Toll樣受體在介導(dǎo)結(jié)核分枝桿菌感染免疫反應(yīng)中的作用

郭雪玲(綜述)，劉輝國(審校)

(華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院呼吸與危重癥醫(yī)學(xué)科，武漢 430030)

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Toll樣受體在介導(dǎo)結(jié)核分枝桿菌感染免疫反應(yīng)中的作用

郭雪玲△(綜述)，劉輝國※(審校)

(華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院呼吸與危重癥醫(yī)學(xué)科，武漢 430030)

結(jié)核分枝桿菌是結(jié)核病的致病菌，機(jī)體免疫反應(yīng)在結(jié)核菌的防御和致病中發(fā)揮關(guān)鍵調(diào)控作用。模式識別受體家族中的Toll樣受體(TLRs)能感知結(jié)核桿菌感染，并參與調(diào)控天然免疫和獲得性免疫應(yīng)答；而TLRs亦能介導(dǎo)結(jié)核分枝桿菌的免疫逃避機(jī)制過程，促進(jìn)慢性感染的發(fā)生、發(fā)展。利用免疫佐劑調(diào)控TLRs的功能水平可能有助于增強(qiáng)機(jī)體抗結(jié)核反應(yīng)，并有望成為結(jié)核病預(yù)防和治療的方向。

結(jié)核分枝桿菌；Toll樣受體；天然免疫；獲得性免疫；免疫逃避

Toll樣受體(Toll-like receptors,TLRs)屬于模式識別受體家族，廣泛表達(dá)于巨噬細(xì)胞、樹突狀細(xì)胞和淋巴細(xì)胞的細(xì)胞膜或內(nèi)吞小體表面，可識別病原體相關(guān)分子模式，對外來病原體進(jìn)行早期識別，啟動天然免疫效應(yīng)機(jī)制，促進(jìn)細(xì)胞吞噬及炎性因子和趨化因子的合成和分泌，誘導(dǎo)抗原呈遞細(xì)胞表面表達(dá)共刺激分子，促使T或B細(xì)胞向效應(yīng)T或B細(xì)胞分化，繼而活化獲得性免疫。機(jī)體通過天然免疫和獲得性免疫系統(tǒng)來防御結(jié)核分枝桿菌的入侵，在結(jié)核菌感染初期，TLRs作為天然免疫細(xì)胞活化的調(diào)節(jié)劑發(fā)揮著重要作用，并且TLRs依賴的細(xì)胞反應(yīng)也對隨后發(fā)生的細(xì)胞免疫特性和程度產(chǎn)生影響；TLRs亦參與調(diào)控結(jié)核菌免疫逃逸的發(fā)生，是導(dǎo)致結(jié)核慢性感染的根源所在[1-4]?，F(xiàn)就TLRs在介導(dǎo)結(jié)核分枝桿菌感染免疫反應(yīng)中的作用予以綜述。

1 TLRs簡介

1.1 TLRs家族 Toll蛋白最早是從果蠅體內(nèi)分離，1997年，Medzhitov等[5]首次在人體中分離出果蠅Toll蛋白的同系物，命名為TLR4。迄今已知哺乳動物的TLRs共有13種，其中有10種表達(dá)于人類細(xì)胞膜上[6-7]，TLR2、TLR4和TLR9與結(jié)核分枝桿菌感染尤為密切[1,8]，TLR8亦可能參與結(jié)核菌的感染免疫反應(yīng)[9]。

1.2 TLRs結(jié)構(gòu)和信號途徑 哺乳動物的TLRs為Ⅰ型跨膜蛋白受體，由胞外段、跨膜段及胞內(nèi)段構(gòu)成。胞外段為富含亮氨酸的重復(fù)基序，參與配體識別；胞外段借助富含半胱氨酸的C端側(cè)翼與跨膜段相連接；胞內(nèi)段結(jié)構(gòu)較保守，與人類白細(xì)胞介素1(interleukin 1,IL-1)受體序列具有高度同源性，亦被稱為Toll/IL-1受體同源區(qū)(Toll/IL-1 receptor, TIR)，能與胞內(nèi)多種轉(zhuǎn)接蛋白交互作用以活化下游信號途徑。細(xì)胞膜上的TLRs主要通過髓樣分化因子88(mycloid differentiation factor 88,MyD88)依賴性的和MyD88非依賴性的信號途徑以誘導(dǎo)下游基因的表達(dá)；除了TLR3外的TLRs均能通過激活MyD88促進(jìn)其下游信號蛋白，如白細(xì)胞介素1受體相關(guān)蛋白激酶(IL-1 receptor associated kinases，IRAK)和腫瘤壞死因子受體相關(guān)受體6(tumor necrosis factor receptor associated factor 6，TRAF6)等的活化繼而介導(dǎo)核因子κB(nuclear factor κB,NF-κB)的早期激活和絲裂原活化蛋白激酶(mitogen-activated protein kinase,MAPKs)家族蛋白的活化進(jìn)而誘導(dǎo)炎性介質(zhì)的合成；而TLR3和TLR4活化后亦可以經(jīng)MyD88非依賴的、由能誘導(dǎo)干擾素β生成且含有TIR功能域的轉(zhuǎn)接蛋白所介導(dǎo)的信號途徑參與NF-κB的延時(shí)激活、并促進(jìn)Ⅰ型干擾素和炎性介質(zhì)的生成[3-7]。

1.3 TLRs所識別的配體 不同的TLRs識別各自相應(yīng)的病原體細(xì)胞組分[6-7]。巨噬細(xì)胞膜表面上的TLR2與TLR1或TLR6所形成異源二聚體(TLR2/TLR1或TLR2/TLR6)能識別的配體有革蘭陽性菌的肽聚糖、磷壁酸和脂蛋白，分枝菌屬細(xì)胞壁上的阿拉伯甘露聚糖脂、脂化甘露聚糖、脂蛋白(相對分子質(zhì)量為38 000和19 000)、磷脂酰肌醇甘露糖苷、三酰脂蛋白(TLR2/TLR1)和乙酰脂蛋白(TLR2/TLR6)等[10-11]。TLR4識別的配體主要包括革蘭陰性菌表面的脂多糖和熱激蛋白(60/65)及結(jié)核菌相對分子質(zhì)量為38 000脂蛋白[12-13]。而雙鏈DNA病毒及細(xì)菌和病毒DNA中非甲基化的CpG序列是目前已明確的TLR9所能識別的分子模式。TLR2和TLR4在感知病原體的入侵及啟動天然免疫后進(jìn)一步誘發(fā)炎性應(yīng)答中起主導(dǎo)作用[2,4,14]。

2 TLRs介導(dǎo)結(jié)核分枝桿菌的天然免疫和獲得性免疫應(yīng)答

2.1 TLRs介導(dǎo)結(jié)核菌的天然免疫過程 結(jié)核分枝桿菌與宿主細(xì)胞之間的相互作用十分復(fù)雜，由結(jié)核菌感染所促發(fā)的免疫反應(yīng)伴隨于結(jié)核菌清除和致病的各個(gè)環(huán)節(jié)。天然免疫應(yīng)答是抵御結(jié)核分枝桿菌感染的第一道防線，始于體內(nèi)免疫細(xì)胞膜上模式識別受體，如TLRs、Nod樣受體、補(bǔ)充受體、甘露糖受體、CD14受體、清道夫受體、Fcγ受體和樹突狀細(xì)胞特異性細(xì)胞間黏附分子等，對結(jié)核菌細(xì)胞壁上相應(yīng)病原體相關(guān)分子模式的識別。其中，TLRs在結(jié)核菌的宿主防御反應(yīng)中作為連接天然免疫和獲得性免疫的“橋梁”，起著關(guān)鍵性的誘導(dǎo)作用[2,8]。

結(jié)核菌主要經(jīng)呼吸道入侵機(jī)體。當(dāng)機(jī)體感染結(jié)核菌后，位于巨噬細(xì)胞和樹突狀細(xì)胞膜上的TLRs特異性地識別結(jié)核菌上的病原體相關(guān)分子模式(如相對分子質(zhì)量為19 000和38 000 的脂蛋白、脂化甘露聚糖、磷脂酰肌醇甘露糖苷、阿拉伯甘露聚糖脂和核酸等)，隨后激活轉(zhuǎn)接蛋白MyD88募集IRAK、TRAF6、MAPKs和轉(zhuǎn)錄生長因子β相關(guān)蛋白激酶1等效應(yīng)分子引起細(xì)胞內(nèi)多條信號通路的活化，聯(lián)合誘導(dǎo)NF-κB的活化轉(zhuǎn)位入核，繼而促使下游多種促炎性因子、趨化因子、黏附分子和受體分子靶基因的轉(zhuǎn)錄表達(dá)[4,8,15]，其中最為關(guān)鍵性分子是腫瘤壞死因子和干擾素[14]。而IL-1、IL-6、IL-8等細(xì)胞因子參與募集單核細(xì)胞、中性粒細(xì)胞和淋巴細(xì)胞等炎性細(xì)胞到相應(yīng)病變部位，誘導(dǎo)單核細(xì)胞向巨噬細(xì)胞的分化。巨噬細(xì)胞膜上的TLRs受配體的激動后能上調(diào)誘導(dǎo)型一氧化氮合酶、一氧化氮、活性氧物質(zhì)和活性氮物質(zhì)的合成，并促進(jìn)胞質(zhì)中吞噬體的酸化及吞噬體和溶酶體融合形成吞噬溶酶體的過程，從而介導(dǎo)巨噬細(xì)胞直接殺菌效應(yīng)的發(fā)揮[16-18]。同時(shí)，TLR4激活可引起細(xì)胞內(nèi)LRG47合成增加而促使結(jié)核菌向自噬體聚集，可見TLRs在聯(lián)系天然免疫和自噬過程中亦起到一定作用[19-20]。此外，結(jié)核菌細(xì)胞壁上相對分子質(zhì)量為19 000 的脂蛋白經(jīng)TLR2識別而啟動受感染的吞噬細(xì)胞的凋亡過程，該過程由半胱氨酸蛋白酶8介導(dǎo)[4,11,21-22]。由此說明，TLRs及其相關(guān)信號通路在結(jié)核菌誘導(dǎo)的天然免疫應(yīng)答過程起著核心調(diào)控作用[2-3]。研究表明，TLR2-/-小鼠無法形成正常的結(jié)核肉芽腫，當(dāng)暴露于高劑量的結(jié)核分枝桿菌時(shí)其結(jié)核病的感染率明顯升高，并伴有調(diào)控慢性結(jié)核感染的能力受損，可表現(xiàn)為肺組織結(jié)核肉芽腫中Fox3+調(diào)節(jié)性T細(xì)胞特征性聚集明顯減少及肺部炎性浸潤增加，給予輸注野生型巨噬細(xì)胞后調(diào)節(jié)性T細(xì)胞聚集增加且肺部炎性浸潤減輕[23]。同時(shí)，TLR缺陷型小鼠肺組織中IL-23表達(dá)受抑制導(dǎo)致T(h)17細(xì)胞數(shù)量降低和趨化因子(CXCL9、CXCL10、CXCL11)合成減少[24]。而MyD88基因敲除小鼠更易受結(jié)核菌感染[25-26]。此外，TLR1、TLR2、TLR4、TLR6、TLR8和TLR9基因多態(tài)性的改變與結(jié)核病的患病風(fēng)險(xiǎn)相關(guān)[9,15,27-29]。

2.2 TLRs介導(dǎo)結(jié)核菌的獲得性免疫過程 抗原呈遞細(xì)胞主要包括巨噬細(xì)胞和樹突狀細(xì)胞，在聯(lián)系天然免疫和獲得性免疫間起著關(guān)鍵性作用，在天然免疫應(yīng)答中，結(jié)核菌上的病原體相關(guān)分子模式(如相對分子質(zhì)量為19 000的脂蛋白)被抗原呈遞細(xì)胞膜上的TLRs(主要為TLR2或TLR4)識別并結(jié)合，促進(jìn)樹突狀細(xì)胞的分化成熟，上調(diào)輔助刺激分子和主要組織相容性抗原分子Ⅱ(major histocompatibility complex Ⅱ,MHCⅡ)的轉(zhuǎn)錄表達(dá)，繼而激活T細(xì)胞，促使其進(jìn)一步釋放促炎性細(xì)胞因子，為適應(yīng)性免疫T細(xì)胞應(yīng)答做準(zhǔn)備[4,14,30]。TLRs在機(jī)體獲得性免疫反應(yīng)的激活中是必不可少的，受結(jié)核菌感染的巨噬細(xì)胞上調(diào)多種抗菌免疫效應(yīng)基因的表達(dá)，這些基因與巨噬細(xì)胞在能激動TLR2或TLR4的結(jié)核菌細(xì)胞組分刺激下所合成靶基因種類基本相同；而MyD88功能缺陷的小鼠無法發(fā)揮抗原特異性的Th1細(xì)胞反應(yīng)[30]。可見，天然免疫和獲得性免疫反應(yīng)的協(xié)同作用才能有效地對抗結(jié)核菌的感染。此外，結(jié)核菌裂解物中的脂蛋白成分，如載脂蛋白G和相對分子質(zhì)量為19 000的載脂蛋白，經(jīng)與TLR2/TLR1異二聚體相互作用，能不依賴于抗原呈遞細(xì)胞的介導(dǎo)而直接激活CD4+記憶T細(xì)胞，并誘導(dǎo)細(xì)胞因子釋放和天然免疫細(xì)胞共刺激分子表達(dá)，從而發(fā)揮直接調(diào)節(jié)獲得性免疫反應(yīng)的作用[31]。

3 TLRs介導(dǎo)結(jié)核分枝桿菌的免疫逃避機(jī)制

TLRs除了具有調(diào)節(jié)天然免疫和獲得性免疫應(yīng)答以促進(jìn)機(jī)體清除結(jié)核菌的作用外，還參與結(jié)核菌免疫逃逸機(jī)制的發(fā)生過程。通常，當(dāng)結(jié)核菌入侵機(jī)體后即啟動一系列免疫防御反應(yīng)，包括釋放細(xì)胞因子γ干擾素與巨噬細(xì)胞表面受體結(jié)合，激活Janus激酶/信號轉(zhuǎn)導(dǎo)子和轉(zhuǎn)錄激活子信號通路，導(dǎo)致信號轉(zhuǎn)導(dǎo)子和轉(zhuǎn)錄激活子α亞基發(fā)生磷酸化形成二聚體而轉(zhuǎn)移入核，特異性地結(jié)合位于啟動子區(qū)域的γ干擾素活化序列，誘導(dǎo)MHCⅡ反式激活子(MHCⅡtransactivator,CⅡTA)的活化，從而上調(diào)MHCⅡ表達(dá)。然而，結(jié)核菌細(xì)胞膜上的部分脂蛋白，如相對分子質(zhì)量為19 000的脂蛋白、載脂蛋白G、載脂蛋白A、PhoS1和CFP-10等，可通過TLR2/MyD88介導(dǎo)的信號途徑抑制巨噬細(xì)胞或樹突狀細(xì)胞表面MHCⅡ分子的表達(dá)水平，降低其抗原呈遞作用，造成結(jié)核菌無法被CD4+T細(xì)胞或CD8+T細(xì)胞識別并削弱T細(xì)胞介導(dǎo)的抗結(jié)核菌炎癥反應(yīng)效能，同時(shí)巨噬細(xì)胞中由TLR2調(diào)控的氧化殺菌效應(yīng)亦受抑制，不僅不利于獲得性免疫反應(yīng)產(chǎn)生，還導(dǎo)致結(jié)核菌在巨噬細(xì)胞中的長期存活[1,4,11,30,32-33]。結(jié)核桿菌誘導(dǎo)的MHCⅡ表達(dá)下調(diào)的可能機(jī)制如下。①M(fèi)HCⅡ基因啟動子受抑制：CⅡTA作為轉(zhuǎn)錄激活因子能特異性地結(jié)合于MHCⅡ編碼基因的啟動子區(qū)域，上調(diào)MHCⅡ表達(dá)。研究發(fā)現(xiàn)，結(jié)核菌能劑量依賴性地抑制由干擾素γ刺激后巨噬細(xì)胞內(nèi)CⅡTA和MHCⅡ的表達(dá)水平，推測胞內(nèi)CⅡTA表達(dá)量下降導(dǎo)致了MHCⅡ基因啟動子受抑制[34]。②CIITA活性的降低：當(dāng)TLRs受刺激后其下游信號分子MyD88/IRAK/TRAF6/NF-κB/MAPKs依次被激活，誘導(dǎo)CCAATT/增強(qiáng)子結(jié)合蛋白β和CCAATT/增強(qiáng)子結(jié)合蛋白δ結(jié)合到CⅡTA啟動子區(qū)域，抑制CⅡTA活性而下調(diào)MHCⅡ的表達(dá)水平[35]。結(jié)核菌細(xì)胞壁上的絲氨酸水解酶1通過抑制TLR2-MyD88信號途徑的轉(zhuǎn)導(dǎo)阻礙巨噬細(xì)胞抗炎效應(yīng)的發(fā)揮，當(dāng)絲氨酸水解酶1發(fā)生突變后TLR2-MyD88的抑制解除，使細(xì)胞內(nèi)抗炎細(xì)胞因子的合成與釋放增加，故推測結(jié)核菌依靠其細(xì)胞壁上的某些組分(如絲氨酸水解酶1)阻礙巨噬細(xì)胞表面TLR2的活化，逃避宿主細(xì)胞的早期識別，延緩抗原呈遞過程，影響獲得性免疫的建立，限制機(jī)體抗炎癥反應(yīng)的強(qiáng)度，從而促進(jìn)疾病的進(jìn)展[26]。此外，部分研究發(fā)現(xiàn)TLRs信號途徑的異常能干擾巨噬細(xì)胞內(nèi)吞噬體的成熟過程和功能發(fā)揮，從而影響結(jié)核菌的殺傷效應(yīng)[36]。但也有另外的研究不支持這一結(jié)論，認(rèn)為吞噬體的成熟并不依賴于TLRs信號通路的調(diào)節(jié)[37]。盡管有爭議的存在，但普遍觀點(diǎn)還是認(rèn)為TLRs信號通路是決定吞噬作用后吞噬體去向的關(guān)鍵因素[3]。因此，通過調(diào)節(jié)TLRs介導(dǎo)的免疫殺菌反應(yīng)和免疫逃避之間的平衡有助于機(jī)體結(jié)核菌的清除以控制感染發(fā)展。

4 結(jié) 語

TLRs在調(diào)控結(jié)核菌感染免疫反應(yīng)中的機(jī)制作用十分復(fù)雜，雖然諸多問題仍有待解答，如各TLRs成員間如何協(xié)作參與結(jié)核菌感染免疫應(yīng)答的發(fā)生、發(fā)展，影響TLRs在介導(dǎo)活化或削弱宿主免疫反應(yīng)中的關(guān)鍵因素是什么，改變相應(yīng)因素能否徹底清除潛伏的結(jié)核菌等，但研究表明利用結(jié)核菌相關(guān)組分所制備的免疫佐劑或純化的TLRs激動劑可直接刺激免疫細(xì)胞以激活天然免疫和獲得性免疫系統(tǒng)，有望逆轉(zhuǎn)結(jié)核菌對免疫系統(tǒng)的抑制作用，增強(qiáng)機(jī)體抗菌免疫能力。同時(shí)，隨著更全面深入的研究對TLRs在介導(dǎo)宿主對結(jié)核桿菌感染免疫應(yīng)答過程中的調(diào)控機(jī)制的闡明，將為新的結(jié)核菌疫苗和抗結(jié)核免疫調(diào)節(jié)劑的研制及開展行之有效的結(jié)核病免疫治療提供參考[2,4,14,26,38]。

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Study on the Effect of Toll-like Receptors in Mediation of Immune Responses in Mycobacterium Tuberculosis Infection

GUOXue-ling,LIUHui-guo.

(DepartmentofRespiratoryandCriticalCareMedicine,TongjiHospitalAffiliatedtoTongjiMedicalCollege,HuazhongUniversityofScienceandTechnology,Wuhan430030,China)

Mycobacterium tuberculosis is the pathogenic agent of tuberculosis.The host immune responses have critical regulation effect on the defense and pathogenesis of tuberculosis.Toll-like receptors(TLRs),belonging to pattern recognition receptors family,act as key sensors of mycobacterial infections and can regulate innate immunity and adaptive immunity.Besides,TLRs participate in the immune evasion process of mycobacterium tuberculosis，so as to facilitate the incidence and development of chronic infection.The immune-adjuvant may help to regulate function of TLRs to enhance the host immune response and would become new direction for the prevention and treatment of tuberculosis.

Mycobacterium tuberculosis; Toll-like receptors; Innate immunity; Adaptive immunity； Immune evasion

R392.32； R378.911

A

1006-2084(2015)12-2142-04

10.3969/j.issn.1006-2084.2015.12.011

2014-09-29

2014-12-03 編輯：伊姍