吳小娥 陳晶 宋淑霞

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·綜述·

固有免疫細(xì)胞對(duì)結(jié)核分枝桿菌的免疫識(shí)別

吳小娥 陳晶 宋淑霞

由結(jié)核分枝桿菌感染引起的肺結(jié)核已成為非常重要的健康問題，全球每年因結(jié)核病死亡的患者超過200萬例。機(jī)體的固有免疫在抵抗結(jié)核分枝桿菌感染過程中發(fā)揮了重要作用。多種模式識(shí)別受體參與了固有免疫細(xì)胞對(duì)結(jié)核分枝桿菌的識(shí)別，包括Toll樣受體(TLR)、C-型凝集素受體及核苷酸結(jié)合寡聚化結(jié)構(gòu)域(NOD)樣受體。在Toll樣受體中，TLR2、TLR4及TLR9及其接頭分子髓樣分化因子(MyD88)在啟動(dòng)針對(duì)結(jié)核分枝桿菌感染的免疫應(yīng)答方面發(fā)揮了主要作用。另外，其他的模式識(shí)別受體，如NOD2、樹突狀細(xì)胞相關(guān)性C型植物血凝素-1(Dectin-1)、甘露糖受體及樹突狀細(xì)胞表面特異性C型凝集素-細(xì)胞間黏附分子3結(jié)合非整合素分子(DC-SIGN)也參與對(duì)結(jié)核分枝桿菌的識(shí)別。流行病學(xué)研究發(fā)現(xiàn)，模式識(shí)別受體基因突變影響機(jī)體對(duì)結(jié)核分枝桿菌感染的易感性。因此，深入研究模式識(shí)別受體對(duì)結(jié)核分枝桿菌的識(shí)別特點(diǎn)及基因多態(tài)性分布特征，對(duì)加深了解結(jié)核分枝桿菌致病特點(diǎn)、設(shè)計(jì)新型抗結(jié)核的免疫制劑可提供理論支持。

受體, 模式識(shí)別; 結(jié)核分枝桿菌； 免疫, 細(xì)胞

肺結(jié)核是一個(gè)主要的公共衛(wèi)生難題，每年新增患者約1000萬例，導(dǎo)致約200萬例死亡。但是在估算的最初感染了Mtb的200萬例患者中，僅有5%～10%的患者發(fā)展為有癥狀的結(jié)核病[1]。

為何有些人感染Mtb后可發(fā)展成活動(dòng)性結(jié)核病，而其他人卻沒有，目前雖尚不完全了解，但參與固有免疫的相關(guān)基因變異在肺結(jié)核易感性中起著重要作用。機(jī)體對(duì)Mtb免疫應(yīng)答的第一步是識(shí)別分枝桿菌，其后是啟動(dòng)適應(yīng)性免疫應(yīng)答。筆者重點(diǎn)介紹機(jī)體固有免疫細(xì)胞對(duì)Mtb的識(shí)別，同時(shí)注重固有免疫細(xì)胞識(shí)別Mtb后細(xì)胞內(nèi)信號(hào)在識(shí)別Mtb中的作用及機(jī)制。最后，討論相關(guān)免疫分子基因變異在結(jié)核病的易感性中所起的作用。

天然免疫應(yīng)答的啟動(dòng)由固有免疫細(xì)胞模式識(shí)別受體(PRRs)對(duì)Mtb的病原體相關(guān)模式分子(PAMPs)的識(shí)別開始[2]。Mtb細(xì)胞壁的成分是免疫細(xì)胞對(duì)其識(shí)別的基礎(chǔ)。

對(duì)Mtb識(shí)別的實(shí)驗(yàn)研究

宿主免疫細(xì)胞對(duì)Mtb的識(shí)別作用是復(fù)雜的，盡管已經(jīng)做了廣泛的研究，但仍未完全闡明其機(jī)理。

一、Toll樣受體(TLRs)

TLRs是哺乳動(dòng)物中由胞漿內(nèi)模式識(shí)別受體(pattern recognition receptors, PRRs)家族中13個(gè)組成成員之一。TLRs是在細(xì)胞膜的表面或者在主要免疫細(xì)胞包括巨噬細(xì)胞和樹突狀細(xì)胞(DCs)的胞吞小泡的膜上表達(dá)。盡管Mtb被TLRs識(shí)別可導(dǎo)致吞噬細(xì)胞的激活，但TLRs與Mtb結(jié)合后并不會(huì)馬上引起吞噬細(xì)胞對(duì)Mtb的攝取。在TLRs識(shí)別了特異性分枝桿菌結(jié)構(gòu)后，信號(hào)通道被觸發(fā)，其中接頭分子髓樣分化因子(myeloid differentiation factor 88,MyD88)起著重要的作用[3]。隨后，在信號(hào)級(jí)聯(lián)中招募白細(xì)胞介素-1受體相關(guān)激酶(IL-1 receptor associated kinase,IRAK)、腫瘤壞死因子受體相關(guān)因子6(TNF receptor-associated factor 6，TRAF6)、轉(zhuǎn)化生長(zhǎng)因子β激活性激酶(TGF β-activated kinase 1，TAK1)和絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)，導(dǎo)致轉(zhuǎn)錄因子[如核因子-κB(nuclear factor kappa B,NF-κB)]的核轉(zhuǎn)運(yùn)[4]。其將引起參與激活天然宿主防御的基因的轉(zhuǎn)錄、主要是前炎性細(xì)胞因子，如TNF-α、IL-1β、IL-12以及一氧化氮[5]。

有關(guān)TLRs在宿主防御分枝桿菌感染中的作用，有人提出多個(gè)TLRs的缺失對(duì)于揭示這些抗分枝桿菌防御受體所起的作用是有必要的。實(shí)際上，TLR2和TLR9雙重敲除的小鼠與2個(gè)單獨(dú)TLR敲除的小鼠相比，前者不僅IL-12和干擾素-γ(interferon-γ,IFN-γ)的產(chǎn)生更少，并且這些小鼠即使是在感染了較低接種量的Mtb時(shí)也會(huì)較早被感染發(fā)病[6]。

二、核苷酸結(jié)合寡聚化結(jié)構(gòu)域(nucleotide-binding oligomerization domain,NOD)樣受體(NOD-like receptors，NLRs)

NLRs蛋白與植物抗病因子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，由超過20個(gè)具有保守結(jié)構(gòu)的成員組成。該分子的核心是由核苷酸結(jié)合結(jié)構(gòu)域形成的，叫做NACHT [NAIP(neuronal apoptosis inhibitor protein)、CⅡTA[major histocompatibility complex(MHC, 主要組織相容性復(fù)合體) class Ⅱ transcription activator]、HET-E(incompatibility locus protein from Podospora anserina，來自于柄孢霉的不相容位點(diǎn)蛋白)、和TP-1(telomerase-associated protein，端粒酶相關(guān)蛋白)][7]或NOD。C端部分由一系列富含亮氨酸的重復(fù)區(qū)組成，可以識(shí)別病原體的病原相關(guān)分子模式(pathogen-associated molecular patterns，PAMPs)和啟動(dòng)該分子的激活。分子的N段部分含有一個(gè)半胱天冬酶活化募集結(jié)構(gòu)域(caspase-activiting and recruitment domain，CARD)(效應(yīng)結(jié)構(gòu)域)，主要參與蛋白間的相互作用[8]。含CARD的NLRs如NOD1和NOD2被認(rèn)為可以形成低聚物，然后經(jīng)CARD-CARD相互作用招募受體相互作用蛋白2(receptor interacting protein 2,RIP2)，其可以通過CARD-CARD相互作用導(dǎo)致NF-κB的募集[9]。

三、C型凝集素

C型凝集素是一個(gè)參與病原體多聚糖結(jié)構(gòu)識(shí)別的PRRs家族。甘露糖受體(mannose receptor，MR；CD206)由8個(gè)連接的碳水化合物識(shí)別結(jié)構(gòu)域和一個(gè)富含半胱氨酸的結(jié)構(gòu)域組成。MR在肺泡巨噬細(xì)胞中高度表達(dá)[10]。分枝桿菌通過MR刺激導(dǎo)致抗炎性細(xì)胞因子IL-4和IL-13的產(chǎn)生，抑制IL-12的產(chǎn)生，且損傷氧化反應(yīng)[11-12]。Mtb的脂阿拉伯甘露糖(lipoarabinomannan，MAN-LAM)和其他Mtb細(xì)胞壁的主要成分，如磷脂酰肌醇(phosphatidylinositol mannosides，PIMs)是分枝桿菌上可被肺泡巨噬細(xì)胞MR識(shí)別的天然配體。此外，將Mtb結(jié)合到MR上可誘導(dǎo)吞噬作用，但是卻限制了吞噬小體-溶酶體的融合[13-15]。

Mtb菌株間的甘露糖基化水平的差異同樣有助于識(shí)別C型凝集素。Torrelles等[16]的實(shí)驗(yàn)顯示，Mtb菌株間毒力的差異可能跟細(xì)胞壁上Man-LAM的表達(dá)有關(guān)。毒性Mtb菌株表面甘露糖基化更少，不能通過MR進(jìn)行吞噬作用，但可依賴補(bǔ)體受體3(complement receptor 3,CR3)調(diào)理作用進(jìn)行對(duì)病原菌的識(shí)別和吞噬作用。這些菌株具有更多的顯示其毒力的其他細(xì)胞膜成分(如磷酸化糖脂和三酰基甘油)[17-18]。這些細(xì)胞成分調(diào)節(jié)對(duì)細(xì)胞因子的反應(yīng)，并使其在細(xì)胞內(nèi)快速生長(zhǎng)并造成顯著的組織損傷[19-20]。相反，大量糖基化的Mtb菌株，如實(shí)驗(yàn)室菌株H37Rv，利用MR受體侵入巨噬細(xì)胞，使其在巨噬細(xì)胞內(nèi)快速增殖，并產(chǎn)生抗炎性細(xì)胞因子，Mtb借此逃避宿主的免疫攻擊，并在巨噬細(xì)胞內(nèi)持續(xù)存活，隨后進(jìn)入休眠狀態(tài)[21]，因此，此類型的識(shí)別可能導(dǎo)致潛伏感染[16]。分枝桿菌并非都如此，如完全缺乏表面甘露糖的突變的牛分枝桿菌菌株，產(chǎn)生的細(xì)胞因子與非突變菌株沒有區(qū)別[22]。

四、樹突狀細(xì)胞表面特異性C型凝集素-細(xì)胞間黏附分子3結(jié)合非整合素分子(DC-SIGN；CD209)

DC-SIGN(CD209)在Mtb-CD相互作用中起著重要的作用。該受體主要在樹突狀細(xì)胞(dendritic cell，DCs)上表達(dá)并主要作為PRR和黏附受體，并參與DC的遷移和DC-T細(xì)胞相互作用[23-24]。DC-SIGN的碳水化合物識(shí)別結(jié)構(gòu)域可識(shí)別Man-LAM和脂質(zhì)甘露聚糖，Man-LAM的量可以決定結(jié)合強(qiáng)度[12]。最近有學(xué)者認(rèn)為α-葡聚糖(一種主導(dǎo)的莢膜多糖)也是DC-SIGN的配體[25]。分枝桿菌通過DC-SIGN感染DC后，一方面促進(jìn)DC的成熟；另一方面，誘導(dǎo)IL-10的產(chǎn)生[12]。近期研究表明，DC-SIGN經(jīng)Raf-1誘導(dǎo)NF-κ B亞單位p65的乙?；l(fā)揮其免疫抑制效應(yīng)，但該效應(yīng)僅發(fā)生在TLR刺激時(shí)才會(huì)發(fā)生[26]。

五、樹突狀細(xì)胞相關(guān)性C型植物血凝素-1(dendritic cell-associated C-type lectin-1, Dectin-1)

Dectin-1是一種具有細(xì)胞外碳水化合物識(shí)別結(jié)構(gòu)域和細(xì)胞內(nèi)免疫受體酪氨酸活化基序(immunoreceptor tyrosine-based activation motif，ITAM)結(jié)構(gòu)域的受體。該受體主要在巨噬細(xì)胞、DCs、中性粒細(xì)胞和T細(xì)胞上表達(dá)。Dectin-1主要識(shí)別出現(xiàn)在真菌病原中的β-葡聚糖，但是有人認(rèn)為其在Mtb識(shí)別中同樣起著重要的作用。盡管Mtb的一些菌株在細(xì)胞表面表達(dá)α葡聚糖[27]作為Dectin-1的配體，但Dectin-1識(shí)別的確切PAMP尚不清楚。當(dāng)小鼠骨髓的巨噬細(xì)胞感染有毒力或者無毒力的分枝桿菌后，可以不依賴Dectin-1方式或者Dectin-1依賴方式產(chǎn)生TNF-α 和IL-6[28]。多個(gè)實(shí)驗(yàn)證實(shí)在識(shí)別真菌病原體時(shí)TLR2和Dectin-1間有協(xié)同效應(yīng)[29-30]，但是對(duì)分枝桿菌的識(shí)別是否有同樣的結(jié)果，目前還沒有明確的證據(jù)。最近一項(xiàng)報(bào)道顯示，Dectin-1可以在不依賴于TLR2的情況下識(shí)別Mtb，并誘導(dǎo)Mtb特異性的Th1和Th17免疫應(yīng)答[31]。

對(duì)Mtb識(shí)別的免疫遺傳研究

為了全面了解PRRs在Mtb防御中所起的作用，體外和動(dòng)物實(shí)驗(yàn)的結(jié)果需要進(jìn)一步臨床實(shí)驗(yàn)的驗(yàn)證。對(duì)Mtb的易感性或者耐受性相關(guān)基因已經(jīng)進(jìn)行了廣泛的研究，并發(fā)現(xiàn)了幾個(gè)重要的Mtb易感性候選基因[32-33]。

TLR2基因位于染色體4q32，由2個(gè)非編碼外顯子和一個(gè)編碼外顯子組成[34]。人類TLR2基因的單核苷酸多態(tài)性(single nucleotide polymorphisms, SNPs)已報(bào)道的有175個(gè)之多。據(jù)報(bào)道土耳其人群中Arg753Gln和結(jié)核病的易感性間有關(guān)聯(lián)[35]，但同樣的結(jié)果在2個(gè)亞洲人群中并未觀察到，因?yàn)閬喼奕巳褐腥狈@種特定的多態(tài)性[36-37]。Arg753Gln似乎僅出現(xiàn)在白種人中，而東亞人群中僅為0.00%～0.49%[37]。在突尼斯人群中，Arg677Trp與結(jié)核病的易感性相關(guān)[38]，但是該結(jié)果因一個(gè)假基因的發(fā)現(xiàn)(該SNP似乎位于其中)而受到了質(zhì)疑[39]。在越南人群體中，TLR2的基因型597CC與結(jié)核病的易感性有相互關(guān)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]。 但中國(guó)漢族人597CC基因型與結(jié)核病的易感性沒有關(guān)系[42]。在肺結(jié)核和非結(jié)核分枝桿菌肺部感染的韓國(guó)人群中[43-44]，在TLR2基因的第2個(gè)內(nèi)含子內(nèi)發(fā)現(xiàn)了1個(gè)高度多態(tài)性的鳥嘌呤-胸腺嘧啶重復(fù)結(jié)構(gòu)，該重復(fù)結(jié)構(gòu)域啟動(dòng)子活性和CD14+外周血單個(gè)核細(xì)胞(peripheral blood mononuclear cells,PBMCs)中TLR2的表達(dá)(重復(fù)越短，啟動(dòng)子活性越弱，TLR2的表達(dá)量越低)相關(guān)。但是這些結(jié)果在臺(tái)灣人群中未發(fā)現(xiàn)[45]。最近的一項(xiàng)研究發(fā)現(xiàn)，一個(gè)似乎可以影響TLR2表達(dá)的基因型變異是-196到-174插入和(或)缺失，該基因變異與結(jié)核病的易感性相關(guān)，但另外一個(gè)實(shí)驗(yàn)顯示其可能只對(duì)全身性癥狀的發(fā)展有影響[46]。其他的與結(jié)核病易感性有關(guān)的TLR2基因多態(tài)性的研究很多，但均需要進(jìn)一步證實(shí)。

由于TLR1和TLR6可以與TLR2形成異二聚物，這些受體中的SNPs可能同樣會(huì)影響TLR2信號(hào)系統(tǒng)。其中一個(gè)例子就是TLR1中的Ile602SerSNP，其可能會(huì)導(dǎo)致異常的TLR1細(xì)胞運(yùn)輸，細(xì)胞表面沒有功能性的TLR1，也可能會(huì)影響對(duì)分枝桿菌的識(shí)別[47]。602I變異在感染了Mtb的非洲裔美國(guó)人中過度表達(dá)[48]。除此之外，TLR6 SNPsSer249Pro和Thr361Thr 與Mtb-誘導(dǎo)的細(xì)胞因子產(chǎn)生有一定的相關(guān)性[49]。

另對(duì)TLR4和TLR8的研究顯示，該基因與結(jié)核病易感性沒有相關(guān)性。TLR4Asp299GlySNP表現(xiàn)出在HIV陽(yáng)性的白人和坦桑尼亞人中與結(jié)核病有相關(guān)性，但是在岡比亞人中沒有[50]。TLR8與各種PAMPs的識(shí)別相關(guān)，但是在一個(gè)印度尼西亞的免疫遺傳學(xué)試驗(yàn)中，位于X染色體上的TLR8基因，是惟一顯示出與結(jié)核病相關(guān)的基因。這些結(jié)果需要進(jìn)一步通過實(shí)驗(yàn)來證實(shí)。

除PRR之外，在TLR信號(hào)通道中的SNPs也可能會(huì)影響Mtb的易感性。Khor等[51]提出在編碼接頭蛋白TIRAP的基因中，西亞人Ser180LeuSNP對(duì)結(jié)核病易感，盡管該突變等位基因的頻率極低。但是這一相關(guān)性并未在一個(gè)包括了來自加納、俄羅斯和印度尼西亞的9000例個(gè)體的試驗(yàn)中得到證實(shí)[52]?？紤]到其他對(duì)于Mtb識(shí)別很重要的PRRs，位于樹突狀細(xì)胞表面特異性C型凝集素-細(xì)胞間黏附分子3結(jié)合非整合素分子(DC-SIGN)啟動(dòng)子區(qū)域的871G和336A變異跟南非患者群體的抗肺結(jié)核保護(hù)力相關(guān)[53]。但是這一發(fā)現(xiàn)并未在突尼斯人群中證實(shí)[54]，而且后來一個(gè)實(shí)驗(yàn)甚至表現(xiàn)出相反方面的相關(guān)性(336G的保護(hù)效應(yīng))[55]。此外，DC-SIGN的頸部區(qū)域的基因變異(其可支持碳水化合物識(shí)別結(jié)構(gòu)域)并未表現(xiàn)出與肺結(jié)核易感性間的關(guān)系[53]。

展 望

雖然有關(guān)機(jī)體對(duì)Mtb識(shí)別的研究已有了重要進(jìn)展，但主要集中在體外實(shí)驗(yàn)和動(dòng)物實(shí)驗(yàn)。體外實(shí)驗(yàn)和動(dòng)物實(shí)驗(yàn)與臨床研究存在一定的差異，因?yàn)椴煌瑏碓吹募?xì)胞PRRs的優(yōu)先表達(dá)可能不同；另外，體外實(shí)驗(yàn)中一般只考慮一個(gè)特定的受體，而體內(nèi)的情況是多個(gè)不同受體的協(xié)同或協(xié)調(diào)作用。在體內(nèi)動(dòng)物試驗(yàn)中，其不足之處是最常用的小鼠結(jié)核病模型不能代表人類的結(jié)核??；小鼠結(jié)核病模型中并不能形成肉芽腫，而肉芽腫的形成是該疾病潛伏期中至關(guān)重要的一步。與人體結(jié)核病更相近的大鼠和猴子模型用的很少。因此，有關(guān)宿主對(duì)Mtb識(shí)別的分子機(jī)制仍需進(jìn)一步研究。

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(本文編輯：薛愛華)

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

河北省科技支撐計(jì)劃項(xiàng)目(13277764D)

100039 北京，武警總醫(yī)院干部病房二科(吳小娥)；武警北京市總隊(duì)第二醫(yī)院骨科(陳晶)；河北醫(yī)科大學(xué)免疫學(xué)教研室(宋淑霞)

宋淑霞， Email：prosongsx@aliyun.com

2014-07-09)