伴胸腺瘤重癥肌無力發(fā)病機(jī)制研究進(jìn)展

王中魁 黃旭升

伴胸腺瘤重癥肌無力發(fā)病機(jī)制研究進(jìn)展

王中魁 黃旭升

重癥肌無力(myasthenia gravis，MG)是以胸腺為靶器官的器官特異性自身免疫性疾病，伴胸腺瘤MG與不伴胸腺瘤MG發(fā)病機(jī)制不同。近年來發(fā)現(xiàn)伴胸腺瘤MG在T細(xì)胞數(shù)量和功能、自身抗體的種類以及遺傳學(xué)等方面與不伴胸腺瘤MG存在差異。本文旨在結(jié)合文獻(xiàn)從胸腺微環(huán)境、T細(xì)胞發(fā)育、自身抗體及遺傳學(xué)等方面在伴胸腺瘤MG發(fā)病機(jī)制中作用進(jìn)行綜述。

重癥肌無力；胸腺瘤；發(fā)病機(jī)制

重癥肌無力(myasthenia gravis，MG)是T細(xì)胞輔助、乙酰膽堿受體抗體(AChR-Ab)介導(dǎo)的神經(jīng)肌肉接頭傳遞障礙的自身免疫性疾病，也是一種以胸腺為靶器官的自身免疫性疾病[1]。MG多伴有胸腺病變，包括胸腺瘤、胸腺增生和胸腺萎縮[2]，其中約15%為胸腺瘤。胸腺瘤是一種來源于胸腺上皮細(xì)胞的良性或低度惡性腫瘤，是成年人最常見的前縱隔腫瘤。流行病學(xué)結(jié)果顯示大約20%～25%胸腺瘤伴發(fā)MG，大約10%～20% MG患者伴發(fā)胸腺瘤[3]。胸腺瘤與MG關(guān)系最為密切，也是伴發(fā)自身免疫病最多的人類腫瘤[4]。伴胸腺瘤MG與不伴胸腺瘤MG比較，臨床特點、治療反應(yīng)及預(yù)后均不盡相同，提示伴/不伴胸腺瘤MG發(fā)病機(jī)制不同。本文對胸腺瘤在MG發(fā)病中的免疫學(xué)機(jī)制進(jìn)行綜述。

1 胸腺瘤微環(huán)境異常

胸腺是重要的免疫器官，初始T細(xì)胞在胸腺內(nèi)經(jīng)歷陽性選擇和陰性選擇發(fā)育、分化為成熟T細(xì)胞[5]。胸腺瘤是來源于胸腺上皮的腫瘤，根據(jù)淋巴細(xì)胞和上皮細(xì)胞的比例，胸腺瘤分為A、AB、B型(包括B1、B2、B3三型)和C型[6]。以髓質(zhì)成分為主的A型胸腺瘤很少伴發(fā)MG[7]，B型胸腺瘤髓質(zhì)區(qū)域內(nèi)缺乏髓質(zhì)特征，取而代之以混亂的皮質(zhì)結(jié)構(gòu)，其中B1型為皮質(zhì)優(yōu)勢型、富含淋巴細(xì)胞，胸腺細(xì)胞含量高，伴有胸腺髓質(zhì)分化，部分腫瘤區(qū)域內(nèi)可有正常的Hassall小體結(jié)構(gòu)；B2、B3胸腺瘤中Hassall小體結(jié)構(gòu)極少[6]。B型胸腺瘤最常伴發(fā)MG。C型胸腺瘤侵襲性強(qiáng)，惡性程度高，卻極少伴發(fā)MG。與胸腺增生相比，胸腺瘤缺乏髓質(zhì)和生發(fā)中心，皮髓質(zhì)區(qū)域分界不清[8]，皮髓質(zhì)結(jié)構(gòu)異常引起T細(xì)胞分化、發(fā)育紊亂和功能障礙，參與MG發(fā)病。與不伴MG胸腺瘤相比，伴胸腺瘤MG胸腺瘤組織可產(chǎn)生并向外周血遷移大量成熟CD4+CD45RA+細(xì)胞[9-11]，而正常AChR抗體反應(yīng)性的成熟T細(xì)胞再循環(huán)到胸腺瘤中后可能被激活并大量釋放至外周免疫系統(tǒng)發(fā)揮致病作用[12]。Belharazem等[13]發(fā)現(xiàn)伴胸腺瘤MG患者外周血及胸腺瘤組織中凋亡抑制蛋白——類FLICE抑制蛋白(c-FLIP)表達(dá)量顯著升高，c-FLIP可促進(jìn)CD4+T細(xì)胞的分化發(fā)育，提示伴胸腺瘤MG發(fā)病可能與中樞及外周淋巴系統(tǒng)免疫耐受功能障礙有關(guān)。

2 胸腺瘤中T細(xì)胞異常發(fā)育

由于胸腺瘤缺乏髓質(zhì)成分，經(jīng)歷了陽性選擇的T細(xì)胞不能充分與樹突狀細(xì)胞(DC)和巨噬細(xì)胞接觸、經(jīng)歷有效的陰性選擇。Inoue等[15]的研究表明了胸腺瘤中HLA-DR(MHCⅡ類分子)的重要調(diào)控因子二類轉(zhuǎn)化活化因子(class Ⅱ transactivator，CⅡTA)表達(dá)降低，而胸腺瘤中CD4+CD8-T細(xì)胞亞群中CD3+細(xì)胞的比例與HLA-DR和CⅡTA顯著相關(guān)[18]。由此推測胸腺瘤上皮細(xì)胞HLA-DR表達(dá)減少引起了胸腺瘤組織中CD4+CD8-單陽性T細(xì)胞分化中陰性選擇功能障礙。自身免疫調(diào)控因子(autoimmune regulator，AIRE)是表達(dá)在胸腺髓質(zhì)上皮細(xì)胞上的轉(zhuǎn)錄因子，調(diào)控胸腺中CHRNA基因位點的AChRα亞單位的表達(dá)[19]，對于自身反應(yīng)性T細(xì)胞陰性選擇和中樞性耐受形成具有重要意義。伴胸腺瘤MG患者胸腺瘤髓質(zhì)上皮細(xì)胞AIRE表達(dá)降低，同時胸腺瘤細(xì)胞與正常胸腺細(xì)胞表達(dá)的包括titin抗原表型的多種抗原表型[20]、HLA-Ⅱ類分子[21-23]以及多種AChR亞單位[24-25]均發(fā)生改變，這些異常表達(dá)的免疫調(diào)節(jié)因子及抗原表型可能導(dǎo)致針對表達(dá)AChRα亞單位受體的T細(xì)胞的陽性選擇或陰性選擇發(fā)生偏倚或功能障礙，這些針對AChRα亞單位自身反應(yīng)性T細(xì)胞進(jìn)入外周免疫系統(tǒng)，攻擊神經(jīng)肌肉接頭處AChRα亞單位，引起MG發(fā)病[26-27]。

3 伴胸腺瘤MG中自身抗體

除去作用機(jī)制研究最清楚的MG自身抗體——AChRAb外，伴胸腺瘤MG患者體內(nèi)還存在多種其他自身抗體，這些抗體可能也參與了伴胸腺瘤MG的發(fā)病。

3.1 抗骨骼肌抗原抗體 連接素(titin)和蘭尼堿受體 (ryanodine receptor，RyR)是最主要的自身抗體攻擊的靶點。約90%的伴胸腺瘤MG患者Titin抗體或RyR抗體陽性，其中Titin抗體是胸腺瘤的標(biāo)記性抗體[28-29]。

3.2 抗細(xì)胞因子抗體 抗細(xì)胞因子抗體是伴胸腺瘤MG常見的血清抗體。體外試驗發(fā)現(xiàn)抗細(xì)胞因子抗體由胸腺瘤細(xì)胞產(chǎn)生[30]，伴胸腺瘤MG中70%和單純胸腺瘤患者中30%體內(nèi)存在針對IFN-α和IFN-ω的中和抗體， 伴胸腺瘤MG中約50%有IL-12的中和抗體[31]。最近一項研究表明伴胸腺瘤MG患者高表達(dá)Ⅰ型IFN分子，包括IFN-α2、IFN-α8、IFN-ω和IFN-β[32]。極少部分胸腺瘤患者體內(nèi)存在針對Th17細(xì)胞相關(guān)細(xì)胞因子的中和抗體，尤其是與控制念珠菌感染相關(guān)的IL-17F和IL-22的中和抗體[33]。

4 胸腺瘤的遺傳學(xué)改變及其與伴胸腺瘤MG發(fā)病的相關(guān)性

HLA 6p21位點雜合缺失是發(fā)生在所有病理類型胸腺瘤的一種遺傳學(xué)改變，該改變可引起HLAⅡ類分子表達(dá)下調(diào)[23，34]，非HLA基因多態(tài)性可以影響CTLA4和蛋白酪氨酸磷酸酶22(PTPN22)[35]等T細(xì)胞受體信號通路分子，這些信號分子表達(dá)改變可以引起陰性選擇功能障礙、自身反應(yīng)性T細(xì)胞的增殖，參與伴胸腺瘤MG發(fā)病。Christopoulos等[36]研究發(fā)現(xiàn)胸腺瘤患者存在CD3 zeta鏈(CD247)基因缺陷，胸腺瘤患者γδ和αβT細(xì)胞的TCR復(fù)合體中CD247數(shù)量減少，初始T細(xì)胞和低反應(yīng)性γδT細(xì)胞、αβT細(xì)胞數(shù)量增高，引起T細(xì)胞免疫功能缺陷，增加了對于感染的易感性。Yang等[37]的研究發(fā)現(xiàn)HLA DQ等位基因中DQA1*0401和DQB1*0604兩種基因型在伴胸腺瘤MG中出現(xiàn)頻率高，DQA1*0501和DQB1*0301在不伴MG胸腺瘤中出現(xiàn)頻率高。該結(jié)果提示HLA DQA和DQB位點突變引起的基因多態(tài)性與MG發(fā)病的易感性有關(guān)，但是具體作用機(jī)制仍不清楚。此外，Xu等[38]通過分析T細(xì)胞免疫球蛋白和黏蛋白結(jié)構(gòu)域-3(Tim-3)574位點多態(tài)性，發(fā)現(xiàn)伴胸腺瘤MG的GT+TT基因型出現(xiàn)率及T等位基因出現(xiàn)率顯著高于不伴MG胸腺瘤。然而該基因多態(tài)性導(dǎo)致MG的具體機(jī)制仍需進(jìn)一步研究。

5 輔助性T細(xì)胞與伴胸腺瘤MG

近年來輔助性T細(xì)胞，包括調(diào)節(jié)性T細(xì)胞(Treg)和Th17輔助細(xì)胞(T helper type 17 cells，Th17細(xì)胞)在MG及胸腺瘤發(fā)病機(jī)制中的作用成為研究熱點。Treg細(xì)胞是一群具有免疫抑制功能的負(fù)調(diào)控細(xì)胞，可與免疫應(yīng)答中多種細(xì)胞如DC、B細(xì)胞等相互作用，通過與免疫效應(yīng)細(xì)胞直接接觸的方式抑制效應(yīng)細(xì)胞的功能，發(fā)揮免疫抑制作用。Masuda等[39]發(fā)現(xiàn)MG患者外周血Treg細(xì)胞比例減少，且治療前后Treg細(xì)胞比例變化與MG臨床評分變化呈正相關(guān)。Scarpino等[40]發(fā)現(xiàn)正常胸腺及增生胸腺中CD4+CD25+FoxP3+Treg較多，主要集中在Hassall小體周圍，Treg細(xì)胞數(shù)量與是否合并MG無關(guān)；胸腺瘤中CD4+CD25+FoxP3+Treg細(xì)胞明顯減少，在B1型髓質(zhì)中Treg細(xì)胞相對較多。Wang等[41]發(fā)現(xiàn)伴胸腺瘤MG的胸腺瘤組織中FoxP3+Treg細(xì)胞較正常胸腺顯著減少，F(xiàn)oxP3mRNA轉(zhuǎn)錄水平下降，其中B1型轉(zhuǎn)錄水平最高，B3型最低，提示FoxP3轉(zhuǎn)錄和表達(dá)可能與胸腺瘤類型和腫瘤上皮細(xì)胞功能有關(guān)，胸腺瘤FoxP3mRNA轉(zhuǎn)錄水平異?？赡軐?dǎo)致Treg細(xì)胞減少，引起自身免疫耐受紊亂，造成MG的發(fā)病。

Th17細(xì)胞是近年新發(fā)現(xiàn)的特征性表達(dá)促炎因子IL-17的功能性CD4+T輔助細(xì)胞亞群[42]。Wang等[43]發(fā)現(xiàn)伴胸腺瘤MG患者外周血的IL-17、IL-1β、IL-23等促炎細(xì)胞因子表達(dá)量增加，伴胸腺瘤MG患者外周血Th17細(xì)胞的比例與血清AChRAb濃度正相關(guān)，且伴胸腺瘤MG組QMG評分與Th17細(xì)胞比例呈正相關(guān)。 胸腺間質(zhì)淋巴細(xì)胞生成素(TSLP)是一種IL-7樣細(xì)胞因子，由胸腺髓質(zhì)Hassall小體上皮細(xì)胞分泌，是淋巴細(xì)胞發(fā)育分化的重要調(diào)節(jié)因子。Watanabe等[44]發(fā)現(xiàn)TSLP可以大量活化cDC，cDC誘導(dǎo)CD4+CD8-CD25-細(xì)胞增殖后，約50%的增殖細(xì)胞分化為CD4+CD8-CD25-FoxP3+Treg細(xì)胞。Salomon等[45]發(fā)現(xiàn)CD28是Treg細(xì)胞發(fā)育必不可少的共刺激信號分子。TSLP是目前所知的惟一可以活化DC表達(dá)CD28配體-CD80/CD86的生理信號[46]。Wang等[47]發(fā)現(xiàn)miR-19b-5p通過轉(zhuǎn)錄后調(diào)控機(jī)制降低TSLP的表達(dá)，證實了miR-19b-5p在胸腺瘤中的異常上調(diào)可能是TSLP減少的關(guān)鍵機(jī)制，證實miR-19b-5p/TSLP調(diào)控通路參與Treg細(xì)胞生成減少、Th17細(xì)胞增多過程的調(diào)控。

濾泡輔助性T細(xì)胞(T follicular helper cells，TFH)表型是CD4+CXCR5+，是CD4+T輔助細(xì)胞的一個亞群。TFH可以遷移到生發(fā)中心內(nèi)，為B細(xì)胞提供刺激信號，促進(jìn)B細(xì)胞分化發(fā)育成長期存活的漿細(xì)胞和記憶B細(xì)胞。TFH細(xì)胞引導(dǎo)效應(yīng)B細(xì)胞和記憶B細(xì)胞產(chǎn)生自身抗體進(jìn)而在MG發(fā)病中發(fā)揮重要作用。TFH高表達(dá)可誘導(dǎo)共刺激分子(ICOS)，程序性死亡1(PD-1)及其配體，轉(zhuǎn)錄因子B細(xì)胞淋巴瘤6(Bcl-6)和調(diào)控因子等分子。Song等[48]的研究亦發(fā)現(xiàn)伴胸腺瘤MG患者胸腺瘤組織中TFH細(xì)胞比例升高，而且TFH相關(guān)分子ICOS，PD-1及其配體，Bcl-6表達(dá)量顯著升高。

綜上，近年來的研究表明胸腺自身免疫耐受機(jī)制的破壞可能是胸腺瘤發(fā)生以及包括MG在內(nèi)的自身免疫性疾病發(fā)生的重要原因。闡明這些可能的機(jī)制，有助于提高對于MG等自身免疫性疾病的認(rèn)識，促進(jìn)此類疾病預(yù)防和治療水平的提高。

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(本文編輯：鄒晨雙)

10.3969/j.issn.1006-2963.2017.02.015

100853 中國人民解放軍總醫(yī)院神經(jīng)科

黃旭升，Email：lewish301@sina.com

R746.1

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1006-2963(2017)02-0139-05

2016-08-03)