蠕蟲感染與過敏性和自身免疫性疾病

楊維平，田 芳，胡雪莉

寄生蠕蟲通常以免疫逃避機(jī)制在感染宿主體內(nèi)建立慢性感染。蠕蟲感染后立即產(chǎn)生蟲源性分子并促進(jìn)先天性免疫和適應(yīng)性免疫反應(yīng)的過程和發(fā)展。蠕蟲感染可以誘導(dǎo)調(diào)節(jié)性T細(xì)胞(Tregs)、調(diào)節(jié)性B細(xì)胞(Bregs)、樹突狀細(xì)胞(DCs)和巨噬細(xì)胞(AAMs)等活化，形成免疫調(diào)節(jié)網(wǎng)絡(luò)，介導(dǎo)免疫抑制。從而在Th1型自身免疫性疾病和Th2型過敏性疾病中抑制寄生蟲特異性損傷和與免疫無關(guān)的病理損傷。然而，一些寄生蟲感染則促進(jìn)或加重過敏反應(yīng)[1]。本文主要介紹蠕蟲感染誘導(dǎo)Tregs和Bregs，介導(dǎo)免疫抑制及其對(duì)免疫相關(guān)疾病影響的研究進(jìn)展。

1 蠕蟲免疫調(diào)控

蠕蟲感染可引起Th2型為主的免疫反應(yīng)，涉及的細(xì)胞因子主要是IL-3、IL-4、IL-5、IL-9、IL-10和IL-13。這些細(xì)胞因子介導(dǎo)免疫反應(yīng)的典型特征是提高循環(huán)IgG抗體、嗜酸性粒細(xì)胞、嗜堿性粒細(xì)胞和肥大細(xì)胞水平[2]。在感染過程中，不同的蠕蟲蟲源分子包括蛋白質(zhì)、脂類和多聚糖，無論是蠕蟲表面抗原或是排泄分泌(ES)抗原都可以誘導(dǎo)機(jī)體免疫系統(tǒng)活化[3]。蟲源性分子與宿主細(xì)胞的相互作用可導(dǎo)致宿主免疫反應(yīng)向一種類型發(fā)展。蟲源性分子可以誘導(dǎo)調(diào)控網(wǎng)絡(luò)，下調(diào)適應(yīng)性免疫。在誘導(dǎo)免疫抑制網(wǎng)絡(luò)過程中，寄生蟲可以通過誘導(dǎo)免疫調(diào)節(jié)細(xì)胞活化和產(chǎn)生細(xì)胞因子發(fā)揮抑制效應(yīng)，從而影響其他免疫相關(guān)疾病[4]。然而，蠕蟲感染與過敏性和自身免疫性疾病之間的調(diào)節(jié)機(jī)制尚無明確的結(jié)論。一些蠕蟲感染可以預(yù)防或抑制這些炎性疾病[5]，而另一些蠕蟲卻加劇疾病的免疫病理損害[6]。

2 蠕蟲誘導(dǎo)免疫調(diào)節(jié)細(xì)胞

2.1Tregs Tregs控制外周免疫反應(yīng)，可能在自身免疫性疾病、感染性或過敏性疾病中發(fā)揮核心作用。根據(jù)Tregs的來源、功能和細(xì)胞表面標(biāo)志物將其分為自然Tregs(CD4+CD25+Foxp3+)和可誘導(dǎo)Tregs(包括IL-10 Tr1細(xì)胞和在外周誘導(dǎo)的Foxp3+T細(xì)胞)兩類[7]，而蠕蟲感染誘導(dǎo)的CD4+CD25+Foxp3+Tregs是最主要的免疫調(diào)節(jié)細(xì)胞[4]。早期的研究已經(jīng)表明在慢性寄生蟲感染者體內(nèi)存在Tregs。研究發(fā)現(xiàn)絲蟲病淋巴水腫與Tregs表達(dá)的Foxp3、GITR(糖皮質(zhì)激素誘導(dǎo)的腫瘤壞死因子受體相關(guān)蛋白)、TGF-β和CTLA-4(細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原4)有關(guān)[8]，而在腸道線蟲(蛔蟲，鞭蟲)感染兒童，除T細(xì)胞為低反應(yīng)，IL-10和TGF-β均為高水平[9-10]。同樣，在血吸蟲感染率較高的肯尼亞和加蓬，CD4+CD25+和CD4+CD25+FOXP3+T細(xì)胞的水平比未感染者高[11]。Wammes等的研究提供了寄生蟲感染者Tregs抑制效應(yīng)的證據(jù)[12]。在印度尼西亞的研究中，蠕蟲感染者比健康者能更有效地誘導(dǎo)T細(xì)胞對(duì)瘧原蟲抗原和結(jié)核活菌苗(BCG)的應(yīng)答，抑制T細(xì)胞增殖和產(chǎn)生IFN-γ。在一例馬來絲蟲病人發(fā)現(xiàn)分泌轉(zhuǎn)化生長(zhǎng)因子同源-2(TGH-2)，是一種TGF-β同源因子[13]。由于重組TGH-2可以結(jié)合哺乳動(dòng)物TGF-β受體，所以認(rèn)為它可以促進(jìn)Tregs的產(chǎn)生，這已經(jīng)在哺乳動(dòng)物體內(nèi)證實(shí)。另一項(xiàng)研究，比較馬來絲蟲感染與非感染宿主感染期幼蟲和微絲蚴期的反應(yīng)，感染宿主明顯不能增加Foxp3和調(diào)控效應(yīng)分子TGF-β、CTLA-4、程序性死亡1(PD-1)和ICOS(誘導(dǎo)共刺激分子)等的表達(dá)[14]。有關(guān)蠕蟲感染動(dòng)物模型中Tregs的作用已有多項(xiàng)研究報(bào)道。在小鼠感染血吸蟲過程中，CD25+Treg細(xì)胞可以抑制寄生蟲卵引起的病理損害[15]，鼠鞭蟲腸道感染也有同樣現(xiàn)象[16]。此外，CD25+Treg隨著結(jié)合CD25和GITR抗體而耗竭，從而增強(qiáng)小鼠對(duì)棉鼠絲蟲(Litomosoidessigmodontis)的免疫力[17]。已證實(shí)在寄生蟲感染過程中隨著Foxp3的表達(dá)，Tregs的數(shù)量逐漸增多。例如，彭亨布魯線蟲(Brugiapahangi)三期幼蟲(L3)感染的BALB / c小鼠表現(xiàn)為CD4+CD25+T細(xì)胞隨著Foxp3和IL-10基因的高表達(dá)而增多[18]。棉鼠絲蟲慢性感染小鼠早期，Tregs介導(dǎo)的應(yīng)答可殺滅和清除寄生蟲[19]。慢性腸道多形螺旋線蟲(Heligmosomoidespolygyrus)感染，在小鼠腸系膜淋巴結(jié)內(nèi)的CD4+T細(xì)胞Foxp3的表達(dá)水平增高并明顯增強(qiáng)CD4+CD25+Tregs的體外抑制活性[20]。用卵清蛋白(OVA)-TCR轉(zhuǎn)基因D011.10小鼠，體外研究旋毛蟲排泄/分泌產(chǎn)物(TspES)對(duì)T細(xì)胞活化的效果，分別加入TspESpulsed-DC+OVA孵育，結(jié)果表明存在高水平的Foxp3+表達(dá)的CD4+CD25+Tregs擴(kuò)增。這些Tregs顯示有抑制活性，并產(chǎn)生TGF-β。結(jié)果表明旋毛蟲分泌產(chǎn)物在體外有誘導(dǎo)Tregs增殖的功能[21]。

2.2Bregs B細(xì)胞的免疫調(diào)節(jié)功能最早是在自身免疫反應(yīng)中被發(fā)現(xiàn)的，Bregs在蠕蟲感染中也具有重要作用。缺少B細(xì)胞可導(dǎo)致在曼氏血吸蟲感染后增強(qiáng)Th2型免疫病理，在小鼠缺少FcγRs時(shí)也同樣出現(xiàn)相似的免疫病理反應(yīng)，這表明抗體的分泌與B細(xì)胞的功能之間的關(guān)系復(fù)雜[22]。Bregs在血吸蟲感染中發(fā)揮重要作用，其活性與T細(xì)胞表面FasL表達(dá)增加和被激活的CD4+T細(xì)胞的凋亡有關(guān)[23]。盡管研究數(shù)據(jù)顯示寄生蟲感染后在抑制免疫病理方面有作用的B細(xì)胞對(duì)血吸蟲有限制作用，但是B細(xì)胞對(duì)中性粒細(xì)胞和細(xì)胞內(nèi)的利什曼原蟲感染的除蟲方面呈現(xiàn)負(fù)調(diào)節(jié)作用。因此，Bregs的調(diào)節(jié)也許代表了蠕蟲調(diào)節(jié)更寬廣的免疫機(jī)制。

在慢性炎性疾病中蠕蟲是強(qiáng)有力的調(diào)節(jié)者，原因可能是蠕蟲可以激活Bregs。相關(guān)證據(jù)是，曼氏血吸蟲誘導(dǎo)的Bregs可以通過IL-10依賴機(jī)制減輕過敏反應(yīng)。曼氏血吸蟲感染促進(jìn)腹膜的B1細(xì)胞和脾臟B細(xì)胞擴(kuò)散，從血吸蟲蟲卵獲得的低聚糖能夠促進(jìn)B細(xì)胞增殖并增加IL-10的分泌。多形螺旋線蟲感染也能誘導(dǎo)Bregs，可減輕OVA引起的過敏性氣道炎(AAI)。然而，在這一過程中只發(fā)現(xiàn)B2細(xì)胞群，并不包括產(chǎn)生IL-10的B細(xì)胞[24]。因此，認(rèn)為蠕蟲誘導(dǎo)的Bregs可能存在多種免疫調(diào)節(jié)機(jī)制。雖然這些結(jié)果都處于實(shí)驗(yàn)?zāi)Ｐ脱芯侩A段，但“蠕蟲療法”為治療慢性炎性疾病提供了一種新的越來越受歡迎的途徑。評(píng)估人體寄生蠕蟲誘導(dǎo)Bregs的作用和確定這些細(xì)胞對(duì)寄生蟲引起的炎性疾病具有潛在的調(diào)節(jié)功能具有重要意義。研究報(bào)道，分泌IL-10的B細(xì)胞在蠕蟲感染的多發(fā)性硬化癥(EAE)患者體內(nèi)成倍增加，并與減輕疾病的嚴(yán)重程度有關(guān)[25]。

3 Bregs負(fù)調(diào)節(jié)T細(xì)胞介導(dǎo)的自身免疫

Bregs的不同亞群在小鼠和人體中都已被發(fā)現(xiàn)，包括能產(chǎn)生抑制性細(xì)胞因子IL-10的B10細(xì)胞亞群。B10細(xì)胞對(duì)調(diào)控Tregs介導(dǎo)的炎癥反應(yīng)、抑制EAE、膠原性關(guān)節(jié)炎(CIA)和炎癥性腸病(IBD)[26]具有潛在作用。在小鼠慢性血吸蟲感染模型中，也證實(shí)存在與保護(hù)和防止過敏性反應(yīng)有關(guān)的B10細(xì)胞[27]。此外，多形螺旋線蟲感染小鼠誘導(dǎo)的B10細(xì)胞可以在IL-10的獨(dú)立作用下抑制變態(tài)反應(yīng)和自身免疫病[28]。

Yoshizaki等的研究還發(fā)現(xiàn)，依賴于IL-21和CD40與T細(xì)胞的同源相互作用是產(chǎn)生CD5+Bregs和IL-10的關(guān)鍵。這些信號(hào)在體外能夠誘導(dǎo)B10細(xì)胞增加數(shù)百萬倍，使B10細(xì)胞成為強(qiáng)有力的能夠調(diào)節(jié)自身免疫病的效應(yīng)細(xì)胞。除了B細(xì)胞受體的特異性，MHC-II的表達(dá)在B10細(xì)胞對(duì)EAE的調(diào)節(jié)性作用中也發(fā)揮著重要作用。此外，發(fā)現(xiàn)體外轉(zhuǎn)移擴(kuò)增的B10細(xì)胞仍可抑制EAE小鼠模型的癥狀。這項(xiàng)研究可為目前缺乏有效療法的嚴(yán)重自身免疫性疾病的治療提供一種新的有效方法。

對(duì)小鼠的抗原特異性炎癥和依賴T細(xì)胞的自身免疫病有負(fù)調(diào)控作用的B10細(xì)胞數(shù)量并不多，在幼鼠中的比例為1%～5%[29]。但是在自身免疫的個(gè)體中數(shù)量增加，脾臟B10細(xì)胞的表型主要是CD1dhiCD5+，在體外條件下經(jīng)競(jìng)爭(zhēng)性CD40多克隆抗體或LPS誘導(dǎo)產(chǎn)生IL-10的B10前體細(xì)胞也是CD1dhiCD5+表型[29]。人和小鼠產(chǎn)生IL-10的B10細(xì)胞的主要功能是對(duì)炎癥和自身免疫病進(jìn)行負(fù)調(diào)控以及參與固有免疫和獲得性免疫反應(yīng)，但是在體內(nèi)調(diào)控IL-10產(chǎn)生的信號(hào)仍然未知。B10細(xì)胞產(chǎn)生IL-10以及B10細(xì)胞調(diào)節(jié)抗原特異性免疫反應(yīng)并不能引起系統(tǒng)性的免疫抑制。其機(jī)理仍然未知。在EAE小鼠模型研究發(fā)現(xiàn)，B10細(xì)胞分化為具有分泌IL-10功能性的成熟效應(yīng)細(xì)胞，這些細(xì)胞在體內(nèi)抑制自身免疫需要IL-21、CD40和T細(xì)胞的同源相互作用。然而，體外提供CD40和IL-21的受體信號(hào)可以促使B10細(xì)胞的形成并使其數(shù)量增加四百萬倍，將這些細(xì)胞轉(zhuǎn)移至具有自身免疫病癥狀的小鼠體內(nèi)能夠產(chǎn)生顯著抑制功能的B10效應(yīng)細(xì)胞，將體外B10細(xì)胞擴(kuò)增并回輸可為目前無法治療的嚴(yán)重自身免疫性疾病提供有效的治療[30]。

4 蠕蟲感染對(duì)過敏性和自身免疫性疾病的影響

蠕蟲感染引起的免疫抑制網(wǎng)絡(luò)不僅有助于控制寄生蟲，而且有利于宿主減少過敏性和自身免疫性疾病。流行病學(xué)分析研究支持蠕蟲感染與過敏性疾病之間存在負(fù)相關(guān)[31-32]，包括感染的線蟲，如似蚓蛔線蟲和美洲板口線蟲[33]。發(fā)現(xiàn)對(duì)感染似蚓蛔線蟲和毛首鞭形線蟲感染者驅(qū)蟲治療可增加皮膚對(duì)塵螨的反應(yīng)[34]。動(dòng)物模型研究證實(shí)寄生蟲感染可以防止過敏性疾病，特別是呼吸系統(tǒng)炎癥。例如，曼氏血吸蟲感染的BALB/c小鼠對(duì)OVA誘導(dǎo)的實(shí)驗(yàn)性AAI有保護(hù)作用[35]。Dittrich等發(fā)現(xiàn)，慢性棉鼠絲蟲感染抑制所有OVA誘導(dǎo)的AAI模型的病理改變[36]。此外，還觀察到絲蟲感染的OVA處理鼠與OVA對(duì)照鼠相比，脾臟和縱隔淋巴結(jié)中的Tregs數(shù)量明顯增加。多形螺旋線蟲感染過程中的AAI抑制涉及Tregs效應(yīng)[37]。一些流行病學(xué)調(diào)查分析了寄生蟲感染對(duì)不同自身免疫性疾病的保護(hù)性影響，如EAE和1型糖尿病(T1D)[38]。研究表明，慢性寄生蟲感染者比未感染者的炎癥性腸病(IBD)發(fā)病率低[39]。人類自身免疫性疾病動(dòng)物模型實(shí)驗(yàn)表明，寄生蠕蟲可以干預(yù)自身免疫性疾病。曼氏血吸蟲感染顯示有保護(hù)T1D[40]和減輕EAE的嚴(yán)重程度[41]，而感染多形螺旋線蟲可抑制實(shí)驗(yàn)性IBD[42]。感染棉鼠絲蟲可阻止NOD鼠糖尿病，其保護(hù)作用與增加Th2應(yīng)答及Tregs數(shù)量增加有關(guān)[43]。比較研究旋毛蟲和弓首蛔蟲對(duì)炎性疾病的效果，結(jié)果旋毛蟲抑制炎癥[44]，而弓首蛔蟲加劇炎癥[45]。旋毛蟲感染也能改善NOD小鼠自身免疫性糖尿病[46]和EAE的嚴(yán)重程度[47]。蟲源性產(chǎn)物的免疫調(diào)節(jié)機(jī)制已被廣泛研究，雖然大多數(shù)研究表明蠕蟲感染具有抑制過敏性和相關(guān)自身免疫反應(yīng)，但是一些研究出現(xiàn)了相反的結(jié)果。流行病學(xué)研究表明，感染弓首蛔蟲、肝片形吸蟲、鉤蟲、蛔蟲或蟯蟲沒有保護(hù)作用，甚至增強(qiáng)過敏性反應(yīng)[48]。一些實(shí)驗(yàn)研究也表明感染蠕蟲對(duì)過敏有促進(jìn)作用，如巴西日?qǐng)A線蟲(Nippostrongylusbrasiliensis)[49]和馬來布魯線蟲(Brugia.malayi)[50]可誘發(fā)或加重過敏反應(yīng)。寄生蠕蟲感染與自身免疫性疾病之間的關(guān)系是復(fù)雜的，在蠕蟲誘導(dǎo)或促進(jìn)自身免疫反應(yīng)方面尚缺乏證據(jù)[51]。

5 結(jié) 語

綜上所述，蠕蟲感染可誘導(dǎo)免疫細(xì)胞活化，產(chǎn)生細(xì)胞因子，形成免疫調(diào)節(jié)網(wǎng)絡(luò)，介導(dǎo)免疫抑制，改善過敏性和自身免疫性疾病。然而，并非所有蠕蟲普遍具有這種特性。蠕蟲種類、是否正常宿主、寄生蟲負(fù)荷、急性感染或慢性感染等可能是影響其結(jié)果的相關(guān)因素。研究蠕蟲免疫調(diào)控與過敏性和自身免疫性疾病之間的免疫學(xué)關(guān)系，評(píng)估寄生蠕蟲誘導(dǎo)調(diào)節(jié)細(xì)胞的作用，明晰免疫調(diào)節(jié)細(xì)胞在過敏性和自身免疫性疾病中的潛在作用與功能，闡明蟲源有效分子誘導(dǎo)免疫抑制的途徑與機(jī)制，對(duì)于探索過敏性和自身免疫性疾病防治的新策略具有重要意義。

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