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固有免疫细胞对结核分枝杆菌的免疫识别

2015-01-22吴小娥陈晶宋淑霞

中国防痨杂志 2015年2期
关键词:凝集素易感性结构域

吴小娥 陈晶 宋淑霞



·综述·

固有免疫细胞对结核分枝杆菌的免疫识别

吴小娥 陈晶 宋淑霞

由结核分枝杆菌感染引起的肺结核已成为非常重要的健康问题,全球每年因结核病死亡的患者超过200万例。机体的固有免疫在抵抗结核分枝杆菌感染过程中发挥了重要作用。多种模式识别受体参与了固有免疫细胞对结核分枝杆菌的识别,包括Toll样受体(TLR)、C-型凝集素受体及核苷酸结合寡聚化结构域(NOD)样受体。在Toll样受体中,TLR2、TLR4及TLR9及其接头分子髓样分化因子(MyD88)在启动针对结核分枝杆菌感染的免疫应答方面发挥了主要作用。另外,其他的模式识别受体,如NOD2、树突状细胞相关性C型植物血凝素-1(Dectin-1)、甘露糖受体及树突状细胞表面特异性C型凝集素-细胞间黏附分子3结合非整合素分子(DC-SIGN)也参与对结核分枝杆菌的识别。流行病学研究发现,模式识别受体基因突变影响机体对结核分枝杆菌感染的易感性。因此,深入研究模式识别受体对结核分枝杆菌的识别特点及基因多态性分布特征,对加深了解结核分枝杆菌致病特点、设计新型抗结核的免疫制剂可提供理论支持。

受体, 模式识别; 结核分枝杆菌; 免疫, 细胞

肺结核是一个主要的公共卫生难题,每年新增患者约1000万例,导致约200万例死亡。但是在估算的最初感染了Mtb的200万例患者中,仅有5%~10%的患者发展为有症状的结核病[1]。

为何有些人感染Mtb后可发展成活动性结核病,而其他人却没有,目前虽尚不完全了解,但参与固有免疫的相关基因变异在肺结核易感性中起着重要作用。机体对Mtb免疫应答的第一步是识别分枝杆菌,其后是启动适应性免疫应答。笔者重点介绍机体固有免疫细胞对Mtb的识别,同时注重固有免疫细胞识别Mtb后细胞内信号在识别Mtb中的作用及机制。最后,讨论相关免疫分子基因变异在结核病的易感性中所起的作用。

天然免疫应答的启动由固有免疫细胞模式识别受体(PRRs)对Mtb的病原体相关模式分子(PAMPs)的识别开始[2]。Mtb细胞壁的成分是免疫细胞对其识别的基础。

对Mtb识别的实验研究

宿主免疫细胞对Mtb的识别作用是复杂的,尽管已经做了广泛的研究,但仍未完全阐明其机理。

一、Toll样受体(TLRs)

TLRs是哺乳动物中由胞浆内模式识别受体(pattern recognition receptors, PRRs)家族中13个组成成员之一。TLRs是在细胞膜的表面或者在主要免疫细胞包括巨噬细胞和树突状细胞(DCs)的胞吞小泡的膜上表达。尽管Mtb被TLRs识别可导致吞噬细胞的激活,但TLRs与Mtb结合后并不会马上引起吞噬细胞对Mtb的摄取。在TLRs识别了特异性分枝杆菌结构后,信号通道被触发,其中接头分子髓样分化因子(myeloid differentiation factor 88,MyD88)起着重要的作用[3]。随后,在信号级联中招募白细胞介素-1受体相关激酶(IL-1 receptor associated kinase,IRAK)、肿瘤坏死因子受体相关因子6(TNF receptor-associated factor 6,TRAF6)、转化生长因子β激活性激酶(TGF β-activated kinase 1,TAK1)和丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs),导致转录因子[如核因子-κB(nuclear factor kappa B,NF-κB)]的核转运[4]。其将引起参与激活天然宿主防御的基因的转录、主要是前炎性细胞因子,如TNF-α、IL-1β、IL-12以及一氧化氮[5]。

有关TLRs在宿主防御分枝杆菌感染中的作用,有人提出多个TLRs的缺失对于揭示这些抗分枝杆菌防御受体所起的作用是有必要的。实际上,TLR2和TLR9双重敲除的小鼠与2个单独TLR敲除的小鼠相比,前者不仅IL-12和干扰素-γ(interferon-γ,IFN-γ)的产生更少,并且这些小鼠即使是在感染了较低接种量的Mtb时也会较早被感染发病[6]。

二、核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)样受体(NOD-like receptors,NLRs)

NLRs蛋白与植物抗病因子R蛋白和凋亡蛋白酶激活因子1(apoptosis protease-activating factor-1,Apaf1)家族高度同源,由超过20个具有保守结构的成员组成。该分子的核心是由核苷酸结合结构域形成的,叫做NACHT [NAIP(neuronal apoptosis inhibitor protein)、CⅡTA[major histocompatibility complex(MHC, 主要组织相容性复合体) class Ⅱ transcription activator]、HET-E(incompatibility locus protein from Podospora anserina,来自于柄孢霉的不相容位点蛋白)、和TP-1(telomerase-associated protein,端粒酶相关蛋白)][7]或NOD。C端部分由一系列富含亮氨酸的重复区组成,可以识别病原体的病原相关分子模式(pathogen-associated molecular patterns,PAMPs)和启动该分子的激活。分子的N段部分含有一个半胱天冬酶活化募集结构域(caspase-activiting and recruitment domain,CARD)(效应结构域),主要参与蛋白间的相互作用[8]。含CARD的NLRs如NOD1和NOD2被认为可以形成低聚物,然后经CARD-CARD相互作用招募受体相互作用蛋白2(receptor interacting protein 2,RIP2),其可以通过CARD-CARD相互作用导致NF-κB的募集[9]。

三、C型凝集素

C型凝集素是一个参与病原体多聚糖结构识别的PRRs家族。甘露糖受体(mannose receptor,MR;CD206)由8个连接的碳水化合物识别结构域和一个富含半胱氨酸的结构域组成。MR在肺泡巨噬细胞中高度表达[10]。分枝杆菌通过MR刺激导致抗炎性细胞因子IL-4和IL-13的产生,抑制IL-12的产生,且损伤氧化反应[11-12]。Mtb的脂阿拉伯甘露糖(lipoarabinomannan,MAN-LAM)和其他Mtb细胞壁的主要成分,如磷脂酰肌醇(phosphatidylinositol mannosides,PIMs)是分枝杆菌上可被肺泡巨噬细胞MR识别的天然配体。此外,将Mtb结合到MR上可诱导吞噬作用,但是却限制了吞噬小体-溶酶体的融合[13-15]。

Mtb菌株间的甘露糖基化水平的差异同样有助于识别C型凝集素。Torrelles等[16]的实验显示,Mtb菌株间毒力的差异可能跟细胞壁上Man-LAM的表达有关。毒性Mtb菌株表面甘露糖基化更少,不能通过MR进行吞噬作用,但可依赖补体受体3(complement receptor 3,CR3)调理作用进行对病原菌的识别和吞噬作用。这些菌株具有更多的显示其毒力的其他细胞膜成分(如磷酸化糖脂和三酰基甘油)[17-18]。这些细胞成分调节对细胞因子的反应,并使其在细胞内快速生长并造成显著的组织损伤[19-20]。相反,大量糖基化的Mtb菌株,如实验室菌株H37Rv,利用MR受体侵入巨噬细胞,使其在巨噬细胞内快速增殖,并产生抗炎性细胞因子,Mtb借此逃避宿主的免疫攻击,并在巨噬细胞内持续存活,随后进入休眠状态[21],因此,此类型的识别可能导致潜伏感染[16]。分枝杆菌并非都如此,如完全缺乏表面甘露糖的突变的牛分枝杆菌菌株,产生的细胞因子与非突变菌株没有区别[22]。

四、树突状细胞表面特异性C型凝集素-细胞间黏附分子3结合非整合素分子(DC-SIGN;CD209)

DC-SIGN(CD209)在Mtb-CD相互作用中起着重要的作用。该受体主要在树突状细胞(dendritic cell,DCs)上表达并主要作为PRR和黏附受体,并参与DC的迁移和DC-T细胞相互作用[23-24]。DC-SIGN的碳水化合物识别结构域可识别Man-LAM和脂质甘露聚糖,Man-LAM的量可以决定结合强度[12]。最近有学者认为α-葡聚糖(一种主导的荚膜多糖)也是DC-SIGN的配体[25]。分枝杆菌通过DC-SIGN感染DC后,一方面促进DC的成熟;另一方面,诱导IL-10的产生[12]。近期研究表明,DC-SIGN经Raf-1诱导NF-κ B亚单位p65的乙酰化而发挥其免疫抑制效应,但该效应仅发生在TLR刺激时才会发生[26]。

五、树突状细胞相关性C型植物血凝素-1(dendritic cell-associated C-type lectin-1, Dectin-1)

Dectin-1是一种具有细胞外碳水化合物识别结构域和细胞内免疫受体酪氨酸活化基序(immunoreceptor tyrosine-based activation motif,ITAM)结构域的受体。该受体主要在巨噬细胞、DCs、中性粒细胞和T细胞上表达。Dectin-1主要识别出现在真菌病原中的β-葡聚糖,但是有人认为其在Mtb识别中同样起着重要的作用。尽管Mtb的一些菌株在细胞表面表达α葡聚糖[27]作为Dectin-1的配体,但Dectin-1识别的确切PAMP尚不清楚。当小鼠骨髓的巨噬细胞感染有毒力或者无毒力的分枝杆菌后,可以不依赖Dectin-1方式或者Dectin-1依赖方式产生TNF-α 和IL-6[28]。多个实验证实在识别真菌病原体时TLR2和Dectin-1间有协同效应[29-30],但是对分枝杆菌的识别是否有同样的结果,目前还没有明确的证据。最近一项报道显示,Dectin-1可以在不依赖于TLR2的情况下识别Mtb,并诱导Mtb特异性的Th1和Th17免疫应答[31]。

对Mtb识别的免疫遗传研究

为了全面了解PRRs在Mtb防御中所起的作用,体外和动物实验的结果需要进一步临床实验的验证。对Mtb的易感性或者耐受性相关基因已经进行了广泛的研究,并发现了几个重要的Mtb易感性候选基因[32-33]。

TLR2基因位于染色体4q32,由2个非编码外显子和一个编码外显子组成[34]。人类TLR2基因的单核苷酸多态性(single nucleotide polymorphisms, SNPs)已报道的有175个之多。据报道土耳其人群中Arg753Gln和结核病的易感性间有关联[35],但同样的结果在2个亚洲人群中并未观察到,因为亚洲人群中缺乏这种特定的多态性[36-37]。Arg753Gln似乎仅出现在白种人中,而东亚人群中仅为0.00%~0.49%[37]。在突尼斯人群中,Arg677Trp与结核病的易感性相关[38],但是该结果因一个假基因的发现(该SNP似乎位于其中)而受到了质疑[39]。在越南人群体中,TLR2的基因型597CC与结核病的易感性有相互关系,尤其是在由特定Mtb基因型家族(“北京基因型”)引起的感染[40-41]。 但中国汉族人597CC基因型与结核病的易感性没有关系[42]。在肺结核和非结核分枝杆菌肺部感染的韩国人群中[43-44],在TLR2基因的第2个内含子内发现了1个高度多态性的鸟嘌呤-胸腺嘧啶重复结构,该重复结构域启动子活性和CD14+外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)中TLR2的表达(重复越短,启动子活性越弱,TLR2的表达量越低)相关。但是这些结果在台湾人群中未发现[45]。最近的一项研究发现,一个似乎可以影响TLR2表达的基因型变异是-196到-174插入和(或)缺失,该基因变异与结核病的易感性相关,但另外一个实验显示其可能只对全身性症状的发展有影响[46]。其他的与结核病易感性有关的TLR2基因多态性的研究很多,但均需要进一步证实。

由于TLR1和TLR6可以与TLR2形成异二聚物,这些受体中的SNPs可能同样会影响TLR2信号系统。其中一个例子就是TLR1中的Ile602SerSNP,其可能会导致异常的TLR1细胞运输,细胞表面没有功能性的TLR1,也可能会影响对分枝杆菌的识别[47]。602I变异在感染了Mtb的非洲裔美国人中过度表达[48]。除此之外,TLR6 SNPsSer249Pro和Thr361Thr 与Mtb-诱导的细胞因子产生有一定的相关性[49]。

另对TLR4和TLR8的研究显示,该基因与结核病易感性没有相关性。TLR4Asp299GlySNP表现出在HIV阳性的白人和坦桑尼亚人中与结核病有相关性,但是在冈比亚人中没有[50]。TLR8与各种PAMPs的识别相关,但是在一个印度尼西亚的免疫遗传学试验中,位于X染色体上的TLR8基因,是惟一显示出与结核病相关的基因。这些结果需要进一步通过实验来证实。

除PRR之外,在TLR信号通道中的SNPs也可能会影响Mtb的易感性。Khor等[51]提出在编码接头蛋白TIRAP的基因中,西亚人Ser180LeuSNP对结核病易感,尽管该突变等位基因的频率极低。但是这一相关性并未在一个包括了来自加纳、俄罗斯和印度尼西亚的9000例个体的试验中得到证实[52]。考虑到其他对于Mtb识别很重要的PRRs,位于树突状细胞表面特异性C型凝集素-细胞间黏附分子3结合非整合素分子(DC-SIGN)启动子区域的871G和336A变异跟南非患者群体的抗肺结核保护力相关[53]。但是这一发现并未在突尼斯人群中证实[54],而且后来一个实验甚至表现出相反方面的相关性(336G的保护效应)[55]。此外,DC-SIGN的颈部区域的基因变异(其可支持碳水化合物识别结构域)并未表现出与肺结核易感性间的关系[53]。

展 望

虽然有关机体对Mtb识别的研究已有了重要进展,但主要集中在体外实验和动物实验。体外实验和动物实验与临床研究存在一定的差异,因为不同来源的细胞PRRs的优先表达可能不同;另外,体外实验中一般只考虑一个特定的受体,而体内的情况是多个不同受体的协同或协调作用。在体内动物试验中,其不足之处是最常用的小鼠结核病模型不能代表人类的结核病;小鼠结核病模型中并不能形成肉芽肿,而肉芽肿的形成是该疾病潜伏期中至关重要的一步。与人体结核病更相近的大鼠和猴子模型用的很少。因此,有关宿主对Mtb识别的分子机制仍需进一步研究。

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(本文编辑:薛爱华)

Innate immune recognition of Mycobacterium tuberculosis

WU Xiao-e*,CHEN Jing,SONG Shu-xia.

*The Second Ward of Cadre Ward,General Hospital of Chinese People Armed Police Forces,Beijing 100039,China

SONG Shu-xia, Email:prosongsx@aliyun.com

Tuberculosis (TB), caused byMycobacteriumtuberculosis(Mtb), is a major health problem, with over 2 million deaths each year in the world. Innate immunity plays an important role in the host defense against Mtb. Several classes of pattern recognition receptors (PPRs) expressed on innate immune cells are involved in the recognition of Mtb, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and NOD-like receptors (NLRs). Among the TLR family, TLR2, TLR4, and TLR9 and their adaptor molecule MyD88 play a leading role in the initiation of the immune response against tuberculosis. In addition to TLRs, other PRRs such as NOD2, Dectin-1, Mannose receptor, and DC-SIGN are also involved in the recognition of Mtb. Human epidemiological studies reveal that genetic variation in genes encoding for PRRs in uences disease susceptibility. Therefore, to explore in depth on the recognition characteristics of PRRs and the distribution of gene polymorphism, does not only lead to a better understanding of the pathogenesis of tuberculosis but also may contribute to the design of novel immunotherapeutic strategies.

Receptors, pattern recognition;Mycobacteriumtuberculosis; Immunity, cellular

10.3969/j.issn.1000-6621.2015.02.014

河北省科技支撑计划项目(13277764D)

100039 北京,武警总医院干部病房二科(吴小娥);武警北京市总队第二医院骨科(陈晶);河北医科大学免疫学教研室(宋淑霞)

宋淑霞, Email:prosongsx@aliyun.com

2014-07-09)

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