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

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

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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)險增加。除了自身反應(yīng)性B細胞產(chǎn)生的血小板自身抗體對血小板的破壞以及Th1/Th2細胞的失衡外，對調(diào)節(jié)性T淋巴細胞的研究也越來越引起重視。經(jīng)典的調(diào)節(jié)性T淋巴細胞是CD4+T淋巴細胞的一個亞群，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淋巴細胞數(shù)量與功能的異常在ITP發(fā)病機制中發(fā)揮的作用做一綜述。

免疫性血小板減少癥；發(fā)病機制；調(diào)節(jié)性T淋巴細胞

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數(shù)降低(血小板<100×109/L)和出血風(fēng)險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實驗室指標(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個月以內(nèi)的ITP患者；(2)持續(xù)性ITP，確診后3～12個月血小板持續(xù)減少的ITP患者；(3)慢性ITP，血小板減少持續(xù)超過12個月的ITP患者；(4)重癥ITP，PLT<10×109/L，且就診時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，患者脾切除后無效或者復(fù)發(fā)，仍需要通過治療以降低出血的風(fēng)險，除其他原因引起的血小板減少癥外，確診為ITP[1]。

1.2 發(fā)病機制 通常認為，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多。目前公認的血小板自身抗體包括抗GPIIb/IIIa和抗GPIb/IX抗體等[2]。此外，T淋巴細胞也參與了ITP的發(fā)病。T淋巴細胞主要包括CD4+T淋巴細胞和CD8+T淋巴細胞。CD8+T淋巴細胞表達FasL和TNF-α，產(chǎn)生穿孔素、顆粒酶等，通過細胞毒作用導(dǎo)致巨核細胞和血小板的凋亡和破壞增加[3-5]。自身反應(yīng)性B淋巴細胞產(chǎn)生血小板自身抗體需要CD4+T細胞的協(xié)助，CD4+T細胞通過分泌多種細胞因子以及提供第二刺激信號等促進B細胞的分化增殖、抗體類別轉(zhuǎn)換等。CD4+T淋巴細胞包括Th1、Th2、Th17和調(diào)節(jié)性T淋巴細胞(regulatory T cell,Treg)等細胞亞群。Th1和Th2細胞是CD4+T輔助細胞(下文簡稱為Th細胞)重要的兩個亞群，已有研究證實ITP中存在Th1細胞的優(yōu)勢，疾病發(fā)作期Th1/Th2比例向Th1細胞傾斜，治療緩解后Th1/Th2比例恢復(fù)正常[6-9]。Th17細胞是另一個CD4+T細胞的亞群，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細胞數(shù)量及其分泌的細胞因子存在異常，而經(jīng)地塞米松治療后可糾正[10-12]。其他的發(fā)病機制包括病毒感染后單核巨噬細胞系統(tǒng)的激活及抗原模擬，骨髓中巨核細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細胞是指CD4+T細胞的一個亞群，而近些年發(fā)現(xiàn)CD8+T細胞也存在Treg細胞。下文主要著眼于Treg細胞數(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淋巴細胞

2.1 CD4+調(diào)節(jié)性T淋巴細胞 Treg細胞特異性表型為CD4+CD25+Foxp3+，其組成性表達細胞毒T淋巴細胞抗原4(CTLA-4)，是免疫共刺激分子CD80和CD86的抑制性受體。Treg細胞可以進一步分為兩個亞型，自然Treg(nreg)和誘導(dǎo)Treg(iTreg)。nTreg由幼稚的胸腺淋巴細胞直接分化而來，天然表達CD25和Foxp3，具有免疫調(diào)節(jié)功能。而iTreg是由幼稚的CD4+T淋巴細胞在IL-2/TGF-β的誘導(dǎo)下分化而來。

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

2.2 CD8+調(diào)節(jié)性T淋巴細胞 CD8+Treg細胞是CD8+T細胞的一個亞群，最先在七十年代Gershon的實驗中被發(fā)現(xiàn)[24]。由于缺乏可靠的表面標(biāo)志來區(qū)分CD8+Treg和傳統(tǒng)CD8+T細胞，其研究一直停滯不前。一些不同的實驗探索了CD8+Treg細胞可能的表面標(biāo)志，如CD8+CD28-[25]、CD8+CD45RO+CCR7+[26]，但仍缺乏統(tǒng)一的標(biāo)準(zhǔn)。Lu等人在小鼠的動物實驗中發(fā)現(xiàn)Qa-1限制性CD8+T細胞可能是最能代表這類Treg的細胞亞群，即能限制性識別MHC-Ib的產(chǎn)物Qa-1。這種CD8+T細胞能識別抗原提呈細胞和CD4+Th細胞表面的Qa-1從而被激活。在人類中的CD8+調(diào)節(jié)性T細胞限制性識別非經(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CD8+Treg細胞的增殖，而不使其表型發(fā)生明顯變化[28]。CD8+Treg細胞的作用機理尚未探索明朗，目前的研究發(fā)現(xiàn)其可以產(chǎn)生免疫抑制因子IL-10[29]以及通過穿孔素介導(dǎo)細胞毒性作用來發(fā)揮免疫抑制作用[30]。

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

3.1 ITP與CD4+調(diào)節(jié)性T淋巴細胞 CD4+Treg細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患者與健康對照者外周血中CD4+Treg細胞的數(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Treg細胞所使用的表面標(biāo)記不同所致，如CD4+CD25+Foxp3+，CD4+CD25highFOXP3+，CD4+FOXP3+等，因此針對了Treg細胞不同的亞群。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細胞數(shù)量的缺陷。通過Treg細胞在體外與效應(yīng)T細胞共培養(yǎng)后檢測效應(yīng)T細胞的增殖情況，檢測血漿中或Treg細胞體外培養(yǎng)后分泌的抑制性細胞因子如IL-10、TGF-β等，發(fā)現(xiàn)了ITP患者外周血中Treg細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受體激動劑均可以提高急性期ITP患者外周血Treg細胞的數(shù)量和比例[41-43]，利妥昔單抗和TPO受體激動劑還可以增強Treg細胞對效應(yīng)T細胞的抑制作用[42-43]。Aslam通過建立小鼠模型，發(fā)現(xiàn)ITP可能是因為胸腺的扣留而導(dǎo)致外周血和脾臟中Treg細胞數(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+的單核細胞抑制了Treg細胞的增殖，使ITP患者出現(xiàn)Treg細胞數(shù)量的缺陷[45]。

2012年Nishimoto通過向BALB/c裸鼠輸注去除Treg細胞的CD4+T細胞來構(gòu)建Treg細胞缺陷小鼠模型。研究發(fā)現(xiàn)在69只CD4+Treg細胞缺陷的小鼠中，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)建小鼠模型時如果預(yù)防性輸注Treg細胞可以預(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細胞則無明顯作用。給予小鼠抗CTLA-4多克隆抗體去封閉CTLA-4，能夠使輸注Treg細胞預(yù)防血小板減少的作用消失。這些都證實了Treg細胞的缺陷在ITP發(fā)病中的重要作用，并且Treg細胞可能是通過CTLA-4來預(yù)防ITP發(fā)生[46]。

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

3.2 ITP與CD8+調(diào)節(jié)性T淋巴細胞 研究者對CD8+T淋巴細胞在許多自身免疫性疾病中的作用都進行了探索。比如一系列動物實驗證實，無論通過注射抗CD8多克隆抗體來去除體內(nèi)CD8+T淋巴細胞，還是先天CD8+T淋巴細胞缺陷的小鼠，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]，說明CD8+T細胞中除了傳統(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)生的細胞，即CD8+Treg細胞。進一步的實驗發(fā)現(xiàn)CD8+Treg細胞的免疫調(diào)節(jié)作用依賴于活化CD4+T細胞表面的Qa-1，CD8+Treg細胞表面的TCR識別Qa-1從而被激活和擴增，Qa-1也可與Qdm結(jié)合形成四聚體后與Treg細胞表面的NKG2A/CD94相互作用產(chǎn)生抑制CD8+Treg細胞的功能[50]。Lu發(fā)現(xiàn)Qa-1 D227K型突變小鼠會發(fā)生嚴重的自身免疫性腦脊髓炎，此種突變的Qa-1不能與CD8+Treg細胞表面的TCR結(jié)合并發(fā)揮作用，因此CD8+Treg細胞不能被激活。而另一種Qa-1 R72A型突變小鼠并不會發(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細胞活性的通路受損，因此CD8+Treg細胞活性增強[51]。這說明激活的CD8+Treg細胞能預(yù)防自身免疫性腦脊髓炎的發(fā)生。HLA-E限制性CD8+T細胞被認為是人類的CD8+Treg細胞。研究發(fā)現(xiàn)多發(fā)性硬化患者血液及腦脊液中CD8+Treg細胞的比例明顯下降[30]。而1型糖尿病患者體內(nèi)CD8+Treg細胞抑制及溶解自身反應(yīng)性CD4+T細胞的功能出現(xiàn)缺陷[52]。這些研究表明，在一些自身免疫性疾病中，CD8+Treg細胞的數(shù)量和功能可能存在受損，并且激活的CD8+Treg對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年的一項動物實驗發(fā)現(xiàn)，CD8+T細胞能夠減輕ITP小鼠的病情，并且對激素的治療反應(yīng)更佳。去除了CD8+T細胞的ITP小鼠病情加重，輸注了CD8+T細胞后ITP病情緩解。流式細胞術(shù)分析小鼠在使用了激素治療前后血液中的CD8+T細胞亞群數(shù)量，結(jié)果顯示治療后CD8+Treg細胞比例出現(xiàn)升高，而CTL的比例則出現(xiàn)下降。進一步的體外實驗證明，CD8+Treg細胞能夠抑制CD4+T細胞和CD19+B細胞的增殖、減少血小板相關(guān)IgG的產(chǎn)生、降低CTL的細胞毒性和血小板的凋亡等[53]。

關(guān)于CD8+Treg細胞在其他自身免疫性疾病發(fā)病機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。通過對比ITP患者急性期、緩解期以及正常人之間體內(nèi)CD8+Treg細胞數(shù)量的變化，與效應(yīng)細胞如效應(yīng)T細胞或血小板等共培養(yǎng)后，檢測效應(yīng)細胞表型改變、增殖速率和細胞因子分泌等情況來反映CD8+Treg細胞的活性和功能改變，都可能是將來研究的新思路。

4 未來的研究方向

一系列的研究用各種方法都揭示了CD4+Treg細胞數(shù)量和功能受損在ITP發(fā)病中發(fā)揮的重要作用，包括對效應(yīng)T細胞增殖的抑制作用減弱、抑制性細胞因子IL-10和TGF-β分泌的減少等。因此提高CD4+Treg細胞的數(shù)量，恢復(fù)Treg細胞的功能可能是將來ITP治療的新方向。而CD4+Treg細胞其他的免疫調(diào)節(jié)機制是否在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。相對而言，CD8+Treg細胞在ITP中的研究還較有限，需要通過大量實驗證明ITP中是否存在其數(shù)量和功能的缺陷，探明CD8+Treg細胞可靠的亞群標(biāo)志和免疫抑制的具體機制。

[ 1 ] Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group[J]. Blood, 2009,113(11):2386-2393.

[ 2 ] McMillan R. Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura[J]. Semin Hematol, 2000,37(3):239-248.

[ 3 ] Olsson B, Andersson PO, Jern?s M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura[J]. Nat Med, 2003,9(9):1123-1124.

[ 4 ] Zhang F, Chu X, Wang L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura[J]. Eur J Haematol, 2006,76(5):427-431.

[ 5 ] Li S, Wang L, Zhao C, et al. CD8+T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura[J]. Br J Haematol, 2007,139(4):605-611.

[ 6 ] Semple JW, Milev Y, Cosgrave D, et al. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity[J]. Blood, 1996,87(10):4245-4254.

[ 7 ] Andersson J. Cytokines in idiopathic thrombocytopenic purpura (ITP)[J]. Acta Paediatr Suppl, 1998,424:61-64.

[ 8 ] Panitsas FP, Theodoropoulou M, Kouraklis A, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response[J]. Blood, 2004,103(7):2645-2647.

[ 9 ] Guo C, Chu X, Shi Y, et al. Correction of Th1-dominant cytokine profiles by high-dose dexamethasone in patients with chronic idiopathic thrombocytopenic purpura[J]. J Clin Immunol, 2007,27(6):557-562.

[10] Zhang J, Ma D, Zhu X, et al. Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura[J]. Haematologica, 2009,94(9):1326-1329.

[11] Hu Y, Ma DX, Shan NN, et al. Increased number of Tc17 and correlation with Th17 cells in patients with immune thrombocytopenia[J]. PLoS One, 2011,6(10):e26522.

[12] Audia S, Samson M, Mahévas M, et al. Preferential splenic CD8(+) T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia[J]. Blood, 2013,122(14):2477-2486.

[13] Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function[J]. Nature, 2007,450(7169):566-569.

[14] Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation[J]. Immunity, 2007,26(5):579-591.

[15] Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+T cells[J]. Nat Immunol, 2007,8(12):1353-1362.

[16] Borsellino G, Kleinewietfeld M, Di Mitri D, et al. Expression of ectonucleotidase CD39 by Foxp3+Tregcells: hydrolysis of extracellular ATP and immune suppression[J]. Blood, 2007,110(4):1225-1232.

[17] Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression[J]. J Exp Med, 2007,204(6):1257-1265.

[18] Grossman WJ, Verbsky JW, Barchet W, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death[J]. Immunity, 2004,21(4):589-601.

[19] Gondek DC, Lu LF, Quezada SA, et al. Cutting edge: contact-mediated suppression by CD4+CD25+regulatory cells involves a granzyme B-dependent, perforin-independent mechanism[J]. J Immunol, 2005,174(4):1783-1786.

[20] Zhao DM, Thornton AM, DiPaolo RJ, et al. Activated CD4+CD25+T cells selectively kill B lymphocytes[J]. Blood, 2006,107(10):3925-3932.

[21] Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+regulatory T cell function[J]. Science, 2008,322(5899):271-275.

[22] Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4[J]. Science, 2011,332(6029):600-603.

[23] Friedline RH, Brown DS, Nguyen H, et al. CD4+regulatory T cells require CTLA-4 for the maintenance of systemic tolerance[J]. J Exp Med, 2009,206(2):421-434.

[24] Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes[J]. Immunology, 1970,18(5):723-737.

[25] Najafian N, Chitnis T, Salama AD, et al. Regulatory functions of CD8+CD28-T cells in an autoimmune disease model[J]. J Clin Invest, 2003,112(7):1037-1048.

[26] Wei S, Kryczek I, Zou L, et al. Plasmacytoid dendritic cells induce CD8+regulatory T cells in human ovarian carcinoma[J]. Cancer Res, 2005,65(12):5020-5026.

[27] Lu L, Cantor H. Generation and regulation of CD8(+) regulatory T cells[J]. Cell Mol Immunol, 2008,5(6):401-406.

[28] Kim HJ, Wang X, Radfar S, et al. CD8+T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice[J]. Proc Natl Acad Sci U S A, 2011,108(5):2010-2015.

[29] Endharti AT, Rifa'I M, Shi Z, et al. Cutting edge: CD8+CD122+ regulatory T cells produce IL-10 to suppress IFN-gamma production and proliferation of CD8+T cells[J]. J Immunol, 2005,175(11):7093-7097.

[30] Correale J, Villa A. Isolation and characterization of CD8+regulatory T cells in multiple sclerosis[J]. J Neuroimmunol, 2008,195(1-2):121-134.

[31] Kouchaki E, Salehi M, Reza Sharif M, et al. Numerical status of CD4(+)CD25(+)FoxP3(+) and CD8(+)CD28(-) regulatory T cells in multiple sclerosis[J]. Iran J Basic Med Sci, 2014,17(4):250-255.

[32] Liu B, Zhao H, Poon MC, et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura[J]. Eur J Haematol, 2007,78(2):139-143.

[33] Ling Y, Cao XS, Yu ZQ, et al.[Alterations of CD4+CD25+regulatory T cells in patients with idiopathic thrombocytopenic purpura][J]. Zhonghua Xue Ye Xue Za Zhi, 2007,28(3):184-188.

[34] Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1[J]. Blood, 2008,112(4):1078-1084.

[35] Yu J, Heck S, Patel V, et al. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura[J]. Blood, 2008,112(4):1325-1328.

[36] Audia S, Samson M, Guy J, et al. Immunologic effects of rituximab on the human spleen in immune thrombocytopenia[J]. Blood, 2011,118(16):4394-4400.

[37] Daridon C, Loddenkemper C, Spieckermann S, et al. Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia[J]. Blood, 2012,120(25):5021-5031.

[38] Li F, Ji L, Wang W, et al. Insufficient secretion of IL-10 by Tregs compromised its control on over-activated CD4+T effector cells in newly diagnosed adult immune thrombocytopenia patients[J]. Immunol Res, 2015,61(3):269-280.

[39] Ma L, Liang Y, Fang M, et al. The cytokines (IFN-gamma, IL-2, IL-4, IL-10, IL-17) and Tregcytokine (TGF-beta1) levels in adults with immune thrombocytopenia[J]. Pharmazie, 2014,69(9):694-697.

[40] Arandi N, Mirshafiey A, Jeddi-Tehrani M, et al. Alteration in frequency and function of CD4+CD25+FOXP3+regulatory T cells in patients with immune thrombocytopenic purpura[J]. Iran J Allergy Asthma Immunol, 2014,13(2):85-92.

[41] Ling Y, Cao X, Yu Z, et al. Circulating dendritic cells subsets and CD4+Foxp3+regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome[J]. Eur J Haematol, 2007,79(4):310-316.

[42] Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents[J]. Blood, 2010,116(22):4639-4645.

[43] Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab[J]. Blood, 2008,112(4):1147-1150.

[44] Aslam R, Hu Y, Gebremeskel S, et al. Thymic retention of CD4+CD25+Foxp3+T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia[J]. Blood, 2012,120(10):2127-2132.

[45] Zhong H, Bao W, Li X, et al. CD16+monocytes control T-cell subset development in immune thrombocytopenia[J]. Blood, 2012,120(16):3326-3335.

[46] Nishimoto T, Satoh T, Takeuchi T, et al. Critical role of CD4(+)CD25(+) regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia[J]. Exp Hematol, 2012,40(4):279-289.

[47] Jiang H, Zhang SI, Pernis B. Role of CD8+T cells in murine experimental allergic encephalomyelitis[J]. Science, 1992,256(5060):1213-1215.

[48] Koh DR, Fung-Leung WP, Ho A, et al. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice[J]. Science, 1992,256(5060):1210-1213.

[49] Penninger JM, Neu N, Timms E, et al. The induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules [corrected][J]. J Exp Med, 1993,178(5):1837-1842.

[50] Kim HJ, Cantor H. Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells[J]. Semin Immunol, 2011,23(6):446-452.

[51] Lu L, Kim HJ, Werneck MB, et al. Regulation of CD8+regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease[J]. Proc Natl Acad Sci U S A, 2008,105(49):19420-19425.

[52] Jiang H, Canfield SM, Gallagher MP, et al. HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes[J]. J Clin Invest, 2010,120(10):3641-3650.

[53] Ma L, Simpson E, Li J, et al. CD8+T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia[J]. Blood, 2015,126(2):247-256.

[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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R 558+.2

A