魏巴金 周琳

·綜述·

Toll樣受體家族基因多態(tài)性與移植后相關疾病研究進展

魏巴金1, 2周琳1

Toll樣受體(TLRs)家族是人體固有免疫系統(tǒng)的重要組成部分，目前共有13種蛋白家族成員。TLRs通過識別病原相關分子模式，在固有免疫應答中發(fā)揮著重要的作用，被認為是連接人體固有免疫與獲得性免疫的橋梁。近年來，關于TLRs家族和移植后相關疾病的研究(如排斥反應、移植物失功及感染等)取得了較大的進展。許多研究發(fā)現(xiàn)，TLRs家族基因多態(tài)性不僅可以影響TLRs家族基因的表達，與器官移植術(shù)后相關疾病也密切相關。本綜述系統(tǒng)闡述了近年來TLRs家族基因多態(tài)性與移植后相關疾病的研究進展，希望為將來臨床上開展同類研究提供一定的參考。

基因多態(tài)性； Toll樣受體； 移植

Toll樣受體(toll-like receptors，TLRs)家族屬于模式識別受體(pattern recognition receptors，PRRs)家族的一員，是人體固有免疫系統(tǒng)的重要組成部分。目前已經(jīng)發(fā)現(xiàn)13種TLRs家族成員，其中TLR1～2、TLR4～6表達于細胞膜表面，其余蛋白家族成員則表達于細胞內(nèi)部。通過識別病原相關分子模式，如細菌細胞壁成分，進而激活下游髓樣分化因子88(myeloid differentiation factor 88，MyD88)依賴和不依賴的信號通路，最終引起諸多細胞因子的分泌，在固有免疫應答中發(fā)揮著重要的作用，被認為是連接人體固有免疫和獲得性免疫的橋梁[1-2]。

移植物對于受者而言是進入身體的“異物”，受者通過自身免疫系統(tǒng)對移植物發(fā)動攻擊，達到清除“異物”的作用。TLRs對移植相關的排斥反應、感染、移植物失功等方面有著重要的影響。部分TLRs的信使RNA(messenger RNA，mRNA)水平在發(fā)生急性排斥反應的腎移植受者中明顯升高，且與炎癥反應密切相關[3]。在一項小鼠腎移植實驗中發(fā)現(xiàn)，通過OPN301抑制TLR2，對移植物的缺血再灌注損傷具有保護作用[4]。丙型肝炎患者肝移植術(shù)后肝硬化與其TLR3和TLR7/8功能缺失存在一定的聯(lián)系[5]。

部分TLRs家族的單核苷酸多態(tài)性(single nucleotide polymorphism，SNP)(如位點rs4986790、rs11536889等)可以引起TLRs蛋白表達改變，繼而影響TLRs及下游相關基因的激活，影響移植術(shù)后受者預后以及并發(fā)癥發(fā)生情況[6-7]。本文就TLRs家族基因多態(tài)性與移植相關疾病的研究進展作一綜述。

1 肝移植

TLR3位點rs3775291等位基因T是肝移植受者術(shù)后發(fā)生急性排斥反應的保護因素，攜帶等位基因T的受者和非攜帶受者相比，急性排斥反應的發(fā)生率降低近60%[8]。而且，單因素研究指出，位點rs3775291的基因多態(tài)性與丙型肝炎患者肝移植預后有關，但多因素分析未能提示陽性結(jié)果[9]。美國一項研究指出，TLR2位點rs5743708純合子基因型與丙型肝炎患者肝移植術(shù)后發(fā)生移植物失功和死亡率存在關聯(lián)[10]。同時，該位點基因多態(tài)性對肝移植術(shù)后感染性疾病也有諸多影響，雖然該位點與肝移植術(shù)后革蘭陽性菌感染無關，但其變異型基因攜帶者具有較高的感染再發(fā)率和休克發(fā)生率[11]；此外，該位點純合子基因型的肝移植受者術(shù)后發(fā)生CMV感染時，CMV復制和發(fā)生組織侵犯性CMV感染的風險均有所提高[12-13]。Brown等[14]研究證明，該位點SNP可以影響TLR2對HCV核心蛋白和非結(jié)構(gòu)蛋白3的識別，可能會為肝移植術(shù)后移植物失功發(fā)病機制的研究提供新的思路。有研究表明，TLR4位點rs4986790和rs4986791基因多態(tài)性與肝移植術(shù)后是否發(fā)生革蘭陰性菌感染無明顯聯(lián)系[15]。Dhillon等[16]認為，受者位點rs4986790是變異型時，丙型肝炎肝移植術(shù)后發(fā)生移植物失功的風險較高；另一項研究指出，供者位點rs11536865和rs5030717對肝移植術(shù)后發(fā)生移植物失功也有影響[17]。一個位于TLR4基因3′-UTR區(qū)的位點rs11536889 CC基因型可能會提高肝移植術(shù)后乙型肝炎復發(fā)風險，后期實驗發(fā)現(xiàn)其還可以影響TLR4的表達和功能[7]。他克莫司的用量也受到供者TLR4位點rs1927907的影響，在移植早期，擁有該位點等位基因A的受者他克莫司濃度/劑量比值一般較低[18]。

2 腎移植

腎移植研究中，關于急性排斥反應、感染、移植物失功等與TLRs基因多態(tài)性的相關性研究愈來愈深入。Nogueira等[19]發(fā)現(xiàn)，在腎移植受者中，TLR2和TLR4的表達均較低，且TLR4位點rs4986790和rs4986791的基因多態(tài)性不僅影響TLR4的基因表達，還可以影響TLR2的基因表達，提示可能存在不同基因間的連鎖不平衡。Ducloux等[20]將擁有TLR4位點rs4986790和rs4986791的任意變異型受者定義為變異型攜帶者，與野生型攜帶者相比，變異型攜帶者腎移植術(shù)后急性排斥反應發(fā)生率較低而感染發(fā)生率較高。TLR4位點rs4986790和rs4986791基因多態(tài)性與腎移植術(shù)后受者是否發(fā)生急性排斥反應無關，但接受攜帶變異型基因型供器官的受者移植術(shù)后急性排斥反應發(fā)生率較低[21]。也有研究指出，TLR4位點rs4986790和rs4986791的基因型變化對受者腎移植術(shù)后急性腎小管壞死、排斥反應和感染等并發(fā)癥的發(fā)生沒有影響[22]。同樣，在關于TLR4和白細胞分化抗原14的一項聯(lián)合研究中，研究人員發(fā)現(xiàn)，TLR4位點rs4986790的基因多態(tài)性未影響受者腎移植術(shù)后急性排斥反應、慢性移植物腎病等并發(fā)癥發(fā)生情況[23]。無論是受者還是供者攜帶TLR4位點rs10759932的等位基因C時，腎移植術(shù)后急性排斥反應發(fā)生率降低，且相比未攜帶等位基因C的受者，攜帶等位基因C的受者術(shù)后急性排斥反應發(fā)生風險降低了近75%[24]。此外，TLR4位點rs4986790和rs4986791的基因多態(tài)性不但與CMV感染相關，而且還是CMV病的影響因素[25]。

在一項德國的研究中，研究人員檢測了TLR2、TLR3、TLR4、TLR5、TLR9內(nèi)11個SNP位點，發(fā)現(xiàn)攜帶TLR3位點rs3775291非等位基因C的受者具有較高的急性排斥反應發(fā)生率，TLR9位點rs5743836的基因多態(tài)性可能提示移植后嚴重心臟不良事件(心肌梗死、惡性心律失常、急性心力衰竭和心臟介入手術(shù)等)，但未發(fā)現(xiàn)TLRs上述位點基因多態(tài)性與移植物生存、移植腎功能和各類術(shù)后感染相關[26]。受者在沒有接受移植術(shù)前預防性用藥的情況下，TLR9位點rs5743836的等位基因TT對于術(shù)后CMV感染的發(fā)生具有明顯的保護作用[27]。在一項關于腎移植受者術(shù)后急性排斥反應發(fā)生情況的研究中，研究人員發(fā)現(xiàn)TLR9位點rs352140等位基因AA與GG相比，具有較好的保護作用，急性排斥風險可以降低約70%[28]。TLR9位點rs187084的等位基因C和rs352140等位基因A緊密連鎖(I2=0.93)，均對腎移植受者術(shù)后急性排斥反應發(fā)生和腎小球濾過率有保護作用[29]。

3 造血干細胞移植

芬蘭一項關于異基因造血干細胞的研究發(fā)現(xiàn)，TLR1位點rs4833079、TLR4位點rs4837656和rs17582214、TLR5位點rs10737416、TLR6位點rs6531656以及TLR10位點rs337629均與移植術(shù)后發(fā)生急性移植物抗宿主病(graft versus host disease，GVHD)相關，而且TLR5的兩個位點rs2800237和rs2800230還與慢性GVHD有關[30]。與其他基因型相比，受者具有TLR4位點rs2770150等位基因TT，其發(fā)生嚴重GVHD的風險提高11倍[31]。供者TLR9位點rs352139和rs352140的基因多態(tài)性被認為可以影響受者移植術(shù)后急性GVHD和CMV感染的發(fā)生情況，二者的單倍體基因型甚至可以作為預測受者5年生存率的影響因子[32]。但西班牙一項研究發(fā)現(xiàn)，TLR9位點rs352140與CMV感染不存在聯(lián)系[33]。Mensah等[34]將TLR4位點rs4986790和rs4986791同時存在變異型定義為“危險等位基因”，其對受者術(shù)后是否發(fā)生革蘭陰性菌感染存在邊緣預測意義(P=0.06)。一項涉及TLR2、TLR3、TLR4、TLR9的基因多態(tài)性與移植后曲霉感染的相關性研究中，非親屬間移植，供者TLR4位點rs4986790和rs4986791組成的單倍體基因型可以預測移植術(shù)后進展性曲霉病發(fā)生情況[35]。

TLR9位點rs5743836對于受者移植術(shù)后病毒性肺炎具有保護作用，TLR4位點rs4986790和rs4986791與移植術(shù)后真菌感染的關系存在不一致現(xiàn)象，即上述2個位點變異型基因型的存在有助于真菌定殖，但卻與真菌感染、真菌肺炎呈負相關[36]。同時，有研究表明，只要TLR4位點rs4986790和rs4986791二者存在任一變異型，受者術(shù)后發(fā)生進展性曲霉病的風險增加，但不影響受者術(shù)后生存時間[37]。荷蘭的一項研究中，研究人員發(fā)現(xiàn)TLR4位點rs4986790的基因多態(tài)性與進展性曲霉病發(fā)生有關[38]。進展性曲霉病發(fā)生不受供者TLR1、TLR4、TLR6基因多態(tài)性的影響，而與受者TLR1位點rs5743611的基因多態(tài)性和由其構(gòu)成的單倍體基因型密切相關[39]。同樣，在對TLR5終止密碼子位點rs5744168的研究中，研究人員發(fā)現(xiàn)受者攜帶等位基因T時，發(fā)生進展性曲霉病風險較高[40]。攜帶TLR4位點rs4986790的變異型受者，發(fā)生造血干細胞移植術(shù)后缺血性膀胱炎的風險降低，這一結(jié)果為研究出血性膀胱炎的發(fā)生機制提供了一些幫助[41]。Kornblit等[42]通過對10個TLRs家族基因的29個SNP位點進行檢測，發(fā)現(xiàn)供者TLR8位點rs3764879基因多態(tài)性與造血干細胞移植預后存在相關性；攜帶TLR9位點rs187084等位基因CC與等位基因CT、TT相比，受者5年生存率提高了約25%[43]。

4 肺移植

位點rs4986790與rs4986790是TLR4基因中功能性SNP，研究表明，攜帶上述位點突變基因型受者肺移植術(shù)后急性排斥反應發(fā)生率較低[44]。在一項涉及TLR1～10基因的64個標簽SNP位點的研究中，TLR2位點rs1898830和rs7656411、TLR4位點rs1927911以及TLR9位點rs352162和rs187084的基因多態(tài)性與肺移植術(shù)后發(fā)生閉塞性細支氣管炎密切相關，多數(shù)發(fā)生閉塞性細支氣管炎的受者攜帶3～4 個危險等位基因[45]。

5 總 結(jié)

雖然目前有關TLRs家族基因多態(tài)性與移植術(shù)后相關疾病的研究結(jié)果大多是初步的，而且缺乏大樣本、多中心的臨床試驗驗證，多數(shù)研究還處于探索階段，僅提供了二者的相關性，可能存在較多的假陽性，而且對于基因多態(tài)性如何影響移植后相關疾病的發(fā)生機制目前研究較少，特別是位于非編碼區(qū)的基因多態(tài)性功能研究較為缺乏，期待在未來的研究中會有更多的發(fā)現(xiàn)。雖然目前的實驗存在許多缺陷，但是為未來個體化診治提供了一種可能的途徑，相信關于TLRs家庭基因多態(tài)性與移植術(shù)后相關疾病的研究將會受到越來越多的重視。隨著測序技術(shù)的不斷提高和應用成本的不斷下降，期待其可以廣泛應用于臨床工作。

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(本文編輯：徐小明)

魏巴金, 周琳. Toll樣受體家族基因多態(tài)性與移植后相關疾病研究進展[J/CD]. 中華移植雜志: 電子版, 2016,10(2):92-96.

Progress on the association between polymorphisms of toll-like receptors and correlated disease after transplantation

WeiBajin1, 2,ZhouLin1.

1KeyLaboratoryofOrganTransplantation,2DiagnosisandTreatmentofBreastDiseasesCenter,theFirstAffiliatedHospital,SchoolofMedicine,ZhejiangUniversity,Hangzhou310003,China

ZhouLin,Email：linzhou19@163.com

Toll-like receptors (TLRs) were a family receptor belonged to the pattern recognition receptors, which played a key role in innate immunity. There were 13 family members at present. TLRs activated the innate immune by recognizing pathogen-associated molecular patterns and they were considered as the bridge which could connect natural immunity and adaptive immunity. Great achievements had been obtained on the relationship between TLRs and correlated diseases after transplantation (rejection, graft dysfunction, infection and so on) in recent years. Polymorphisms in TLRs were also found to not only influence expression of itsself but also correlated diseases after transplantation. This review tried to review progress on the association between polymorphisms of TLRs family and correlated disease after transplantation, hoping to provide reference for carrying forward similar research in the furture.

Gene polymorphism; Toll-like receptors; Transplantation

10.3877/cma.j.issn.1674-3903.2016.02.010

310003 杭州，浙江大學醫(yī)學院附屬第一醫(yī)院器官移植重點實驗室1，乳腺疾病診治中心2

周琳，Email: linzhou19@163.com

2016-02-17)