BAFF/APRIL系统研究进展

BAFF和APRIL是新近发现的TNF配体超家族2个关系密切的成员。虽然它们共用2个受体BCMA和TACI,但转基因和基因敲除小鼠模型揭示它们各自功能并不冗余。BAFF是外周血B细胞一个关键的存活与成熟因子,它的活性通过其特异性受体BAFF-R调节,其过表达与自身免疫性疾病发生和B细胞肿瘤形成有关。APRIL在不依赖T细胞的Ⅱ型抗原反应和T细胞存活过程中扮演重要角色,同时它也能诱导一些非淋巴细胞的增殖和存活,在许多肿瘤细胞株和肿瘤组织文库中发现有高表达的APRIL。针对BAFF/APRIL系统设计出治疗相关疾病的生物制剂有着非常令人乐观的应用前景。     

自身免疫性疾病治疗性疫苗研究进展

自身免疫性疾病的发生与体内自身反应性T／B细胞的异常活化有关。病理性自身免疫应答是多发性硬化、重症肌无力等自身免疫性疾病的主要致病原因。针对已感染致病原的无症状携带者或发病的患者的自身免疫性疾病治疗性疫苗能特异性地调节异常的免疫应答,具有重要的理论价值和应用前景。     

BAFF及相关疾病

BAFF是TNF超家族的一个新成员,属Ⅱ型跨膜蛋白,由285个氨基酸组成,通过与其受体结合而广泛参与B、T淋巴细胞增殖和功能的调节。BAFF缺乏可导致免疫功能低下,过表达则与多种自身免疫性疾病的发生和发展密切相关,BAFF可能还与某些肿瘤的发生有关。以BAFF及受体为作用靶点,可以设计治疗相关疾病的新策略。     

自身免疫性疾病治疗制剂的美国市场预测

人体免疫系统是一个复杂系统,它能极好地协调起来,攻击机体不欢迎的入侵者,癌症细胞或传染性疾病。但有时它会分不清敌友,攻击正常而健康组织,导致产生自身免疫性疾病,如类风湿性关节炎、系统性红斑狼疮、多发性硬化症或重症肌无力。     

血清腺苷脱氨酶检测在几种自身免疫性疾病中的临床意义研究

目的:探讨血清腺苷脱氨酶(ADA)检测在几种自身免疫性疾病诊断中的应用价值。方法:收集确诊的系统性红斑狼疮(127例)、类风湿性关节炎(103例)和重症肌无力患者(34例)的血清标本,以同时期体检的正常成人(149例)为对照,采用ADA偶联嘌呤核苷磷酸化酶(PNP)和黄嘌呤氧化酶(XOD)法检测血清中ADA活性。结果:系统性红斑狼疮、类风湿性关节炎、重症肌无力患者和正常体检者血清中的ADA活性均值分别为(12.91±5.82)U/L、(10.91±3.70)U/L、(9.21±3.57)U/L、(8.73±2.79)U/L。系统性红斑狼疮、类风湿性关节炎患者血清中ADA活性均显著高于正常体检者(P0.05),而重症肌无力患者血清中ADA活性和正常体检者相比差别无统计学意义(P0.05)。ROC结果显示将血清ADA活性10U/L同时作为RA和SLE诊断的阳性值,ADA活性诊断SLE的AUC为0.748,敏感性为59.8%,特异性为83.2%。ADA活性诊断RA的敏感性为42.7%,特异性为83.2%。血清ADA活性为10 U/L作为诊断的参考值上限,其诊断SLE的效果优于ESR和hs-CRP,其诊断RA的效果低于ESR和hs-CRP。结论:系统性红斑狼疮、类风湿性关节炎患者血清ADA活性均有升高,在系统性红斑狼疮患者中升高更为明显,可作为系统性红斑狼疮潜在的辅助诊断标志物。     

白细胞介素-18在部分自身免疫性疾病中的作用

白细胞介素-18(interleukin-18,IL-18)是一个多肽片段,具有促进T细胞增殖、增强细胞毒性T细胞和自然杀伤细胞活性等功能。自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织损害所引起的疾病。IL-18在免疫调节中有着高效、广泛的作用,部分自身免疫性疾病发病与免疫系统的异常会伴随IL-18的高表达,且不同病程IL-18表达量会有规律性变化,因此IL-18可作为一种自身免疫性疾病较敏感的标志物。现对IL-18在常见自身免疫性疾病如系统性红斑狼疮、成人Still病、自身免疫性心肌炎和类风湿关节炎中的作用作一综述。     

间充质干细胞来源的外泌体在自身免疫性疾病中的治疗作用（英文）

自身免疫性疾病往往累及多个器官,可以引起多种并发症。近年来,自身免疫性疾病的新疗法被广泛提出,而间充质干细胞(mesenchymal stem cells, MSCs)因其独特的免疫调节能力成为了研究热点。外泌体是MSCs等细胞分泌的一种小囊泡,通过携带蛋白质、mRNA、microRNA、脂质等细胞内容物,参与细胞间物质和信息的传递,调节受体细胞的生物学功能,这可能是MSCs免疫调节功能的潜在机制。越来越多的研究表明,MSCs分泌的外泌体具有与MSCs相似甚至更好的免疫调节功能,其在自身免疫性疾病治疗中的作用已在某些疾病的动物模型中得到证实。本综述总结了MSCs及其外泌体对免疫系统和免疫细胞的作用,以及近年来MSCs来源的外泌体在自身免疫性疾病中作用的研究进展。     

细胞因子TNFSF13B的结构与功能及其在相关疾病发生中的作用

TNFSF13B是于1999年发现并克隆的一种重要的细胞因子,它广泛参与了T、B淋巴细胞的增殖及功能调节。该介绍TNFSF13B的结构及功能特点、TNFSF1B在相关疾病(如免疫功能低下、某些自身免疫性疾病及某些肿瘤等)发生中的作用以及TNFSF13B在相关疾病治疗中的应用前景等。     

孕激素在自身免疫疾病中的免疫调节作用

孕激素是一种免疫调节分子,它主要通过与孕激素受体结合发挥免疫调节作用。大量研究证实,孕激素受体在多种淋巴细胞表达,孕激素在免疫调节中可诱导Th2细胞反应,抑制Th1细胞反应,抑制巨噬-单核细胞、自然杀伤细胞的杀伤活力。血清孕激素水平降低,孕激素受体表达调节障碍将影响自身免疫功能的调节,导致自身免疫性疾病的发生和发展。     

The current status of targeting BAFF/BLyS for autoimmune diseases

It is increasingly recognized that B cells have multiple functions that contribute to the pathogenesis of autoimmunity. Specific targeting of B cells might therefore be an appropriate therapeutic intervention. The tumor necrosis factor-like molecule BAFF (BLyS) is a key B cell survival factor and its receptors are expressed on most peripheral B cells. Several different BAFF antagonists are under development and in early clinical trials. We review here the rationale for BAFF blockade, and its predicted mechanism of action in autoimmune diseases.     

B cell-activating factor and its targeted therapy in autoimmune diseases

B cells play a pivotal role in the pathogenesis of autoimmune disease (AD) by the production of autoantibodies, secretion of cytokines and presentation of autoantigens. As a pro-survival factor mainly produced by myeloid cells, B cell-activating factor (BAFF) maintains B cell maturation and homeostasis at various B cell differentiation stages. Under autoimmune conditions, BAFF acts on autoreactive B cells that have escaped checkpoint apoptosis from negative selection. Numerous studies have shown increased levels of BAFF in patients with ADs and in mouse models with ADs wherein the production of autoantibodies is a prominent feature of immunopathology. Compelling evidence has indicated a key function of BAFF in driving autoreactive B cell response during autoimmune progression. Recent clinical studies have demonstrated BAFF as a therapeutic target in various ADs. Here, we review recent findings on BAFF expression and its effector mechanisms in autoimmune pathogenesis as well as newly developed therapeutic targeting of BAFF in the treatment of ADs.     

The function of BAFF on T helper cells in autoimmunity

B cell-activating factor belonging to the TNF family (BAFF) exerts its pathogenic role in supporting the survival and proliferation of B cells, regulating class switch recombination as well as the selection of autoreactive B cells. Overexpression of BAFF induces a dramatic expansion of activated B cells, particularly marginal zone B cells, as well as hypergammaglobulinemia, autoantibody production and immune complex deposition. However, in addition to its effect on B cells, recent work has also demonstrated that BAFF can promote T cell activation, proliferation and differentiation. In this review, we have discussed the recent progress on the function and role of BAFF on T cells and T cell-mediated diseases.     

B-cell activating factor (BAFF) promotes CpG ODN-induced B cell activation and proliferation

It is controversial whether naïve B cells are directly activated in response to TLR9 ligand, CpG ODN. Although bovine blood-derived CD21⁺ B cells express TLR9 and proliferate in response to CpG in mixed-cell populations, purified bovine B cells do not proliferate significantly in response to CpG ODN, even when the B cell receptor is engaged. When co-cultured with CD14⁺ myeloid cells and/or B-cell activating factor (BAFF), a cytokine produced by activated myeloid cells, there was a significant increase in CpG-specific B cell proliferation, and the number of large B cells in general or positive for CD25, all of which are markers for B cell activation. These data suggest that activated myeloid cells and BAFF prime B cells for significant CpG-specific activation. Understanding the signals required to mediate efficient CpG-induced, antigen-independent and T-cell independent activation of B cells has implications for polyclonal B cell activation and the development of autoimmune diseases.     

非洲爪蟾BAFF及其信号通路相关基因的比较生物信息学分析

目的:对非洲爪蟾BAFF和BAFF信号通路相关基因进行了分析.方法:采用生物信息学方法对两栖类重要的模式生物-非洲爪蟾的基因组和EST数据库进行分析.结果:非洲爪蟾BAFF cDNA全长为557 bp,编码218个氨基酸.与人BAFF序列相似性为37.5％.该文一共得到了14个BAFF信号通路相关基因.通过与人BAFF信号通路进行比较,对非洲爪蟾这14个BAFF信号通路相关基因进行了分析.结论:BAFF和BAFF信号通路在进化过程中较为保守,这为进一步研究低等脊椎动物BAFF功能和信号通路具有重要的指导作用.     

Plasma levels of BAFF and APRIL are elevated in patients with asthma in Saudi Arabia

B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor superfamily of cytokines and can induce B cell activation, differentiation, and antibody production via interaction with their receptors, including transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and B-cell activating factor receptor (BAFF-R). Herein, we assessed the plasma protein levels of BAFF and APRIL in patients with asthma to determine whether their expression is correlated with total IgE production and examined the surface expression of BAFF/APRIL receptors on B cells. Blood samples were collected from 47 patients with controlled asthma symptoms and 20 healthy normal controls, and plasma levels of APRIL, BAFF, and total IgE protein were quantified by corresponding ELISA assays. Furthermore, lymphocytes were isolated and B cells were analyzed for the presence of BAFF-R, BCMA, and TACI receptors using flow cytometry. Our results showed that IgE, BAFF, and APRIL plasma levels were markedly increased in patients with asthma compared with healthy controls. Moreover, expression of BAFF-R and BCMA, but not that of TACI, was significantly increased in patients with asthma compared with healthy controls. Overall, the findings suggest BAFF and APRIL as key mediators of asthma, and determination of their plasma levels may be useful in monitoring asthma symptoms and treatment response.     

Th细胞亚群在自身免疫病的发病及治疗中作用的实验研究进展

本文回顾了Ｔｈ细胞亚群的功能、交互调节、影响其分化的因素以及Ｔｈ细胞亚群在自身免疫病发病中的可能作用;概括了通过调节Ｔｈ细胞亚群来治疗自身免疫病的方法,包括：上调ＣＤ１ｄ治疗、给予相关细胞因子治疗、佐剂治疗、用抗细胞因子、细胞因子受体、ＣＤ４０配体和Ｂ７分子的单克隆抗体治疗以及ＣＴＬＡ和ＣＴＬＡＩｇ治疗。这些方法为自身免疫病的治疗提供了新的思路。     

The role of BAFF and APRIL in rheumatoid arthritis

Development and activation of B cells quickly became clear after identifying new ligands and receptors in the tumor necrosis factor superfamily. B cell–activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are the members of membrane proteins Type 2 family released by proteolytic cleavage of furin to form active, soluble homotrimers. Except for B cells, ligands are expressed by all such immune cells like T cells, dendritic cells, monocytes, and macrophages. BAFF and APRIL have two common receptors, namely TNFR homolog transmembrane activator and Ca2+ modulator and CAML interactor (TACI) and B cell–maturation antigen. BAFF alone can also be coupled with a third receptor called BAFFR (also called BR3 or BLyS Receptor). These receptors are often expressed by immune cells in the B-cell lineage. The binding of BAFF or APRIL to their receptors supports B cells differentiation and proliferation, immunoglobulin production and the upregulation of B cell–effector molecules expression. It is possible that the overexpression of BAFF and APRIL contributes to the pathogenesis of autoimmune diseases. In BAFF transgenic mice, there is a pseudo-autoimmune manifestation, which is associated with an increase in B-lymphocytes, hyperglobulinemia, anti-single stranded DNA, and anti-double-stranded DNA antibodies, and immune complexes in their peripheral blood. Furthermore, overexpressing BAFF augments the number of peripheral B220+ B cells with a normal proliferation rate, high levels of Bcl2, and prolonged survival and hyperactivity. Therefore, in this review article, we studied BAFF and APRIL as important mediators in B-cell and discussed their role in rheumatoid arthritis.     

sBAFF mutants induce neutralizing antibodies against BAFF

B cell activating factor belonging to the TNF family (BAFF) is a novel member of the tumor necrosis factor (TNF) ligand family and plays an important role in B lymphocyte maturation and survival. Overexpression of BAFF is closely involved in the pathogenesis and progression of many kinds of autoimmune disorders; therefore, BAFF has been considered as an ideal therapeutic target for these conditions. In this study, we generated several candidate immune inhibitors of human BAFF by conjugating foreign immunodominant T-helper cell (Th) epitopes to the N- or C-terminus of five BAFF mutants. The recombined proteins were successfully expressed in Escherichia coli (E. coli) and purified by Ni-NTA chromatography. BALB/c mice immunized with the recombinant proteins produced high levels of anti-BAFF antibodies, and their sera inhibited the lymphocyte proliferation-inducing activity of recombinant soluble BAFF and natural soluble BAFF. Moreover, antibodies cross-reactive with BAFF were detected in sera from hu-SCID mice immunized with the recombinant proteins. These results indicated that the recombinant BAFF mutants modified with Th epitopes could induce neutralizing antibodies against BAFF in vivo. This study may provide a valuable strategy for treating BAFF-associated autoimmune diseases.     

性别与自身免疫性疾病

自身免疫性疾病在人群中感染率5-10%,具有明显的性别差异,女性患者显著高于男性,具体机制仍未研究清楚。研究发现,除了机体自身的遗传易感体质外,雌激素,微嵌合体和性染色体都与自身免疫性疾病发病有关。