2020, Vol. 55
2015~2020年是中药和天然药物研究与发展极其重要的年度, 特别是屠呦呦青蒿素研究获得2015年度诺贝尔生理学或医学奖, 2016年获国家最高科学技术奖, 2019年获得共和国勋章、联合国教科文组织-赤道几内亚国际生命科学研究奖, 使全世界看到了中药和天然药物的巨大发展潜力。2019年, 屠呦呦研究员等5位专家在New England Journal of Medicine上提出了切实可行的应对“青蒿素抗药性”的合理方案, 随后在Lancet子刊再次阐述了方案的可行性及合理性[1]; 同时阐明了青蒿素耐药性的定义[2, 3]; 国际顶级医学类教科书《牛津医学教科书》 (第6版)章节: “传统医药的范例:中医药”, 2019年已正式出版。近年来, 青蒿素及其衍生物在抗寄生虫、抗癌、抗炎、治疗红斑狼疮等方面均具有良好的疗效[4, 5]; 双氢青蒿素对治疗系统性红斑狼疮效果明显, 其适应症临床试验已获国家药品监督管理局《药物临床试验批件》。
1 AID概述AID是各种原因造成的自身免疫功能错误识别, 攻击自身抗原产生免疫应答, 而损伤自身组织器官造成的慢性炎症性疾病。根据器官特性分类可分为系统自身免疫病和器官特异性自身免疫病。前者常见的有系统性红斑狼疮(systemic lupus erythematosus, SLE)、类风湿性关节炎(rheumatoid arthritis, RA)、原发性舍格伦综合征(primary Sjögren's syndrome, pSS)等, 器官特异性自身免疫病包括银屑病、多发性硬化症(multiple sclerosis, MS)和天疱疮等。AID患者多数病因不明, 女性发病率高于男性, 发病率随年龄增加而增加, 具有一定的遗传倾向[7]。临床特征表现为血清中存在多重自身抗体或自身反应性致敏淋巴细胞, 组织器官以免疫炎症为主要病理变化, 损伤范围与自身抗体或自身反应性致敏淋巴细胞针对的抗原分布对应[8]。因AID病情迁延, 多数无根治方法, 因此, 明确发病机制, 发现有效的治疗靶点是目前AID的研究热点。
2 lncRNA与AID 2.1 lncRNA概况lncRNA是基因组长度超过200个核苷酸的非编码RNA, 无蛋白翻译功能。lncRNA的来源方式多种多样, 包括蛋白编码基因结构被破坏而转录产生, 非编码序列在本身复制过程中因反移位产生, 局部复制子发生串联产生, 基因中插入一个转座成分而产生, 两个未被转录基因和另外一个独立基因沟通染色质重组串联产生等[9, 10]。lncRNA有3种分类方式, 根据lncRNA与蛋白质编码基因的位置关系可分为正向lncRNA、反向lncRNA、双向lncRNA、基因内lncRNA和基因间lncRNA[11]; 以lncRNA在DNA序列中的作用分为以调节邻近基因表达为主的顺式lncRNA、调节远处或其他基因表达的反式lncRNA[12]; 按照lncRNA的作用机制分为诱饵分子、信号分子、引导分子和支架分子[13]。
2.2 lncRNA调控基因表达的机制lncRNA广泛参与机体的生理和病理活动, 可与蛋白质、DNA和RNA相互作用, 从表观遗传学、转录水平、转录后加工水平和蛋白质代谢等方面调控基因的表达[14, 15]。Li等[16]研究发现, lncRNA可与DNA或RNA的碱基互补, 以顺式或反式作用调节靶基因的转录。Luo等[17]通过顺式和反式模型分析lncRNA与靶基因之间的潜在调控关系, 显示lncRNA能在编码区上游启动子区进行转录, 干扰基因下游的转录, 并参与mRNA的剪切, 影响其转录。Lee等[18]研究发现, lncRNA EB病毒编码RNA2存在于EB病毒(Epstein-Barr virus, EBV)基因组的末端重复序列(terminal repeats, TRs), 可与TRs转录产物杂交, 将转录因子配对盒基因5募集至TRs, 调控附近基因的表达, 控制EBV的裂解性复制。此外, lncRNA可作为Piwi和miRNA等小分子RNA的前体分子参与转录, 并参与蛋白的活性调节等诸多功能[19-21]。
2.3 lncRNA参与调控AID机制lncRNA参与机体的固有免疫和适应性免疫调节, 在AID的发生和发展过程中有重要的调控作用。Aune等[22]通过对健康人与AID患者进行全转录组测序研究, 发现AID患者新测序的lncRNA基因座并未随机分布在基因组中, 而是位于白细胞的转录增强子区, 与AID相关的单核苷酸多态性位点更为接近, 说明lncRNA的表达与AID的发生和病理改变有关。Morchikh等[23]研究发现, lncRNA富含丰富的转录本1, 能与转录因子环六亚甲基二乙酰胺诱导蛋白结合形成多亚基复合物, 通过环鸟苷酸-腺苷酸合成酶/干扰素刺激基因/干扰素调节因子-3信号途径激活天然免疫应答的关键核调节因子, 发挥抗AID的作用。另有研究[24]证实, lncRNA通过控制mRNA表达和加工的转录及转录后调控, 可作为天然免疫应答的有效调节因子, 参与抗病毒反应和AID的调节。以上研究说明, lncRNA能够调控机体的免疫应答, 参与AID的发生发展。
3 CD4+ T细胞亚群与AID 3.1 CD4+ T细胞亚群概况CD4+ T细胞也可称为T淋巴辅助细胞, 在机体的免疫应答中有重要作用。初始CD4+ T细胞受病原微生物刺激后可分化为辅助型T细胞1 (T helper 1, Th1)、Th2、调节性T细胞(regulatory cells, Treg)、Th9、Th17等细胞亚群以及滤泡辅助性T细胞(T follicular helper, Tfh)[25]。不同的细胞亚群功能不同, 而又相互联系, 组成机体免疫调节网络, 维持机体免疫稳定。当机体的内环境改变, 可造成细胞之间的相互拮抗, 引起T淋巴效应细胞的紊乱和细胞因子网络的失衡, 进而引起AID的发生[26]。
3.2 Th1/Th2细胞与AIDT细胞效应不同, 分泌的细胞因子谱有所差异, 在机体免疫系统中的作用亦不相同。Th1主要分泌γ-干扰素(interferon-γ, INF-γ)、白细胞介素-2 (interleukin-2, IL-2)、IL-12和肿瘤坏死因子-α/β (tumor necrosis factor-α/β, TNF-α/β)等细胞因子。Th2细胞主要分泌IL-4、IL-5、IL-6和IL-9等细胞因子。Th1参与细胞免疫, 介导细胞毒性和迟发超敏性炎症的相关免疫应答, 辅助抗体的生成。研究[27]显示, 在克罗恩病和银屑病等疾病中均有Th1细胞的异常表达。Th2主要辅助B细胞完成体液免疫应答, 能刺激B细胞的增殖和抗体的产生, 参与抗蠕虫和其他细胞外病原体的感染。研究[28]显示, SLE存在Th1/Th2细胞失衡的情况, 表现为Th2细胞因子的高表达, 可促进B细胞向浆细胞的分化, 参与疾病的发生发展。
3.3 Treg细胞与AIDTreg细胞在维持机体免疫耐受中有重要作用, 经胸腺产生后可输送至外周, 通过主动调节抑制机体内潜在的自身反应性T细胞的活化和增殖, 从而调节机体的免疫功能[29]。Treg细胞可分为自然调节性Treg细胞(CD4+CD25+ T细胞)、适应性调节性T细胞[包括Tr1和Th3等细胞, 主要分泌IL-10和转化生长因子-β (transforming growth factor-β, TGF-β)发挥免疫负调控作用]、CD8+ Treg及自然杀伤T细胞(natural killer T, NKT)[30]。正常情况下, 各细胞因子在Treg细胞分化的过程中相互调节制约, 在机体微环境失调时细胞因子比例的失调和功能异常可影响机体的免疫耐受, 导致AID的发生。研究[31, 32]证实, 银屑病和RA患者存在外周血Treg和(或) Th17细胞表达升高, Th17/Treg比例失衡的情况说明Treg细胞的水平异常参与银屑病、RA的发生发展。
3.4 Th9细胞与AIDTh9细胞是幼稚型CD4+ T细胞在IL-4与TGF-β作用下分泌IL-9的新型T细胞亚群, 可影响多种细胞功能介导炎症性疾病的发生, 在AID的发生中有重要作用[33]。Medrano-Campillo等[34]的研究证实, SLE患者存在Th1、Th2、Th9和Th17的异常表达。银屑病患者中存在Th9/Treg细胞表达升高的情况[35]。王波等[36]通过敲除RA小鼠模型可诱导共刺激因子基因, 可降低Tfh、Th9的表达, 改善炎症, 提示RA免疫应答过程亦有Th9细胞参与。
3.5 Th17细胞与AIDTh17细胞主要分泌IL-17, 参与机体适应性免疫应答, 还可通过募集和活化中性粒细胞, 刺激IL-1β、IL-6和TNF-α等炎症因子的分泌, 引起局部炎症反应, 并可作用于特定的细胞调节适应性免疫[37]。研究[38]显示, IL-6和TGF-β能通过活化Toll样受体4/核因子κB (nuclear factor kappa-B, NF-κB)信号分子, 诱导Th17的生成。Th17细胞及其效应分子IL-17首先在AID的研究中被发现, 在MS和RA等AID的发生发展中均有参与[39, 40]。SLE患者被证实存在外周血Th17/Treg细胞自噬情况, 并参与活动性SLE的发病[41]。
3.6 Tfh细胞与AIDTfh细胞是专职辅助B细胞的CD4+ T细胞, 在促进B细胞活化、体内生发中心的形成、免疫球蛋白类别转换及维持长时间体液免疫应答方面有决定性作用, 产生细胞因子IL-21, 其表达和功能的异常可造成免疫功能紊乱, 引发多种自身免疫性疾病[42]。梁一晨等[43]研究发现Tfh在SLE患者外周血中明显升高, 与抗双链RNA抗体有一定的相关性, 参与SLE的病情进展。王宁等[44]研究显示, RA小鼠外周免疫器官中Tfh细胞比例及其相关免疫分析表达异常升高, 血浆中IL-21显著升高, 证实Tfh细胞与RA的发生和病情进展密切相关。杨雯雯[45]认为IL-21可促进B细胞的增殖分化、抗体类别转换及疾病活动, 参与pSS的发病过程。
4 lncRNA与AID中CD4+ T细胞亚群分化的关系近年来随着对lncRNA研究的不断深入, 证实其在基因调控、染色体复制和RNA剪接方面发挥重要作用。T辅助细胞作为机体免疫调节网络的重要组成部分, 在抗原刺激下的基因表达变化受lncRNA的调控[46]。各种基因敲除与RNA干扰的研究已证实, lncRNA在T细胞的分化、激活和功能调节方面有重要作用[47]。进一步了解lncRNA与AID中CD4+ T细胞亚群分化的关系, 可为AID的发病机制及靶向治疗研究提供更多参考(图 1)。
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Figure 1 Relationship between lncRNA and CD4+ T cell subset differentiation in AID. lcnRNA: Long non-coding RNA; AID: Autoimmune disease; NF-κB: Nuclear factor kappa-B; Th1: T helper 1; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; RA: Rheumatoid arthritis; MAF: Monoclonal antibody to V-maf musculoaponeurotic fibrosarcoma oncogene homolog; DDIY4: DNA damage inducible transcript 4; MS: Multiple sclerosis; INF-1: Interferon-1; OAS: 2'-5' Oligoadenylates synthesis; ETS1: E26 transformation-specific sequence 1; Tfh: T follicular helper; SLE: Systemic lupus erythematosus; PRINS: Psoriasis susceptibility related RNA induced by stress; TLR9: Toll-like receptor; pSS: Primary Sjögren's syndrome; MAPK: Mitogen-activated protein kinase; STAT3: Signal transducer and activator of transcription; PM/DM: Polymyositis-dermatomyositis; GAS5: Growth-arrest specific transcript 5; RhoB: Ras homolog gene family, member B; CLDN8: Claudin 8; UC: Ulcerative colitis |
RA以关节滑膜浸润、关节炎症和软骨破坏为主, 本病的发生是病原体和遗传基因相互作用的结果。病原体进入机体后首先被巨噬细胞吞噬, 后与人白细胞抗原-DR分子结合成复合物, 此复合物可被T细胞受体识别, 激活T辅助细胞和B细胞并促进其分化为浆细胞, 分泌大量的免疫球蛋白, 包括类风湿因子, 引起一系列的免疫反应[48]。NF-κB是关键性的核转录因子, 能诱导CD4+ T细胞向Th1/Th2及Th17分化, 促进TNF-α和IL-1β等炎症因子的分泌, 参与RA的发生。研究[49]发现, 长链非编码RNA母系表达基因3能通过自身基因启动子区甲基化调控核苷酸结合寡聚化结构域受体家族含CARD结构域5蛋白分子的表达, 调节TNF-α和IL-6水平, 参与RA的发生发展。Zhang等[50]证实, lncRNA Hotair通过靶向miR-138和抑制NF-κB途径可缓解RA病情。亦有研究[51]证实, lncRNA-p21可通过部分隔离NF-κB的亚蛋白p65 mRNA抑制NF-κB的活性, 达到抗炎、缓解RA病情的作用。以上研究均表明, lncRNA能通过影响CD4+ T细胞亚群Th1/Th2及Th17的分化, 调节RA患者的病情发展。
4.2 lncRNA与MS中CD4+ T细胞亚群分化的关系MS的病变特点为中枢神经系统白质脱髓鞘, Th1和Th17细胞分泌的细胞因子介导的免疫炎症与本病的发生密切相关[52]。研究[53]显示, lncRNA V-maf肌肉腱膜纤维肉瘤癌基因同源物-4 (monoclonal antibody to V-maf musculoaponeurotic fibrosarcoma oncogene homolog-4)是具有Th1细胞特征性的lncRNA, 可抑制转录因子MAF的表达, 促进T细胞向Th1细胞的分化, 参与MS的发病。Zhang等[54]发现, MS等多种自身免疫性疾病患者中, 其DNA损伤诱导转录因子4 (DNA damage inducible transcript 4, DDIT4)及其相关的lncRNA DDIT4能抑制Th17细胞分化, 幼稚CD4+ T细胞中lncRNA DDIT4的过度表达可增强DDIY4的表达和抑制DDIY4/哺乳动物雷帕霉素靶蛋白途径的激活从而抑制Th17分化, 说明lncRNA DDIT4通过直接靶向DDIT4调节Th17细胞分化, 参与MS的发生。
4.3 lncRNA与SLE中CD4+ T细胞亚群分化的关系SLE属于器官非特异性AID, 其免疫学行为改变较为复杂, 涉及自身反应性T、B细胞的增殖活化、细胞因子的分泌及受体的表达异常、多种自身抗体的产生、补体系统缺陷和NK功能异常等。唐敏等[55]研究发现lncRNA MIR155HG在SLE患者血清中高表达, 其表达水平与疾病活动度相关, 可作为SLE的潜在治疗靶点。MIR155HG中包含miR-155的前体序列, miR-155的过表达可增加SLE中IL-21介导的转录激活因子3信号传导和IL-21的产生, 影响SLE的发生发展[56]。Gao等[57]通过研究lncRNA人肺腺癌转移相关转录本1基因(metastasis associated in lung adenocarcinoma transcript 1, MALAT1)在SLE中的发病机制, 发现SLE患者CD4+ T细胞中的MALAT1水平与I型INF (INF-1)下游效应子2'-5'寡聚腺苷酸合成酶(2'-5' oligoadenylates synthesis, OAS) 2、OAS3和OAS样细胞表达呈正相关, lncRNA MALAT1可通过上调OAS2、OAS3和OAS参与INF-1介导的SLE。戴超[58]研究发现, SLE患者存在Th17细胞比例失衡的情况, SLE患者CD4+ T细胞中miR326可通过抑制E26转录因子1基因转录, 促进Th17的分化。以上研究说明, lncRNA影响CD4+ T细胞中Th17分化, 参与SLE的疾病活动。
4.4 lncRNA与银屑病中CD4+ T细胞亚群分化的关系银屑病是一种以角质形成细胞异常增殖为病理特征的红斑鳞屑性皮肤病。研究[59]显示, CD4+ T细胞在经抗原刺激后活化, 导致外周血Th1、Th2细胞分化失衡, INF-γ、IL-4的分泌增加, 在银屑病中发病机制中有重要作用。Ahn等[60]通过转录组测序技术进行基因共表达, 分析鉴定3个与银屑病显著相关的基因模块和6个与生物治疗显著相关的基因模块, 结果只有16%的银屑病相关基因和5%的治疗相关基因通过差异表达分析被鉴定, 其中超过50%的共表达基因是lncRNA, 说明lncRNA在银屑病的发病机制中发挥重要作用。应激性银屑病相关非编码RNA (psoriasis susceptibility related RNA induced by stress, PRINS)是一个被发现的与银屑病相关的lncRNA, 其在银屑病患者皮损中的表达水平高于正常人[61]。Danis等[62]证实, PRINS能与IL-6在特定位点处结合, 导致IL-6的表达和相应蛋白分泌减少, 抑制炎症反应, 说明lncRNA PRINS能通过降低Th2分泌的IL-6水平, 参与银屑病的炎症过程。
4.5 lncRNA与其他AID中CD4+ T细胞亚群的分化关系此外, 其他不常见的AID中仍有lncRNA的异常表达, 影响CD4+ T细胞亚群的分化, 参与疾病的进展。研究[63]发现lncRNA n340599能调控Toll样受体9信号通路的激活, 刺激INF-γ和IL-17a水平的升高, 在pSS发病早期起促进作用。李玉生[64]研究中, lncRNA AK124826的表达增加能激活丝裂原活化蛋白激酶通路和信号传导及转录激活蛋白3通路, 调控Th17/Treg细胞的分化, 促进CD4+CD45RA+ T细胞向Th17细胞分化, 抑制向Treg细胞分化, 并通过该机制参与多发性皮肌炎/肌炎的发生发展。另外, lncRNA亦可以通过调控生长停滞特异性转录因子5、Rho亚家族蛋白B和紧密连接蛋白8影响IL-1β和IL-6的表达, 参与天疱疮和溃疡性结肠炎等疾病的发生发展[65, 66]。
5 总结与展望CD4+ T细胞各亚群在机体的免疫系统中是相互影响、相互制衡的整体, 在各自的分化过程中受多因素的影响而相互转化。目前, 虽有多项证据表明lncRNA能调控CD4+ T细胞的增殖、分化和功能进而影响AID的发生发展, 但关于其具体参与机制仍未明确。目前, 有明确生物学功能的lncRNA仅是lncRNA家族中的一小部分, 关于lncRNA能否作为AID的预防、诊断、治疗及预后判断指标尚待进一步研究。今后, 仍需深入探索lncRNA家族结构特征和相关基因在病理生理学方面的作用机制, 以阐明其通过CD4+ T细胞影响AID发生发展的具体机制, 为AID的治疗研究提供更有力的参考依据。
作者贡献:刘楠负责文章的选题、文献查找及文章撰写; 李纳、马晓华负责文章部分撰写和修改; 朱琳负责文章修改; 时程程负责文章的选题、思路和框架的提出及文章修改。
利益冲突:所有作者均不存在利益冲突。
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