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调节性B细胞在HIV感染中的作用研究进展

2017-01-12康文臻党便利孙永涛第四军医大学唐都医院全军感染病诊疗中心陕西西安710038

转化医学电子杂志 2017年4期
关键词:调节性免疫调节感染者

康文臻,党便利,孙永涛 (第四军医大学唐都医院全军感染病诊疗中心,陕西西安710038)

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调节性B细胞在HIV感染中的作用研究进展

康文臻,党便利,孙永涛 (第四军医大学唐都医院全军感染病诊疗中心,陕西西安710038)

调节性B细胞(Breg)作为负向调控免疫应答的B细胞,通过分泌IL⁃10、TGF⁃β1等细胞因子发挥免疫调节作用,进而影响HIV感染及疾病进展.本研究主要对Breg细胞的功能相关分子、免疫应答以及其在HIV感染中的作用等方面进行综述.

调节性B细胞;人类免疫缺陷病毒;白介素⁃10

0 引言

艾滋病是一种以CD4细胞减少为特征的免疫衰竭性疾病,B细胞在患者感染HIV(human immunode⁃ficiency virus,HIV)后易于凋亡且其免疫调节等功能发生异常,导致B细胞依赖的体液免疫应答受到影响[1-4].调节性B细胞(regulatory B cells,Breg)是近来备受关注的负性调控细胞,在免疫性疾病的病理调控机制及维持免疫系统平衡中均发挥着重要的作用.Breg的缺失会加剧炎症、自身免疫疾病、癌症和感染性疾病等疾病的病症[4-9].本研究主要对Breg细胞的功能相关分子、作用机制以及与艾滋病的致病机制相关性等方面进行综述.

1 Breg的来源和分化

1.1 Breg的来源Breg来源于B细胞,可分为原始型及获得型[10].原始型Breg主要来自肠系膜淋巴结,在脂多糖(lipopolysaccharide,LPS)等刺激下通过Toll样受体途径诱使分化为获得型Breg.目前Breg的真正起源及其表面标志尚不完全清楚,大量的试验证据[11]表明所有的B细胞在一定条件才能分化为Breg亚群.

1.2 Breg的分化体内外适当的条件刺激可以促进Breg的生成[12].TLR2、TLR4等Toll样受体(Toll like receptor,TLR)能潜在的诱导B细胞发挥负性调节功能,而TLR9与CpG基序的寡核苷酸(CpG motif⁃oligodeoxynucleotides)能够有效诱导记忆B细胞CD27+、CD5+B细胞和非成熟过渡期B细胞(CD24hiCD38hi)产生IL⁃10[13].近来发现,低剂量B细胞活化因子(B cell activation factor,BAFF)促使B细胞发育成熟,并诱导CD1dhiCD5+B细胞分泌IL⁃10[14].CD40属于肿瘤坏死因子(tumor necrosis factor,TNF)受体超家族成员,在体内CD40与T细胞表面的CD40配体(CD154)相交联是激活Breg的1个基本路径[15].有报道[16]显示,CD40缺陷的实验性自身免疫性脑脊髓膜炎(experimental autoimmune encephalomyelitis,EAE)小鼠体内Breg分泌的IL⁃10水平显著降低,同时Th17和Th1免疫应答明显升高.除TLR和CD40之外,Breg的分化还需要B细胞抗原受体(B cell antigen receptor,BCR)、IL⁃21等其它信号分子参与[17-19].

2 Breg的免疫调控机制

多项研究证实,Breg主要以分泌IL⁃10的方式介导负性免疫调控.Wolf等[20]通过EAE鼠模型证实了发现产生IL⁃10的Breg缺陷是造成EAE症状显著加剧的原因.值得注意的是,Breg通过IL⁃10恢复Th1/Th2的平衡或直接抑制细胞固有炎症反应来抑制有害的免疫反应[21-24].在各种实验性炎症小鼠体内,如炎症性肠病(Inflammatory bowel disease,IBD)、EAE、关节炎及红斑狼疮(lupus erythematosus,LE)等,Breg被激活可以产生大量IL⁃10[25-31].这些炎症诱发的产生IL⁃10的Breg可以抑制炎症进展或促进实验炎症性疾病如IBD、EAE、关节炎和LE的恢复[26-27,29-31].除了动物实验外,许多研究报道了人类具有与小鼠Breg类似的负性免疫调节功能[32].Simma等[33]用CD40和BCR刺激健康人静脉血分离的B细胞,并检测了B细胞产生的IL⁃10、IL⁃4、IL⁃6、IL⁃12、TNF⁃α和IFN⁃γ,也同样证实了Breg细胞的存在,并发现它们参与了机体的免疫调节.

另外,还有一些Breg亚群通过TGF⁃β1抑制效应T细胞(Teff)和诱导效应T、B细胞凋亡,并产生效应分子以减轻炎症等免疫应答中发挥负性免疫调节作用[22].产生TGF⁃β1的Breg亚群可以参与小剂量诱导口服耐受[28,34].有趣的是,在受体小鼠内产生TGF⁃β1的Breg通过诱导效应T细胞凋亡抑制糖尿病[35],进而发挥免疫抑制作用.然而,不同于分泌IL⁃10的Breg,产生TGF⁃β1的Breg在体内无法增殖[36].同时,Breg也可以通过细胞间接触,介导调节性T细胞(regulatory T cells,Treg)的Foxp3(forkhead box P3)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte⁃associated antigen⁃4,CTLA⁃4)表达水平上调[37].

3 Breg在HIV感染中的作用

研究发现,Breg在机体的免疫调控网络中介导免疫耐受,参与不同的疾病致病机制.Siewe等[6]发现Breg在HIV感染者体内显著升高,与HIV病毒载量呈正相关,同时也与T细胞免疫损伤密切相关.国内研究组研究结果与上述报道类似,HIV感染过程中Breg频率与HIV病毒载量呈正相关,而与CD4细胞数量呈负相关,同时证实Breg的活化有助于降低CTL的活性[8].本研究结果显示,HIV感染者的Breg及其分泌的IL⁃10水平均显著升高,且两者呈正相关[38].Huang等[39]通过RT⁃PCR和ELISA方法检测了IL⁃10的表达,发现IL⁃10可由AIDS相关B细胞系(AIDS⁃associated B⁃cell lines,AABCL)分泌,其受体IL⁃10R1和IL⁃10R2在多种B细胞上均有表达,这提示Breg功能的变化可能参与了HIV感染发病过程的同时导致IL⁃10水平的变化.

研究[40]提示,高水平的IL⁃10可能与HIV感染免疫功能失调有关.有学者关于Breg在T细胞免疫中的作用研究发现,在体外IL⁃10hiPD⁃L1hi调节B细胞可以降低HIV特异性CD8介导CTL活性.Breg可能通过IL⁃10和PD⁃L1协同机制抑制APC功能和CD4+T细胞增殖进而降低抗HIV的CTL活性并抑制病毒复制[41].IL⁃10受体拮抗剂(IL⁃10 receptorant antagonist,IL⁃10Rα)通过阻断IL⁃10通路可以显著上调HIV特异性CD4 T细胞的增殖及其效应功能,HIV特异性CD4 T细胞所分泌的IFN⁃γ和IL⁃2也明显增加[42-43].另有报道称[42,44],IL⁃10对HIV感染者CD4 T细胞具有促凋亡的作用.因此,阻断IL⁃10可以抑制CD4 T细胞亚群的凋亡[42,45].本研究结果显示,ART促使HIV感染者的HIV病毒复制被有效控制、CD4细胞数量上升,同时Breg比例和IL⁃10水平均有所降低,提示Breg与HIV疾病进展密切相关,且ART治疗可能通过恢复部分Breg及IL⁃10的表达水平来治疗HIV.未启动ART的HIV感染者可能通过Breg的扩增对抗机体炎症,进而减缓HIV病情[40].这提示Breg可能通过IL⁃10介导T细胞的免疫损伤,并抑制HIV病毒复制,对HIV感染预后发挥一定的调节作用.

4 结语

综上所述,HIV感染会使T细胞免疫受损从而导致免疫功能失调,在此过程中Breg通过分泌IL⁃10等相关细胞因子,在HIV感染者机体的免疫恢复和疾病进展过程中发挥重要作用,且ART治疗可能通过恢复部分Breg及IL⁃10的水平来治疗HIV.然而,在HIV感染中参与Breg负性调控的信号通路、T细胞受损与Breg相关性、产生IL⁃10的Breg是否独立进行免疫调控均鲜有报道,有待进一步研究.因此,研究HIV感染者细胞免疫网络的相互作用与机制,尤其是明确Breg的免疫调控及其相关信号转导在其中的作用,对HIV免疫学治疗具有重要意义.

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Research progress of the effect of regulatory B cells on the immune responses of HIV in⁃fection

KANG Wen⁃Zhen,DANG Bian⁃Li,SUN Yong⁃Tao
Department of Infectious Disease,Tangdu Hospital,Fourth Mili⁃tary Medical University,Xi'an 710038,China

Regulatory B cells(Breg)may play an important role in HIV disease to negetively regulate immune responses.They are capable of performing regulatory functions through secretion of inhibitory cytokines to monitor HIV disease infection and progres⁃sion,such as interleukin⁃10 and TGF⁃β1.The review focuses on molecules associated with the differentiation and function of the Breg as well as the effect of Breg on the immune responses of HIV infection.

regulatory B cells;HIV;IL⁃10

R392.12

A

2095⁃6894(2017)04⁃05⁃03

2016-12-01;接受日期:2016-12-18

国家“十二五”科技重大专项(2012ZX10001⁃003⁃003⁃004,2012ZX10001⁃003⁃004⁃010);第四军医大学科技发展基金(学2016XD255)

康文臻.副教授.研究方向:艾滋病免疫学发病机制及诊断.E⁃mail:kangwz@fmmu.edu.cn

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