CD4+新亚群Th9细胞与常见自身免疫病相关性的研究进展

2019-10-19 21:29张会宁王嘉军
中国医药导报 2019年28期
关键词:免疫病亚群分化

张会宁 王嘉军

[摘要] Th9细胞是CD4+T细胞新发现的分化细胞亚群,该细胞通过分泌白细胞介素-9(IL-9)参与机体的免疫应答。在类风湿关节炎、系统性红斑狼疮等自身免疫病患者血液和组织中Th9细胞比例和IL-9的含量会产生较大变化,表明其与自身免疫病的发生发展有着密切关系。本文就近几年Th9细胞与常见自身免疫病相关性研究进展进行综述。

[关键词] Th9细胞;自身免疫病;类风湿关节炎;系统性红斑狼疮;白细胞介素-9

[中图分类号] R392.12          [文献标识码] A          [文章编号] 1673-7210(2019)10(a)-0048-04

Research progress on correlation between CD4+ new subsets of Th9 cells and common autoimmune diseases

ZHANG Huining1   WANG Jiajun2

1.Department of Nurse, An-Ning Sub-Hospital in 940th Hospital in Joint Logistic Support Force of the People′s Liberation Army of China, Gansu Province, Lanzhou   730070, China; 2.Teaching and Research Section of Medical Immunology, School of Medicine, Hubei Minzu University, Hubei Province, Enshi   445000, China

[Abstract] Th9 cells are a newly discovered subset of differentiated CD4+T cells that participate in the body′s immune response by secreting interleukin-9 (IL-9). In patients with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, the proportion of Th9 cells and the content of IL-9 in the blood and tissues will change greatly, indicating that it is closely related to the occurrence and development of autoimmune diseases. This paper reviews the research progress on the correlation between Th9 cells and common autoimmune diseases in recent years.

[Key words] Th9 cells; Autoimmune disease; Rheumatoid arthritis; Systemic lupus erythematosus; Interleukin-9

初始CD4+T細胞在树突状细胞(dendritic cells,DC)提呈的双信号及细胞因子的作用下活化、增殖,而细胞因子微环境的差异决定其同时分化为不同效应的细胞亚群。CD4+T效应性细胞亚群有分泌干扰素(IFN)、肿瘤坏死因子(TNF)等为主的Th1,辅助B细胞活化的Th2,分泌白细胞介素(IL)-17、23诱导炎性反应的Th17,以及新近发现的Th9亚群。Th9细胞是IL-4和转化生长因子-β(TGF-β)共同诱导下激活的多种下游转录因子如富含嘌呤盒1(purine-rich box 1,PU.1)、干扰素调节因子4(interferon regulatory factor-4,IRF4)、转录信号转导及活化因子6(signal transducer and activator of transcription-6,STAT6)后分化,分泌高浓度的IL-9作为主要效应分子新亚群[1-2]。近年研究发现,多种常见自身免疫病发生、发展及病情严重程度与Th9细胞密切相关[3]。现将Th9细胞的生物学特性及与自身免疫病相关性的研究进展综述如下:

1 Th9细胞概述

2008年,两个研究组[4-5]均发现在TGF-β和IL-4共同作用小鼠初始CD4+T细胞后诱导分化为可分泌IL-9、IL-10等,但不表达Th1细胞T-bet、Th2的GATA-3、Treg的Foxp3和Th17的RORγt等转录因子,却表达PU.1和IRF4等转录因子的T细胞亚群,这种T细胞亚群被命名为“Th9”细胞。2010年有学者在过敏患者的外周血中发现了Th9细胞[6],随后在正常和炎性皮肤中也相继检测出Th9细胞[7]。

2 诱导及抑制Th9细胞分化的细胞因子

IL-4和TGF-β是诱导初始CD4+T细胞分化为Th9细胞的主要调节因子。其中TGF-β可单独诱导Th2细胞转化为Th9细胞。动物实验显示[8],TGF-β受体Ⅱ基因缺陷小鼠即使给予IL-4和TGF-β刺激,其初始CD4+T细胞仍无法分化为Th9细胞,提示完整的TGF-β受体是促使初始CD4+T细胞分化为Th9细胞的关键分子。而缺乏IL-4时,IL-1α、IL-1β、IL-18和IL-33均可取代或替代IL-4的作用和TGF-β共同刺激诱导产生Th9细胞。IL-1β能促进该细胞分泌高浓度的IL-9[9]。此外,动物实验提示,IL-21或IL-21受体缺陷型小鼠CD4+T细胞较野生型小鼠更易分化为Th9细胞[10]。IL-21抑制Th9细胞合成分泌IL-9。

3 调控Th9细胞信号通路与转录因子

3.1 TGF-β途径和PU.1

TGF-β信号诱导转录因子PU.1表达,直接结合活化IL-9基因启动子,是Th9细胞分化的唯一特异性转录因子[11]。PU.1对人和鼠Th9细胞生成IL-9有重要的调控作用,如初始CD4+T细胞PU.1缺陷,则很难分化为Th9,同时分泌IL-9降低[12]。Th9细胞中PU.1表达显著高于Th2细胞[13],表明PU.1促使向Th9细胞转化。

3.2 IL-4途径和IRF4

IL-4-STAT6途径激活IRF4基因,IRF4可以与IL-9基因启动子结合进而促进IL-9表达,促使初始CD4+T细胞向Th9细胞亚群分化[14]。敲除或siRNA阻断IRF4表达的CD4+T胞则无法分化为Th9细胞[15]。尽管IRF4对Th9细胞的分化作用重大[16],但它也参与Th2和Th17细胞的分化,并非是Th9特异性的转录因子[17]。

3.3 Notch协同Smad途径

Smad与Notch胞内区域NICD1结合,在RBP-JK协同下与IL-9启动子结合后开始转录并表达,从而诱导分化为Th9细胞,敲除Notch1和Notch2受体,Th9细胞分化明显减弱[18]。

3.4 活化NF-κB的信号通路

OX40/OX40L和GITR/DTA-1信号通路:Th细胞上OX40(即CD134)与APC膜分子OX40L结合后[19]或初始CD4+T细胞的GITR与配体DTA-1结合后[20],均可通过激活TRAF6,向下激活NF-κB,启动IL-9表达,诱导分化为Th9细胞。OX40/OX40L对IL-9表达具有选择特异性,可抑制或沉默IL-4、IL-5等其他因子的表达[21]。

4 Th9细胞与自身免疫病

Th9细胞分泌IL-9,可促进Th17细胞分泌促炎因子IL-17、IFN-γ、IL-1和TNF,共同介导炎性反应,协同促进自身免疫病的发生、发展,参与这些疾病的病理过程。

4.1 类风湿关节炎(rheumatoid arthritis,RA)

Ciccia等[22]发现RA患者IL-9及受体、IL-4及TGF-β水平在滑膜组织中都升高,认为Th9可能参与了RA的发病机制。RA患者外周血单核细胞中Th9比例显著高于对照组;中度活动和高度活动患者组Th9的表达率均高于对照组;且高度活动患者组血清中IL-9的表达率显著高于中度活动组。IL-9表达的百分率与RA患者的红细胞沉降率、关节压痛数、关节肿胀数及类风湿因子呈正相关,这一结果提示Th9及IL-9參与RA的发病,且与病情程度有关,但具体机制仍需进一步研究[23]。

4.2 系统性红斑狼疮(systemic lupus erythematosus,SLE)

国外学者[24-25]发现狼疮倾向MRL/lpr实验小鼠B细胞增殖和自身抗体、Th9细胞分化以及IL-9的表达有一定相关性,同时发现SLE小鼠脾脏Th9细胞数目、血清IL-9和抗双链DNA抗体浓度均显著高于正常小鼠,提出Th9细胞可能是SLE诱因之一。Ouyang等[26]检测结果显示,SLE患者血清中IL-9含量和外周血中单核细胞IL-9mRNA表达均显著高于正常组,活动期水平更高。SLE患者使用大剂量氢化考地松治疗后,IL-9含量显著降低,表明IL-9与SLE炎症有关。另有研究显示,褪黑素可有效抑制IL-9的表达,有助于SLE治疗[27]。由此推断,阻断IL-9表达是治疗SLE潜在的有效靶点[28]。

4.3 溃疡性结肠炎(ulcerative colitis,UC)

研究发现UC活检组织中IL-9水平、IL-9mRNA显著增高,增高水平与UC严重程度呈正相关[29-30]。IL-9可诱导肠上皮细胞分泌炎症介质,抑制细胞增殖,改变肠道黏膜屏障的通透性,损伤屏障作用,阻止黏膜伤口愈合。有结果显示,IL-9可造成肠道正常菌群紊乱、阻止溃疡愈合、增强炎症进展[31]。此外,有研究报道,Th9细胞可诱导STAT6、IRF4和PU.1基因转录,且表达水平与UC炎症呈正相关[32]。

4.4 银屑病(Psoriasia)

动物实验结果显示,模型小鼠皮内注射IL-9,不仅CD4+T转化为Th17细胞增加,而且局部炎症增强,血管内皮生长因子(VEGF)和CD31分子表达增强。而注射抗IL-9抗体后,病变炎症和血管增生减轻,既可延缓疾病发展,还能降低多种炎症细胞造成的表皮增生和浸润[33]。注射抗IL-17抗体,小鼠炎症细胞中IL-9 mRNA及血中IL-9含量降低,IL-9诱导的炎症和表皮增生缓解。临床资料显示,患者皮损局部IL-9R表达显著高于正常组,推断可能是IL-9诱导病变局部炎症及血管增生,进一步加重患者皮肤损伤[34]。

4.5 实验性自身免疫重症肌无力(experimental autoimmune myasthenia gravis,EAMG)

Yao等[35]在研究完全弗氏佐剂组(CFA组)和EAMG组兔子淋巴结中的单核细胞实验时发现,早期时,两组中Th9细胞无显著性差异。但晚期时,EAMG组Th9细胞百分比较对照组明显增高。提取单核巨噬细胞(M?拚)总RNA,实时定量PCR结果显示,CFA组PU.1mRNA表达较EAMG组显著降低。EAMG组病情发展以AchR表达显著降低为特征,使用IL-9-Ab可有效抑制体液免疫应答,降低抗乙酰胆碱受体抗体(AchR-Ab)的合成分泌,从而减少或阻断抗AchR-Ab与特异性乙酰胆碱受体(AchR)结合,缓解EAMG症状,产生保护作用.

4.6 桥本甲状腺炎(hashimoto thyroiditis,HT)

HT患者外周血中Th9細胞百分比、PU.1mRNA表达及IL-9含量均较对照组显著升高,且与甲状腺特异性自身抗体含量呈正相关,提示Th9细胞可能与HT发生发展有关[36]。

4.7 实验性自身免疫性脑脊髓炎(experimental autoimmune cerebrospinal meningitis,EAE)

移植使用髓鞘少突胶质糖蛋白35-55(MOG35-55)体外诱导分化的Th9细胞可过继诱发受试小鼠表现EAE,表明Th9细胞可引起中枢神经炎症。有学者发现EAE中IL-9R表达增加,IL-9诱导星形胶质细胞高表达趋化因子CCL20,促使Th17细胞在神经系统聚集产生免疫作用。Th9和IL-9在EAE的发生发展中发挥重要作用[37]。通过抑制IL-9的作用,EAE病情得到改善。应用抗IL-9McAb,阻断IL-9和IL-9R的结合,有效抑制IL-9诱导的炎症。既可预防EAE的发生,又能减轻EAE病情。此外,有报道提示[38],抗IL-9McAb可能通过显著降低特异性CD4+T细胞促发炎症细胞亚群如Th1、Th9和Th17细胞在小鼠脊髓中的浸润和脱髓鞘,大大降低EAE发病率。

5 展望

CD4+T细胞常在TGF-β和IL-4共同作用下诱导分化为Th9细胞,是受多种因素影响的新型T细胞亚群。Th9细胞通过分泌IL-9等细胞因子参与自身免疫病、肿瘤、炎症性疾病等多种疾病的发生发展。深入研究Th9细胞的生物学功能和自身免疫病的关系,既可更好地理解自身免疫疾病发病的机制,还能为疾病的治疗、预防寻找适当的新靶点。

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(收稿日期:2019-05-15  本文编辑:顾家毓)

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