAFF and anti‐BAFF antibodies. Anti‐BAFF autoantibody levels correlated negatively with clinical disease activity, anti‐dsDNA and BAFF levels, suggesting that they may be disease‐modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti‐cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti‐cytokine therapies.     

B cells and atherosclerosis in systemic lupus erythematosus

Introduction: Cardiovascular (CV) events, as a result of accelerated atherosclerosis, are an important cause of mortality in patients with Systemic lupus erythematosus (SLE). The etiology of SLE is multifactorial and still unclear; among other potential culprits, excessive B cell activation seems to play a crucial role. Accumulating evidence supports a contributory role of B cells in the pathogenesis of atherosclerosis as well.

Areas covered: This article focuses on the contribution of both B cells and autoantibodies in the pathogenesis of atherosclerosis in both general and lupus populations. Review of the published literature on experimental models has also been performed.

Expert opinion: Distinct B cell subsets seem to exhibit separate effects on the progression of atherosclerosis, with B2 B cells displaying a mainly atherogenic phenotype, while B1 B cells are mostly viewed as atheroprotective. Selective B2 inhibition by anti-B cell therapies seems a promising therapeutic strategy against atherosclerosis development in the setting of lupus.     

Belimumab for the treatment of systemic lupus erythematosus

Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management of SLE.     

Subcutaneous and intravenous belimumab in the treatment of systemic lupus erythematosus: a review of data on subcutaneous and intravenous administration

Introduction: Loss of B cell tolerance is a hallmark feature of the pathogenesis of Systemic Lupus Erythematosus (SLE). Recent advances in B cell therapy have focused on targeted therapy aimed at inhibiting B cell activation and reducing B cell survival. Belimumab, a human monoclonal antibody against B cell activating factor (BAFF) was licensed in 2011 for the treatment of SLE.

Areas covered: We review the data on the intravenous and subcutaneous formulations of belimumab in the management of patients with SLE. BLISS-52 and BLISS-76 demonstrated the efficacy of intravenous belimumab (10mg/kg) as an add-on therapy in SLE patients with active disease. A recent phase III trial of intravenous belimumab reported similar results in North East Asian patients. Subcutaneous belimumab (200mg/weekly) has demonstrated similar efficacy, safety and tolerability and was approved by the FDA in 2017 for the treatment of active autoantibody positive SLE patients receiving standard therapy.

Expert commentary: Belimumab is generally safe and well tolerated. The most common clinical manifestations of SLE in the clinical trials were arthritis, mucocutaneous disease and serositis. Patients with severe lupus nephritis and central nervous system disease were excluded from these clinical trials.     

New insights into the progression from cutaneous lupus to systemic lupus erythematosus

ABSTRACT

Introduction

Between 5 and 25% of patients with cutaneous lupus erythematosus (CLE) can progress to systemic lupus erythematosus (SLE) during the course of the disease. There is no clear predictive guideline for the progression of CLE to SLE.     

New therapies for systemic lupus erythematosus

In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.     

Atherosclerosis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that has a late mortality phase owing mainly to cardiovascular manifestations. Atherosclerosis itself is characterized by inflammatory components, fulfilling the criteria of Witebsky and Rose for an autoimmune disease. SLE patients have increased risk for cardiovascular events, and these are the result of both atherosclerosis and thromboembolic events. Risk factors for atherosclerosis in SLE include “traditional” risk factors (mainly the Framingham risk factors), as well as disease-related factors including disease duration, steroid therapy, and renal disease, and inflammatory mechanisms that specifically contribute to enhanced atherosclerosis in SLE. These include specific antibodies to β2GPI; anticardiolipin antibodies; anti-oxidized low-density lipoprotein; and antibodies to heat shock proteins, complement activation, impaired ability to activate TGF-β1, and elevated levels of CRP. These findings stress the importance of surveillance and preventive strategies to control atherosclerosis in SLE.     

Case report and review of lupus erythematosus cells in cytology fluids

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease typically diagnosed by a combination of physical findings and clinical laboratory testing. Several decades ago, the diagnosis of lupus included the lupus erythematosus (LE) cell assay. Autoimmune serology techniques such as anti-nuclear antibody staining have replaced the LE cell assay. However, as presented in this report and review of the literature, the in vivo finding of LE cells by cytopathology remains an important finding consistent with the diagnosis of SLE.     

炎性细胞因子在系统性红斑狼疮中的作用

系统性红斑狼疮是一个全身性自身免疫病,常伴多器官受累,许多炎性细胞因子参与了系统性红斑狼疮的发病与发展,该病的活动性及器官损伤程度与不同的细胞因子相关。     

系统性红斑狼疮患者血清BAFF和IL-21的变化及意义

目的：探讨系统性红斑狼疮患者血清BAFF和IL-21水平的变化意义。方法：采用酶联免疫吸附试验的方法（ELISA）对血清中两种物质进行检测。结果：系统性红斑狼疮患者血清BAFF和IL-21高于对照组；狼疮肾炎肾活检组中BAFF随病理改变加重而升高，IL-21在Ⅱ、Ⅲ型、Ⅳ型狼疮肾炎中有升高，但在Ⅳ型中改变最明显；狼疮伴干燥综合症改变组BAFF和IL-21均增加明显；应用糖皮质激素治疗1周后的患者血清BAFF和IL-21水平均呈下降趋势，但以BAFF下降最明显；系统性红斑狼疮患者血清BAFF和IL-21的变化与患者体内的主要免疫指标变化相关；在Ⅳ型狼疮肾炎患者中BAFF和IL-21的变化呈正相关。结论：系统性红斑狼疮患者血清BAFF和IL-21均增加，T、B淋巴细胞异常功能及协同作用在不同脏器的损伤和不同的病理过程中，各自发挥作用的程度不同。