盧雨萌， 程韻楓

復(fù)旦大學(xué)附屬中山醫(yī)院血液科，上海 200032

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原發(fā)免疫性血小板減少癥中調(diào)節(jié)性T淋巴細(xì)胞的異常

盧雨萌， 程韻楓*

復(fù)旦大學(xué)附屬中山醫(yī)院血液科，上海 200032

原發(fā)免疫性血小板減少癥(immune thrombocytopenia, ITP)是一種自身免疫性疾病，表現(xiàn)為血小板減少和出血風(fēng)險(xiǎn)增加。除了自身反應(yīng)性B細(xì)胞產(chǎn)生的血小板自身抗體對(duì)血小板的破壞以及Th1/Th2細(xì)胞的失衡外，對(duì)調(diào)節(jié)性T淋巴細(xì)胞的研究也越來(lái)越引起重視。經(jīng)典的調(diào)節(jié)性T淋巴細(xì)胞是CD4+T淋巴細(xì)胞的一個(gè)亞群，能抑制免疫反應(yīng)。而最近研究發(fā)現(xiàn)CD8+的調(diào)節(jié)性T淋巴細(xì)胞也與ITP發(fā)病和治療有關(guān)?，F(xiàn)著眼于調(diào)節(jié)性T淋巴細(xì)胞數(shù)量與功能的異常在ITP發(fā)病機(jī)制中發(fā)揮的作用做一綜述。

免疫性血小板減少癥；發(fā)病機(jī)制；調(diào)節(jié)性T淋巴細(xì)胞

1 免疫性血小板減少癥

1.1 介紹 免疫性血小板減少癥(immune thrombocytopenia, ITP)，以前被稱為特發(fā)性血小板減少性紫癜，是以外周血血小板計(jì)數(shù)降低(血小板<100×109/L)和出血風(fēng)險(xiǎn)增加為特征的一種自身免疫性疾病。ITP分為原發(fā)性ITP和繼發(fā)性ITP。原發(fā)性ITP是指排除其他可能導(dǎo)致ITP的誘因或疾病后只有血小板減少一項(xiàng)實(shí)驗(yàn)室指標(biāo)異常的自身免疫性疾病。繼發(fā)性ITP是指除原發(fā)性ITP以外的所有ITP，常見(jiàn)病因如系統(tǒng)性紅斑狼瘡，丙型肝炎病毒感染，以及幽門螺桿菌感染等。ITP按臨床病程及病情可分為：(1)新診斷的ITP，確診后3個(gè)月以內(nèi)的ITP患者；(2)持續(xù)性ITP，確診后3～12個(gè)月血小板持續(xù)減少的ITP患者；(3)慢性ITP，血小板減少持續(xù)超過(guò)12個(gè)月的ITP患者；(4)重癥ITP，PLT<10×109/L，且就診時(shí)存在需要治療的出血癥狀或常規(guī)治療中發(fā)生新的出血癥狀；(5)難治性ITP，患者脾切除后無(wú)效或者復(fù)發(fā)，仍需要通過(guò)治療以降低出血的風(fēng)險(xiǎn)，除其他原因引起的血小板減少癥外，確診為ITP[1]。

1.2 發(fā)病機(jī)制 通常認(rèn)為，ITP患者體內(nèi)的血小板自身抗體是引起血小板減少的主要原因，自身抗體導(dǎo)致血小板的免疫性破壞過(guò)多。目前公認(rèn)的血小板自身抗體包括抗GPIIb/IIIa和抗GPIb/IX抗體等[2]。此外，T淋巴細(xì)胞也參與了ITP的發(fā)病。T淋巴細(xì)胞主要包括CD4+T淋巴細(xì)胞和CD8+T淋巴細(xì)胞。CD8+T淋巴細(xì)胞表達(dá)FasL和TNF-α，產(chǎn)生穿孔素、顆粒酶等，通過(guò)細(xì)胞毒作用導(dǎo)致巨核細(xì)胞和血小板的凋亡和破壞增加[3-5]。自身反應(yīng)性B淋巴細(xì)胞產(chǎn)生血小板自身抗體需要CD4+T細(xì)胞的協(xié)助，CD4+T細(xì)胞通過(guò)分泌多種細(xì)胞因子以及提供第二刺激信號(hào)等促進(jìn)B細(xì)胞的分化增殖、抗體類別轉(zhuǎn)換等。CD4+T淋巴細(xì)胞包括Th1、Th2、Th17和調(diào)節(jié)性T淋巴細(xì)胞(regulatory T cell,Treg)等細(xì)胞亞群。Th1和Th2細(xì)胞是CD4+T輔助細(xì)胞(下文簡(jiǎn)稱為Th細(xì)胞)重要的兩個(gè)亞群，已有研究證實(shí)ITP中存在Th1細(xì)胞的優(yōu)勢(shì)，疾病發(fā)作期Th1/Th2比例向Th1細(xì)胞傾斜，治療緩解后Th1/Th2比例恢復(fù)正常[6-9]。Th17細(xì)胞是另一個(gè)CD4+T細(xì)胞的亞群，可以產(chǎn)生IL-17(也稱為IL-17A)和IL-17F，有研究發(fā)現(xiàn)ITP患者血液中Th17細(xì)胞數(shù)量及其分泌的細(xì)胞因子存在異常，而經(jīng)地塞米松治療后可糾正[10-12]。其他的發(fā)病機(jī)制包括病毒感染后單核巨噬細(xì)胞系統(tǒng)的激活及抗原模擬，骨髓中巨核細(xì)胞的成熟障礙和凋亡增加以及ITP的基因易感性等。

經(jīng)典的Treg細(xì)胞是指CD4+T細(xì)胞的一個(gè)亞群，而近些年發(fā)現(xiàn)CD8+T細(xì)胞也存在Treg細(xì)胞。下文主要著眼于Treg細(xì)胞數(shù)量及功能的異常在ITP發(fā)病中所起的作用。

2 調(diào)節(jié)性T淋巴細(xì)胞

2.1 CD4+調(diào)節(jié)性T淋巴細(xì)胞 Treg細(xì)胞特異性表型為CD4+CD25+Foxp3+，其組成性表達(dá)細(xì)胞毒T淋巴細(xì)胞抗原4(CTLA-4)，是免疫共刺激分子CD80和CD86的抑制性受體。Treg細(xì)胞可以進(jìn)一步分為兩個(gè)亞型，自然Treg(nreg)和誘導(dǎo)Treg(iTreg)。nTreg由幼稚的胸腺淋巴細(xì)胞直接分化而來(lái)，天然表達(dá)CD25和Foxp3，具有免疫調(diào)節(jié)功能。而iTreg是由幼稚的CD4+T淋巴細(xì)胞在IL-2/TGF-β的誘導(dǎo)下分化而來(lái)。

CD4+Treg細(xì)胞能通過(guò)幾種不同的機(jī)制抑制免疫反應(yīng)：(1)產(chǎn)生并分泌免疫調(diào)節(jié)性細(xì)胞因子，如IL-10，IL-35和TGF-β[13-14]；(2)細(xì)胞表面的CD25是IL-2受體家族的一員，可競(jìng)爭(zhēng)性作用于效應(yīng)T細(xì)胞的IL-2，抑制其增殖[15]；(3)細(xì)胞表面的CD39和CD73可以水解ATP，產(chǎn)生腺苷酸，與效應(yīng)細(xì)胞表面的腺苷酸受體結(jié)合后，抑制效應(yīng)T細(xì)胞的增殖和樹(shù)突狀細(xì)胞的功能[16-17]；(4)產(chǎn)生穿孔素B，溶解靶細(xì)胞[18-20]；(5)細(xì)胞間接觸和相互作用，如通過(guò)Treg細(xì)胞表面CTLA-4競(jìng)爭(zhēng)性結(jié)合CD80/CD86，傳遞負(fù)性調(diào)節(jié)信號(hào)，抑制APC和其他免疫效應(yīng)細(xì)胞的活化和功能[21-23]。

2.2 CD8+調(diào)節(jié)性T淋巴細(xì)胞 CD8+Treg細(xì)胞是CD8+T細(xì)胞的一個(gè)亞群，最先在七十年代Gershon的實(shí)驗(yàn)中被發(fā)現(xiàn)[24]。由于缺乏可靠的表面標(biāo)志來(lái)區(qū)分CD8+Treg和傳統(tǒng)CD8+T細(xì)胞，其研究一直停滯不前。一些不同的實(shí)驗(yàn)探索了CD8+Treg細(xì)胞可能的表面標(biāo)志，如CD8+CD28-[25]、CD8+CD45RO+CCR7+[26]，但仍缺乏統(tǒng)一的標(biāo)準(zhǔn)。Lu等人在小鼠的動(dòng)物實(shí)驗(yàn)中發(fā)現(xiàn)Qa-1限制性CD8+T細(xì)胞可能是最能代表這類Treg的細(xì)胞亞群，即能限制性識(shí)別MHC-Ib的產(chǎn)物Qa-1。這種CD8+T細(xì)胞能識(shí)別抗原提呈細(xì)胞和CD4+Th細(xì)胞表面的Qa-1從而被激活。在人類中的CD8+調(diào)節(jié)性T細(xì)胞限制性識(shí)別非經(jīng)典MHC分子HLA-E，其與Qa-1有73%的同源性[27]。Qa-1缺陷的小鼠容易發(fā)生自身免疫性疾病如自身免疫性腦脊髓炎，而給予了Qa-1限制性CD8+T細(xì)胞后則控制了腦脊髓炎的發(fā)展及復(fù)發(fā)。在體外，IL-15能促進(jìn)CD8+Treg細(xì)胞的增殖，而不使其表型發(fā)生明顯變化[28]。CD8+Treg細(xì)胞的作用機(jī)理尚未探索明朗，目前的研究發(fā)現(xiàn)其可以產(chǎn)生免疫抑制因子IL-10[29]以及通過(guò)穿孔素介導(dǎo)細(xì)胞毒性作用來(lái)發(fā)揮免疫抑制作用[30]。

3 ITP中調(diào)節(jié)性T淋巴細(xì)胞的數(shù)量和功能異常

3.1 ITP與CD4+調(diào)節(jié)性T淋巴細(xì)胞 CD4+Treg細(xì)胞在多種自身免疫性疾病中均存在數(shù)量及功能的異常，如系統(tǒng)性紅斑狼瘡和多發(fā)性硬化[31]等。ITP作為一種自身免疫性疾病，CD4+Treg細(xì)胞可能發(fā)揮的作用引起許多關(guān)注，因此也有一系列相關(guān)的研究。從2007年至今，大多數(shù)的研究結(jié)果都表明，ITP患者外周血中CD4+Treg細(xì)胞的數(shù)量和比例有明顯降低，并且急性期和未緩解ITP患者外周血CD4+Treg細(xì)胞的數(shù)量和比例低于緩解期[32-33]。但有少部分的研究卻給出了不同的結(jié)果，其并未發(fā)現(xiàn)ITP患者與健康對(duì)照者外周血中CD4+Treg細(xì)胞的數(shù)量和比例有差異[34-35]。這些不同的研究結(jié)果可能是由于對(duì)Treg細(xì)胞所使用的表面標(biāo)記不同所致，如CD4+CD25+Foxp3+，CD4+CD25highFOXP3+，CD4+FOXP3+等，因此針對(duì)了Treg細(xì)胞不同的亞群。除了外周血，ITP患者骨髓和脾臟也可能有Treg細(xì)胞的數(shù)量及比例的降低[34, 36]，Daridon等發(fā)現(xiàn)脾臟生發(fā)中心和增生性淋巴小結(jié)區(qū)的Treg細(xì)胞數(shù)量的減少[37]。這些都提示了ITP患者外周循環(huán)和淋巴器官Treg細(xì)胞數(shù)量的缺陷。通過(guò)Treg細(xì)胞在體外與效應(yīng)T細(xì)胞共培養(yǎng)后檢測(cè)效應(yīng)T細(xì)胞的增殖情況，檢測(cè)血漿中或Treg細(xì)胞體外培養(yǎng)后分泌的抑制性細(xì)胞因子如IL-10、TGF-β等，發(fā)現(xiàn)了ITP患者外周血中Treg細(xì)胞的功能也有明顯降低[32-33,35,38-40]。地塞米松、利妥昔單抗和TPO受體激動(dòng)劑均可以提高急性期ITP患者外周血Treg細(xì)胞的數(shù)量和比例[41-43]，利妥昔單抗和TPO受體激動(dòng)劑還可以增強(qiáng)Treg細(xì)胞對(duì)效應(yīng)T細(xì)胞的抑制作用[42-43]。Aslam通過(guò)建立小鼠模型，發(fā)現(xiàn)ITP可能是因?yàn)樾叵俚目哿舳鴮?dǎo)致外周血和脾臟中Treg細(xì)胞數(shù)量的下降，并且大劑量丙種球蛋白治療可以扭轉(zhuǎn)這種異常[44]。此外，Zhong發(fā)現(xiàn)可能是CD16+的單核細(xì)胞抑制了Treg細(xì)胞的增殖，使ITP患者出現(xiàn)Treg細(xì)胞數(shù)量的缺陷[45]。

2012年Nishimoto通過(guò)向BALB/c裸鼠輸注去除Treg細(xì)胞的CD4+T細(xì)胞來(lái)構(gòu)建Treg細(xì)胞缺陷小鼠模型。研究發(fā)現(xiàn)在69只CD4+Treg細(xì)胞缺陷的小鼠中，25只出現(xiàn)了持續(xù)至少5周的血小板減少伴隨外周血血小板相關(guān)抗體的升高。構(gòu)建小鼠模型時(shí)如果預(yù)防性輸注Treg細(xì)胞可以預(yù)防血小板減少的發(fā)生，但當(dāng)血小板減少發(fā)生后再輸注Treg細(xì)胞則無(wú)明顯作用。給予小鼠抗CTLA-4多克隆抗體去封閉CTLA-4，能夠使輸注Treg細(xì)胞預(yù)防血小板減少的作用消失。這些都證實(shí)了Treg細(xì)胞的缺陷在ITP發(fā)病中的重要作用，并且Treg細(xì)胞可能是通過(guò)CTLA-4來(lái)預(yù)防ITP發(fā)生[46]。

這一系列的研究揭示了ITP患者體內(nèi)Treg細(xì)胞數(shù)量及功能的缺陷，同時(shí)發(fā)現(xiàn)地塞米松、TPO受體激動(dòng)劑和丙種球蛋白等能扭轉(zhuǎn)這種異常。這些均提示Treg細(xì)胞既參與了ITP的發(fā)病，同時(shí)在ITP的緩解中也扮演重要角色。

3.2 ITP與CD8+調(diào)節(jié)性T淋巴細(xì)胞 研究者對(duì)CD8+T淋巴細(xì)胞在許多自身免疫性疾病中的作用都進(jìn)行了探索。比如一系列動(dòng)物實(shí)驗(yàn)證實(shí)，無(wú)論通過(guò)注射抗CD8多克隆抗體來(lái)去除體內(nèi)CD8+T淋巴細(xì)胞，還是先天CD8+T淋巴細(xì)胞缺陷的小鼠，均容易發(fā)生多種自身免疫性疾病，如自身免疫性腦脊髓炎、自身免疫性心肌炎等[47-49]，說(shuō)明CD8+T細(xì)胞中除了傳統(tǒng)的CTL之外，還存在一群能調(diào)節(jié)免疫反應(yīng)并預(yù)防自身免疫性疾病發(fā)生的細(xì)胞，即CD8+Treg細(xì)胞。進(jìn)一步的實(shí)驗(yàn)發(fā)現(xiàn)CD8+Treg細(xì)胞的免疫調(diào)節(jié)作用依賴于活化CD4+T細(xì)胞表面的Qa-1，CD8+Treg細(xì)胞表面的TCR識(shí)別Qa-1從而被激活和擴(kuò)增，Qa-1也可與Qdm結(jié)合形成四聚體后與Treg細(xì)胞表面的NKG2A/CD94相互作用產(chǎn)生抑制CD8+Treg細(xì)胞的功能[50]。Lu發(fā)現(xiàn)Qa-1 D227K型突變小鼠會(huì)發(fā)生嚴(yán)重的自身免疫性腦脊髓炎，此種突變的Qa-1不能與CD8+Treg細(xì)胞表面的TCR結(jié)合并發(fā)揮作用，因此CD8+Treg細(xì)胞不能被激活。而另一種Qa-1 R72A型突變小鼠并不會(huì)發(fā)生自身免疫性腦脊髓炎，此種突變的Qa-1不能和NKG2A有效結(jié)合，使抑制CD8+Treg細(xì)胞活性的通路受損，因此CD8+Treg細(xì)胞活性增強(qiáng)[51]。這說(shuō)明激活的CD8+Treg細(xì)胞能預(yù)防自身免疫性腦脊髓炎的發(fā)生。HLA-E限制性CD8+T細(xì)胞被認(rèn)為是人類的CD8+Treg細(xì)胞。研究發(fā)現(xiàn)多發(fā)性硬化患者血液及腦脊液中CD8+Treg細(xì)胞的比例明顯下降[30]。而1型糖尿病患者體內(nèi)CD8+Treg細(xì)胞抑制及溶解自身反應(yīng)性CD4+T細(xì)胞的功能出現(xiàn)缺陷[52]。這些研究表明，在一些自身免疫性疾病中，CD8+Treg細(xì)胞的數(shù)量和功能可能存在受損，并且激活的CD8+Treg對(duì)防止這些自身免疫性疾病的發(fā)生和發(fā)展發(fā)揮一定作用。

CD8+Treg細(xì)胞在ITP發(fā)病中所發(fā)揮作用的研究仍然十分有限。2015年的一項(xiàng)動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)，CD8+T細(xì)胞能夠減輕ITP小鼠的病情，并且對(duì)激素的治療反應(yīng)更佳。去除了CD8+T細(xì)胞的ITP小鼠病情加重，輸注了CD8+T細(xì)胞后ITP病情緩解。流式細(xì)胞術(shù)分析小鼠在使用了激素治療前后血液中的CD8+T細(xì)胞亞群數(shù)量，結(jié)果顯示治療后CD8+Treg細(xì)胞比例出現(xiàn)升高，而CTL的比例則出現(xiàn)下降。進(jìn)一步的體外實(shí)驗(yàn)證明，CD8+Treg細(xì)胞能夠抑制CD4+T細(xì)胞和CD19+B細(xì)胞的增殖、減少血小板相關(guān)IgG的產(chǎn)生、降低CTL的細(xì)胞毒性和血小板的凋亡等[53]。

關(guān)于CD8+Treg細(xì)胞在其他自身免疫性疾病發(fā)病機(jī)制中所起作用的研究成果較多，但其在ITP中的探索則剛起步。通過(guò)對(duì)比ITP患者急性期、緩解期以及正常人之間體內(nèi)CD8+Treg細(xì)胞數(shù)量的變化，與效應(yīng)細(xì)胞如效應(yīng)T細(xì)胞或血小板等共培養(yǎng)后，檢測(cè)效應(yīng)細(xì)胞表型改變、增殖速率和細(xì)胞因子分泌等情況來(lái)反映CD8+Treg細(xì)胞的活性和功能改變，都可能是將來(lái)研究的新思路。

4 未來(lái)的研究方向

一系列的研究用各種方法都揭示了CD4+Treg細(xì)胞數(shù)量和功能受損在ITP發(fā)病中發(fā)揮的重要作用，包括對(duì)效應(yīng)T細(xì)胞增殖的抑制作用減弱、抑制性細(xì)胞因子IL-10和TGF-β分泌的減少等。因此提高CD4+Treg細(xì)胞的數(shù)量，恢復(fù)Treg細(xì)胞的功能可能是將來(lái)ITP治療的新方向。而CD4+Treg細(xì)胞其他的免疫調(diào)節(jié)機(jī)制是否在ITP中有所缺陷，如CD39和CD73水解ATP產(chǎn)生腺苷酸的能力、CTLA-4調(diào)節(jié)免疫效應(yīng)細(xì)胞活化狀態(tài)等，都等待著研究者們?nèi)ヌ剿?，并為臨床治療提供新的思路和方法。相對(duì)而言，CD8+Treg細(xì)胞在ITP中的研究還較有限，需要通過(guò)大量實(shí)驗(yàn)證明ITP中是否存在其數(shù)量和功能的缺陷，探明CD8+Treg細(xì)胞可靠的亞群標(biāo)志和免疫抑制的具體機(jī)制。

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[本文編輯] 廖曉瑜， 賈澤軍

Abnormalities of regulatory T lymphocytes in primary immune thrombocytopenia

LU Yu-meng, CHENG Yun-feng*

Department of Hematology, ZhongshanHospital, FudanUniversity, Shanghai 200032, China

Primary immune thrombocytopenia is a kind of autoimmune disease, characterized by decreased platelets and an increased risk of bleeding. Besides destruction of platelet by platelet specific antibodies produced by auto-reactive B cells and the imbalance of Th1/Th2 cells, the study of regulatory T lymphocytes is getting more and more attention. Regulatory T lymphocytes are a subset of CD4+T lymphocytes that can suppress immune response. However, recent studies have discovered that a sublineage of CD8+regulatory T lymphocytes is also associated with the pathogenesis and treatment of ITP. This review focuses on the role of abnormalities in the number and function of regulatory T lymphocytes in the pathogenesis of ITP.

immune thrombocytopenia; pathogenesis; regulatory T lymphocytes

2016-04-26 [接受日期] 2016-07-25

盧雨萌，博士生. E-mail: cao_ming_rain@sina.com

*通信作者(Corresponding author). Tel: 021-60267312, E-mail: yfcheng@fudan.edu.cn

10.12025/j.issn.1008-6358.2016.20160519

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