胸腺瘤相關(guān)重癥肌無力發(fā)病的免疫學(xué)機制研究進展

王衛(wèi)(綜述)，魏東寧(審校)

·綜 述·

胸腺瘤相關(guān)重癥肌無力發(fā)病的免疫學(xué)機制研究進展

王衛(wèi)(綜述)，魏東寧(審校)

重癥肌無力(MG)是一種細(xì)胞免疫依賴、體液免疫介導(dǎo)、補體參與的獲得性自身免疫疾病，但其引起免疫應(yīng)答的始動環(huán)節(jié)仍不十分清楚。由于絕大多數(shù)MG患者伴隨胸腺異常，故推測導(dǎo)致MG發(fā)生的免疫反應(yīng)起始部位可能在胸腺。胸腺是T細(xì)胞分化、發(fā)育、成熟的場所，后者在此經(jīng)歷陽性選擇和陰性選擇，從而獲得識別外來抗原的能力，但同時也去除了對自身抗原的反應(yīng)性，因此胸腺的重要作用之一在于誘導(dǎo)自身免疫耐受，從而避免自身免疫性疾病的發(fā)生。在伴胸腺增生的MG患者中，胸腺肌樣細(xì)胞表達的抗原表位與神經(jīng)肌肉接頭的乙酰膽堿受體(AchR)類似，是交叉免疫發(fā)生的基礎(chǔ)。胸腺瘤來源于胸腺上皮細(xì)胞，是可誘導(dǎo)T細(xì)胞分化、發(fā)育的功能性腫瘤，約15%的MG患者伴有胸腺瘤。由于胸腺瘤相關(guān)MG與胸腺增生相關(guān)MG的病因并不相同，所以本文通過綜述近年來針對胸腺、胸腺瘤與MG發(fā)病機制的相關(guān)研究，對胸腺瘤在MG發(fā)病中的免疫作用機制進行探討和闡釋。

重癥肌無力；胸腺瘤；胸腺；變態(tài)反應(yīng)和免疫學(xué)

重癥肌無力(myasthenia gravis，MG)是細(xì)胞免疫依賴、體液免疫介導(dǎo)、補體參與的一種獲得性自身免疫疾病[1-2]，其發(fā)病機制為體內(nèi)產(chǎn)生的乙酰膽堿受體(acetylcholine receptor，AchR)抗體在補體參與下與突觸后膜的AchR產(chǎn)生應(yīng)答，大量AchR被破壞，無法產(chǎn)生足夠的終板電位，導(dǎo)致突觸后膜傳導(dǎo)障礙，從而發(fā)生肌無力。但是，引起MG免疫應(yīng)答的始動環(huán)節(jié)仍不清楚。由于幾乎所有MG患者都伴隨胸腺異常，所以推測誘發(fā)免疫反應(yīng)的起始部位應(yīng)該在胸腺。胸腺瘤為來源于胸腺上皮的腫瘤[3]，是最常伴發(fā)自身免疫病的人類腫瘤之一，且與MG的關(guān)系密切[4]。然而，伴發(fā)胸腺瘤的MG與非胸腺瘤MG的臨床特點、治療反應(yīng)及預(yù)后均有所不同，說明兩者的發(fā)病機制可能存在差異。本文旨在通過綜述近年來針對胸腺、胸腺瘤及MG的相關(guān)研究，闡述胸腺瘤在MG發(fā)病中的免疫學(xué)機制。

1 胸腺的作用

盡管胸腺及細(xì)胞免疫在MG發(fā)病中的確切作用機制仍不是十分清楚，但大量臨床證據(jù)顯示，MG的發(fā)生與胸腺相關(guān)，80%～90%的MG患者伴有胸腺異常[5]，其中85%為胸腺增生，15%為胸腺瘤。

胸腺是重要的免疫器官，是T細(xì)胞分化、發(fā)育和成熟的場所。胸腺皮質(zhì)-髓質(zhì)交界處血管豐富，祖T細(xì)胞由此進入胸腺，隨后移行至胸腺被膜下的皮質(zhì)，再由皮質(zhì)向髓質(zhì)遷移。在遷移過程中，祖T細(xì)胞在胸腺微環(huán)境作用下，歷經(jīng)發(fā)育、增殖、分化，最終變?yōu)楣δ艹墒斓腡細(xì)胞，進而離開胸腺。胸腺內(nèi)發(fā)育的T細(xì)胞均經(jīng)歷陽性選擇和陰性選擇階段。陽性選擇指僅表達與自身MHC分子有中等親和力的T細(xì)胞受體的T細(xì)胞才能進一步發(fā)育，該過程發(fā)生在胸腺的皮質(zhì)，使T細(xì)胞獲得抗原識別的主要組織相容性復(fù)合體(MHC)限制性。某些經(jīng)陽性選擇的T細(xì)胞表達識別自身抗原肽的T細(xì)胞受體，這些細(xì)胞將在陰性選擇階段被剔除。

陰性選擇主要發(fā)生在胸腺的深皮質(zhì)、皮-髓質(zhì)交界區(qū)及髓質(zhì)，經(jīng)歷陽性選擇的T細(xì)胞與胸腺髓質(zhì)樹突細(xì)胞及巨噬細(xì)胞提呈的自身抗原發(fā)生接觸，只有不能識別自身抗原的胸腺細(xì)胞才能得以發(fā)育，而那些與自身抗原產(chǎn)生應(yīng)答的胸腺細(xì)胞則發(fā)生凋亡。

陰性選擇一般會受到自身免疫調(diào)節(jié)因子(autoimmune regulator，AIRE)的控制，后者是一種轉(zhuǎn)錄調(diào)節(jié)因子，通常在胸腺及濾泡樣增生的髓質(zhì)上皮細(xì)胞中高度表達[6]，它是調(diào)節(jié)免疫耐受的關(guān)鍵因子，通過調(diào)節(jié)胸腺髓質(zhì)內(nèi)組織特異性自身抗原的表達或提呈從而發(fā)揮作用。AIRE能上調(diào)某些自身抗原在髓質(zhì)樹突細(xì)胞中的轉(zhuǎn)錄，增強抗原在胸腺中的提呈作用，影響共同刺激分子在樹突細(xì)胞的表達以及與外圍成熟T細(xì)胞之間的相互作用[7]。在小鼠胸腺中，表達AIRE的胸腺髓質(zhì)上皮細(xì)胞的數(shù)量與通過陰性選擇的胸腺細(xì)胞相關(guān)[8]，并且胸腺剔除自身反應(yīng)性T細(xì)胞的作用具有明顯的AIRE基因依賴性[9]。

經(jīng)歷了陽性選擇和陰性選擇的T細(xì)胞獲得了自身免疫耐受性及對外源性抗原應(yīng)答的能力。對于自身免疫性疾病來講，胸腺最重要的作用在于誘導(dǎo)自身免疫耐受以避免自身免疫病的發(fā)生和自我傷害。胸腺的病理性改變，包括胸腺增生和胸腺瘤，則可能破壞這種自身耐受的機制，導(dǎo)致自身免疫病如MG的發(fā)生。

2 胸腺增生與MG

胸腺增生相關(guān)MG的發(fā)病機制已經(jīng)被廣為接受，即增生胸腺內(nèi)肌樣細(xì)胞表達與神經(jīng)肌肉接頭AchR類似的抗原表位，導(dǎo)致了交叉免疫的發(fā)生[10]。證據(jù)是伴胸腺增生的MG患者血清中存在胎兒型AchR抗體，而胎兒型AchR抗體只存在于肌樣細(xì)胞及部分眼外肌纖維[11]。

胸腺增生的重要特征是具有淋巴細(xì)胞浸潤和異位生發(fā)中心，且具有能表達線性和天然AchR的胸腺上皮細(xì)胞和肌樣細(xì)胞，存在AchR抗體反應(yīng)性T細(xì)胞及能產(chǎn)生高親和性AchR抗體反應(yīng)性B細(xì)胞[12]。重要的是，所有能發(fā)動T細(xì)胞和B細(xì)胞針對胸腺AchR反應(yīng)所需的分子及細(xì)胞成分在增生的胸腺中都同時存在。Shiono等[13]提出胸腺產(chǎn)生AchR抗體的“兩步模式”(two-step model)：產(chǎn)生針對胸腺上皮細(xì)胞表達的線性AchR的低親和力抗體是第一步；第二步是在T細(xì)胞的幫助下，形成生發(fā)中心，并在皮-髓質(zhì)交界及髓質(zhì)內(nèi)形成針對肌樣細(xì)胞上功能性AchR結(jié)構(gòu)性表位的高親和性抗體。在此過程中，炎性損傷募集抗原提呈細(xì)胞，刺激生發(fā)中心形成，導(dǎo)致抗原多樣化和補體激活?？贵w離開胸腺后即發(fā)動針對神經(jīng)肌肉接頭處AchR的自身免疫攻擊，導(dǎo)致MG。但是，在胸腺中導(dǎo)致AchR相關(guān)抗原抗體反應(yīng)的初始原因并不清楚，可能包括IFN-1誘導(dǎo)基因[14]和Toll樣受體4[15]的過度表達、胸腺EB病毒和脊髓灰質(zhì)炎病毒的感染[16-17]等。

3 胸腺瘤與MG

研究發(fā)現(xiàn)，胸腺瘤中不存在肌樣細(xì)胞，胸腺瘤相關(guān)MG的病因與胸腺增生相關(guān)MG并不相同[18-21]，伴胸腺瘤MG及非胸腺瘤MG患者的臨床特點亦有不同[22-24]，如伴胸腺瘤MG患者發(fā)病年齡顯著高于非胸腺瘤患者，男女比例相同或男性略多于女性，MG病情上累及呼吸肌及咽喉肌者增多，血清Titin抗體及Ryr抗體陽性率較高，胸腺切除對改善MG的療效不滿意等，提示胸腺瘤在MG發(fā)病中的作用機制與胸腺增生不同。

胸腺瘤是來源于胸腺上皮的腫瘤。約15%的MG患者伴有胸腺瘤，而35%的胸腺瘤患者患有MG[25-26]。與增生的胸腺相比，胸腺瘤缺乏髓質(zhì)，不含B細(xì)胞和生發(fā)中心，另外，能增強AchRα亞單位表達的肌樣細(xì)胞、MHCⅡ分子和AIRE在胸腺瘤中都不存在[27-28]，提示胸腺瘤與胸腺增生誘發(fā)MG的免疫機制不同。同時，幾乎所有與MG相關(guān)的胸腺瘤都具有一些共同特征[11]，如按WHO組織病理學(xué)分型[29]，所有MG相關(guān)的胸腺瘤病理分型均為A、AB、B1－B3型，其中以B2、B1及AB型為主，A型及B3型的比例≤10%[30-32]，而C型胸腺瘤及其他非胸腺上皮細(xì)胞來源的胸腺腫瘤如胸腺內(nèi)分泌腫瘤、胸腺淋巴瘤等均不見于MG患者中[19]。說明只有具有類似胸腺結(jié)構(gòu)或胸腺上皮細(xì)胞來源的胸腺瘤才與MG相關(guān)，考慮與其能使祖T細(xì)胞歸巢，并促進祖T細(xì)胞向成熟T細(xì)胞發(fā)育和分化有關(guān)[11]。

正常情況下，T細(xì)胞在其成熟過程中經(jīng)歷三個發(fā)育階段[33]：最初骨髓來源的祖T細(xì)胞為CD 4－、CD 8－雙陰性，此后T細(xì)胞受體基因發(fā)生重排，中間階段發(fā)育為CD 4+CD 8+雙陽性T細(xì)胞，并與胸腺上皮細(xì)胞的MHCⅡ類或MHCⅠ類分子以適當(dāng)?shù)挠H和力進行特異性結(jié)合，繼續(xù)分化為CD4+或CD8+單陽性細(xì)胞，若為CD 4+CD 8+雙陽性T細(xì)胞以高親和性與MHC分子結(jié)合或不能結(jié)合，在胸腺皮質(zhì)中發(fā)生凋亡，這個過程就是陽性選擇，陽性選擇賦予CD4+CD8－或CD4－CD8+T細(xì)胞分別與MHCⅡ類或MHCⅠ類分子限制性識別的能力。經(jīng)歷陽性選擇的CD4+CD8－或CD4－CD8+T細(xì)胞還須經(jīng)過陰性選擇，才能發(fā)育為成熟的、能夠識別外來抗原的T細(xì)胞。這種經(jīng)過復(fù)雜選擇過程，具有MHC限制性識別能力、具有自身耐受性的CD4+CD8－或CD4－CD8+單陽性T細(xì)胞最終成為成熟T細(xì)胞，經(jīng)血流遷移至外周淋巴組織。但是在胸腺瘤患者中，T細(xì)胞的陽性和(或)陰性選擇紊亂，在MG的發(fā)生中可能起到關(guān)鍵作用。

3.1胸腺瘤的陽性選擇與MG 研究顯示，所有MG相關(guān)胸腺瘤中都富含大量針對AchR抗原的特異性自身免疫性T細(xì)胞[11]，并且部分自身反應(yīng)性T細(xì)胞是CD4+CD8+雙陽性T細(xì)胞[34-35]。

另一些研究發(fā)現(xiàn)，盡管胸腺瘤存在MHCⅡ類分子表達缺陷，但胸腺瘤中的T細(xì)胞仍能夠經(jīng)歷陽性選擇[36-38]，且與不伴MG的胸腺瘤相比，MG相關(guān)胸腺瘤的陽性選擇更加有效[39]，很少伴發(fā)MG的AB型胸腺瘤中幾乎不發(fā)生CD4+CD8－T細(xì)胞的陽性選擇，而與MG關(guān)系密切的B1、B2型胸腺瘤發(fā)生CD4+CD8－T細(xì)胞陽性選擇的比例則明顯升高。針對胸腺瘤組織學(xué)分型與MHC表達的研究表明，皮質(zhì)型胸腺瘤或分化較好的胸腺瘤具有大量的MHCⅡ類分子表達，而髓質(zhì)型及混合型胸腺瘤則呈較低表達或不表達[40]。

Buckley等[41]的研究發(fā)現(xiàn)，伴發(fā)胸腺瘤的MG患者血中存在CD4+及CD8+單陽性T細(xì)胞，說明胸腺瘤不但產(chǎn)生了成熟T細(xì)胞，而且這些成熟T細(xì)胞還被釋放至外周。進一步研究證明，盡管胸腺瘤產(chǎn)生并釋放了成熟T細(xì)胞，但外周血中的T細(xì)胞亞群成分發(fā)生了變化，如CD4+/CD8+比例減低、Treg細(xì)胞數(shù)量減少及功能障礙等，而這些都與伴發(fā)MG有關(guān)[42-43]。

綜上，盡管胸腺瘤保留了胸腺皮質(zhì)上皮細(xì)胞的部分功能，能夠誘導(dǎo)T細(xì)胞的發(fā)育及分化，然而這種功能存在缺陷，產(chǎn)生的T細(xì)胞并不成熟(CD 4+CD 8+雙陽性)；或是盡管部分經(jīng)歷陽性選擇，但由于MHCⅡ類分子表達缺陷，造成T細(xì)胞亞群中CD4+/CD8+比例減低、Treg細(xì)胞數(shù)量減少及功能障礙。這些“有缺陷”的T細(xì)胞進入外周即可成為自身反應(yīng)性T細(xì)胞，或打破自身免疫耐受的平衡。

3.2胸腺瘤的陰性選擇與MG 由于胸腺瘤缺乏髓質(zhì)成分，經(jīng)歷了陽性選擇的T細(xì)胞不能充分與樹突細(xì)胞和巨噬細(xì)胞接觸、經(jīng)歷有效的陰性選擇。表達能與自身抗原肽結(jié)合的受體的T細(xì)胞未經(jīng)陰性選擇進入外周即成為自身反應(yīng)性T細(xì)胞，從而誘發(fā)自身免疫病。研究證實，小鼠的胸腺皮質(zhì)能表達MHCⅡ類分子并產(chǎn)生經(jīng)陽性選擇的T細(xì)胞，但relB缺陷小鼠由于缺少胸腺髓質(zhì)，導(dǎo)致胸腺陰性選擇缺乏[44-45]。

另一方面，AIRE在陰性選擇中也發(fā)揮重要作用，它控制著胸腺對來自CHRNA基因位點的AchRα亞單位的表達[46]，樹突細(xì)胞提呈自身抗原亦需要AIRE的表達[8-9,47]，然而胸腺瘤中AIRE的表達下調(diào)[48]，導(dǎo)致針對表達AchRα亞單位受體的T細(xì)胞的陰性選擇缺失。這似乎是為何胸腺瘤在眾多自身免疫病中與MG聯(lián)系最為密切的原因。而且，由于AIRE主要由胸腺髓質(zhì)上皮細(xì)胞表達，但胸腺瘤卻主要來源于胸腺皮質(zhì)上皮細(xì)胞，所以AIRE在胸腺瘤中表達缺乏。這亦可解釋臨床上為何不同組織學(xué)分型的胸腺瘤與MG的關(guān)系有所差異，以髓質(zhì)成分為主的A型胸腺瘤很少伴發(fā)MG，而以皮質(zhì)上皮細(xì)胞為主的B1、B2型胸腺瘤則與MG關(guān)系密切[49]。

4 總 結(jié)

盡管胸腺瘤在MG發(fā)病中的作用仍不是十分明確，但近年來的研究表明，胸腺自身免疫耐受機制破壞是胸腺瘤患者發(fā)生包括MG在內(nèi)的自身免疫性疾病的重要原因。據(jù)此推測，盡管胸腺瘤保存有接近正常胸腺組織結(jié)構(gòu)的上皮及淋巴細(xì)胞，并能促進祖T細(xì)胞向成熟T細(xì)胞發(fā)育、分化，但由于胸腺瘤本身結(jié)構(gòu)和功能異常，破壞了胸腺的陽性和(或)陰性選擇，產(chǎn)生了成熟但有“缺陷”的T細(xì)胞，進入外周淋巴器官，成為自身反應(yīng)性T細(xì)胞而致病。闡明這些可能的機制，可提高臨床工作者對MG等自身免疫性疾病的認(rèn)識，對促進疾病治療有重要意義。

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Immune mechanism of thymomas in the development of myasthen ia gravis

WANG Wei, WEI Dong-ning
Department of Neurology, 309 Hospital of PLA, Beijing 100091, China

Myasthenia gravis is an acquired autoimmune disorder which is cellular-immunity-dependent, humoral-immunitymediated and complement participated. It is still not clear which initial factor causes the immune response. The characteristic of myasthenia gravis is that many of the patients have an abnormality in their thymus. So it is speculated that the immune response is initiated in thymus. The thymus is the central organ of the immune system, playing the key role in T cell generation, diversification and maturation. T cells are positively selected for their recognition of antigens associated with MHC expressed in the thymus, and negatively selected according to their response to the self-antigens. The result of these selection is that the T cell use the MHC expressed on the other cells of the body for recognition of foreign antigens but do not react with self-antigens. Perhaps the most important role of thymus is the induction of immune self-tolerance that functions to prevent self-harm or autoimmunity. Thymomas are functional tumors originated from epithelial of the thymus, which have the capacity to induce T cell to differentiate and mature. What mechanism is myasthenia gravis associated thymoma initiated by? This review will summarize the existing evidence of thymus, thymoma and myasthenia gravis and try to clarify the immune mechanism of initiation of myasthenia gravis associated thymomas.

myasthenia gravis; thymoma; thymus gland; allergy and immunology

R746.1

A

0577-7402(2013)07-0606-05

2013-03-12；

2013-04-09)

(責(zé)任編輯：沈?qū)?

王衛(wèi)，副主任醫(yī)師，博士研究生。主要從事重癥肌無力和腦血管病方面的研究

100091 北京 解放軍309醫(yī)院神經(jīng)內(nèi)科(王衛(wèi)、魏東寧)