雙相障礙的免疫學(xué)研究進(jìn)展

張 麗，蒙華慶

(重慶醫(yī)科大學(xué)附屬第一醫(yī)院，重慶 400016*通信作者：蒙華慶，E-mail：mhq99666@126.com)

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綜 述

雙相障礙的免疫學(xué)研究進(jìn)展

張 麗，蒙華慶*

(重慶醫(yī)科大學(xué)附屬第一醫(yī)院，重慶 400016*通信作者：蒙華慶，E-mail：mhq99666@126.com)

雙相障礙是一類病程復(fù)雜、治療難度大、致殘率高的慢性精神疾病。在過去的幾十年中，雖然對(duì)雙相障礙的研究取得了一定進(jìn)展，但其確切的病因及發(fā)病機(jī)制仍不明確。近年來，越來越多的研究顯示免疫系統(tǒng)失調(diào)可能是雙相障礙的一個(gè)發(fā)病機(jī)制。本文總結(jié)了雙相障礙患者外周血及中樞神經(jīng)系統(tǒng)炎癥因子的研究，并探討了以炎癥因子為靶點(diǎn)的免疫治療方法在雙相障礙治療中的研究進(jìn)展。

雙相障礙；免疫系統(tǒng)；細(xì)胞因子；小膠質(zhì)細(xì)胞；免疫治療

1 概 述

雙相障礙(Bipolar disorder，BD)是具有心境變高和變低的兩極性，包括1次及以上的躁狂、輕躁狂或混合發(fā)作的一類精神疾病。其臨床表現(xiàn)多變，包括躁狂、輕躁狂、抑郁、混合狀態(tài)或維持階段。BD患者發(fā)病年齡較小，發(fā)作次數(shù)頻繁，且治療難度較單相抑郁更大。在長期隨訪中發(fā)現(xiàn)僅7%的患者在首次發(fā)病后不再復(fù)發(fā)，而45%的患者首次發(fā)病后會(huì)出現(xiàn)1次及以上的復(fù)發(fā)可能[1]。2004年，BD被WHO列為所有年齡段第十二種最常見的中重度致殘性疾病。2011年，全球范圍內(nèi)BD的終生患病率達(dá)2.4%，該病無性別、人種或種族易患性。其致殘作用不僅局限于有癥狀的階段，也發(fā)生在維持階段[2]。截至目前，大量研究表明該類疾病的病因和發(fā)病機(jī)制十分復(fù)雜，涉及全身多個(gè)系統(tǒng)，與遺傳、環(huán)境及心理狀況等多方面因素密切相關(guān)，同時(shí)越來越多的研究發(fā)現(xiàn)免疫系統(tǒng)失調(diào)可能是該類疾病重要的發(fā)病機(jī)制之一[3]。

細(xì)胞因子是一類由免疫細(xì)胞分泌的具有生物活性的蛋白分子，在細(xì)胞之間充當(dāng)信息傳遞的角色，它們不僅可以協(xié)調(diào)免疫反應(yīng)，還能參與調(diào)節(jié)神經(jīng)化學(xué)和神經(jīng)內(nèi)分泌過程，包括白細(xì)胞介素(interleukin，IL)、腫瘤壞死因子(tumor necrosis factor，TNF)、干擾素(interferon，IFN)、生長因子(growth factor，GF)等幾大類，根據(jù)其在炎癥反應(yīng)中的不同作用又分為抗炎性細(xì)胞因子(如IL-3、 IL-4、IL-10等)和致炎性細(xì)胞因子(如IFN-α、IFN-γ、IL-1、IL-2、IL-6、IL-12、TNF-α、TNF-β等，其中 IL-1、IL-6、TNF又稱為前炎性細(xì)胞因子，是炎癥反應(yīng)啟動(dòng)的關(guān)鍵細(xì)胞因子)。免疫系統(tǒng)與神經(jīng)和內(nèi)分泌系統(tǒng)一起形成了神經(jīng)-內(nèi)分泌-免疫網(wǎng)絡(luò)，在調(diào)節(jié)整個(gè)機(jī)體內(nèi)環(huán)境的穩(wěn)定中發(fā)揮重要作用[4]。大量研究表明炎癥介質(zhì)和免疫調(diào)節(jié)異常在精神疾病如精神分裂癥、抑郁癥和阿爾茨海默病的發(fā)病機(jī)制中起作用[5-8]。最近，越來越多的證據(jù)表明，炎癥和免疫調(diào)節(jié)異常在BD中發(fā)揮重要作用[9]。

2 BD的免疫學(xué)研究

2.1 BD血清炎癥因子水平的研究

細(xì)胞免疫是BD相關(guān)研究的焦點(diǎn)，通過測量血清中炎癥標(biāo)記物和細(xì)胞因子，達(dá)到反應(yīng)細(xì)胞因子水平的目的[10]。一項(xiàng)薈萃分析顯示，與健康對(duì)照組和BD心境愉快患者組相比，雙相躁狂患者組的TNF-α、可溶性腫瘤壞死因子受體1型(sTNFR1)和可溶性白介素2受體(sIL2R)水平升高；與健康對(duì)照組相比，BD心境愉快患者組的sTNFR1水平升高[11]。BD患者的細(xì)胞因子水平似乎有階段性差異，雙相躁狂患者血清TNF-α、IL-2、IL-4水平升高[12]，雙相抑郁患者血清IL-8、IL-6水平升高[13]。有研究表明BD的不同階段細(xì)胞因子的異常有差異，疾病早期，所有白細(xì)胞介素和TNF-α水平升高，而在疾病的后期，TNF-α和IL-6水平繼續(xù)升高，IL-10卻不再升高。因此，這些細(xì)胞因子可以作為BD進(jìn)展的重要標(biāo)志之一[14]。Berk等[9]推測，炎癥介質(zhì)與BD患者的認(rèn)知功能減退有關(guān)。BD心境愉快狀態(tài)患者趨化因子水平存在異常，誘導(dǎo)趨化作用(即白細(xì)胞向炎癥部位移動(dòng))，這表明在疾病的臨床靜止期仍有持續(xù)性的炎癥[13]。少有研究比較BD和其他精神疾病患者血漿中細(xì)胞因子的變化水平，現(xiàn)有研究發(fā)現(xiàn)，不管何種心境狀態(tài)，BD患者與精神分裂癥患者外周血sTNFR1、IL-1ra、IL-6、IL-10和IL-12水平差異均無統(tǒng)計(jì)學(xué)意義[15-18]，與重性抑郁癥患者的TNF-α、IL-6和IL-12水平差異也無統(tǒng)計(jì)學(xué)意義[17,19-21]。Mota等[22]研究發(fā)現(xiàn)，與重性抑郁癥患者相比，BD患者在心境障礙發(fā)作時(shí)(抑郁相或躁狂相)IL-1β水平降低。

2.2 BD中樞神經(jīng)系統(tǒng)炎癥水平的研究

神經(jīng)炎癥是中樞神經(jīng)系統(tǒng)免疫反應(yīng)的結(jié)果，涉及中樞神經(jīng)系統(tǒng)先天免疫系統(tǒng)、血腦屏障和外周免疫系統(tǒng)之間復(fù)雜的相互作用[10]。有研究發(fā)現(xiàn)BD存在神經(jīng)炎癥。S?derlund等[23]的一項(xiàng)研究發(fā)現(xiàn)，BD患者的IL-1β水平在外周及中樞神經(jīng)系統(tǒng)均較高。同時(shí)，在BD患者前額葉皮質(zhì)發(fā)現(xiàn)IL-1β及其受體的mRNA和蛋白水平均有顯著增加[24]。尸檢發(fā)現(xiàn)，相對(duì)于健康對(duì)照組，BD患者前額葉皮質(zhì)存在炎性改變，主要表現(xiàn)為抗炎因子水平下降而炎癥因子水平升高[25]。Dean等[26]研究發(fā)現(xiàn)，BD患者背外側(cè)前額葉皮質(zhì)的TNFR2蛋白水平降低，而前扣帶回區(qū)的TNF-α蛋白水平上調(diào)。已知背外側(cè)前額葉和前扣帶回皮質(zhì)是情緒調(diào)節(jié)和認(rèn)知功能疾病常涉及的腦區(qū)，故上述研究結(jié)果支持了炎癥反應(yīng)在BD中發(fā)揮重要作用的觀點(diǎn)。小膠質(zhì)細(xì)胞是一種神經(jīng)膠質(zhì)細(xì)胞，在中樞神經(jīng)系統(tǒng)發(fā)揮巨噬細(xì)胞的作用，是中樞神經(jīng)系統(tǒng)的第一道免疫防線，同時(shí)也是最主要的防線。神經(jīng)損傷、感染或缺血時(shí)，可以通過小膠質(zhì)細(xì)胞表面的模式識(shí)別受體激活小膠質(zhì)細(xì)胞。小膠質(zhì)細(xì)胞被激活，隨后激活核轉(zhuǎn)錄因子κB(nuclear factor kappa B，NF-κB)和絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)，進(jìn)而釋放炎癥細(xì)胞因子(如IL-1β，TNF-α，IL-6)和趨化因子。雖然小膠質(zhì)細(xì)胞的激活是先天免疫的重要組成部分，可保護(hù)中樞神經(jīng)系統(tǒng)免遭有害刺激，但小膠質(zhì)細(xì)胞過度激活可導(dǎo)致神經(jīng)毒性和神經(jīng)變性[27-28]。已有文獻(xiàn)報(bào)道在BD中，小膠質(zhì)細(xì)胞在過度激活狀態(tài)通過釋放TNF-α、IL-1、IL- 6和NO而導(dǎo)致神經(jīng)炎癥[29]，加速神經(jīng)元損傷和損失[30]。TNF-α作用于TNFR1，通過激活凋亡蛋白酶啟動(dòng)凋亡機(jī)制，從而參與神經(jīng)細(xì)胞凋亡[31-32]，上述過程最終可能使BD患者額葉的體積減少和活性降低，而已有研究表明TNF-α介導(dǎo)的BD患者額葉的改變可能與邊緣系統(tǒng)的脫抑制有關(guān)[33-34]。

細(xì)胞因子IL-1β可增加N-甲基-D-天冬氨酸受體(N-methyl-D-aspartate receptors，NMDAR)，參與谷氨酸所致神經(jīng)毒性[35]。Kaindl等[36]研究表明，小膠質(zhì)細(xì)胞NMDAR的激活觸發(fā)炎癥和細(xì)胞死亡，這又可以反過來進(jìn)一步激活小膠質(zhì)細(xì)胞并形成一個(gè)反饋環(huán)。細(xì)胞因子如IL-6和TNF-α激活腎上腺軸使皮質(zhì)醇水平增加，從而毒害神經(jīng)，也可能是抑郁癥狀和認(rèn)知減退的核心發(fā)病機(jī)制[37-38]；皮質(zhì)醇水平升高可減少突觸后膜5-羥色胺(5-HT)受體，降低5-HT反應(yīng)性水平和腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor，BDNF)水平，從而影響神經(jīng)遞質(zhì)調(diào)節(jié)和神經(jīng)可塑性[39]。IFN-α水平與廣泛雙側(cè)皮質(zhì)下區(qū)域的葡萄糖代謝增加有關(guān)，這些皮質(zhì)下區(qū)域包括基底核和前扣帶回，二者分別與疲勞和認(rèn)知效應(yīng)有關(guān)[40-41]。

小膠質(zhì)細(xì)胞與其他神經(jīng)膠質(zhì)細(xì)胞(即星形膠質(zhì)細(xì)胞和少突膠質(zhì)細(xì)胞)有密切的相互作用，這在神經(jīng)、認(rèn)知和行為功能方面起重要作用[42]。星形膠質(zhì)細(xì)胞維持血腦屏障的完整性、調(diào)節(jié)突觸傳遞，并且負(fù)責(zé)抑制小膠質(zhì)細(xì)胞引起的有害炎癥。星形膠質(zhì)細(xì)胞表達(dá)Toll樣受體(Toll-like receptor，TLR，一種模式識(shí)別受體)，并可通過分泌補(bǔ)體成分和趨化因子增強(qiáng)中樞神經(jīng)系統(tǒng)的先天免疫反應(yīng)。星形膠質(zhì)細(xì)胞能減少毒性谷氨酸的影響，但中樞神經(jīng)系統(tǒng)炎癥反應(yīng)能減弱星形膠質(zhì)細(xì)胞功能，從而加重中樞神經(jīng)系統(tǒng)的毒性[43-44]。少突膠質(zhì)細(xì)胞參與髓鞘形成過程，可通過分泌抗炎細(xì)胞因子抑制小膠質(zhì)細(xì)胞的炎性反應(yīng)[42,45]。TNF-α對(duì)少突膠質(zhì)細(xì)胞有直接的毒性作用，可能導(dǎo)致細(xì)胞凋亡和髓鞘脫失[46]，TNF-α水平與BDNF的濃度呈負(fù)相關(guān)，BD患者中BDNF水平降低[47-48]?？傊?，小膠質(zhì)細(xì)胞激活導(dǎo)致的炎癥級(jí)聯(lián)激活產(chǎn)生一系列下游介質(zhì)，可導(dǎo)致少突膠質(zhì)細(xì)胞凋亡、血腦屏障損傷、線粒體功能障礙和神經(jīng)損傷[10]。然而，BD的小膠質(zhì)細(xì)胞過度活化的機(jī)制尚不明確。

3 BD免疫治療的研究

目前BD的藥物治療是基于神經(jīng)遞質(zhì)功能障礙?，F(xiàn)有的藥物治療在控制躁狂發(fā)作及預(yù)防其復(fù)發(fā)方面效果好，但雙相抑郁的治療仍面臨巨大的挑戰(zhàn)[49]。此外，目前的治療藥物沒有找到特定的治療靶點(diǎn)，甚至可能加重BD相關(guān)的并發(fā)癥，如肥胖和胰島素抵抗[50]。值得注意的是，治療BD使用的心境穩(wěn)定劑和其他藥物的作用機(jī)制并不完全清楚。臨床前和臨床證據(jù)表明這些藥物也在調(diào)節(jié)細(xì)胞因子和促炎通路中發(fā)揮作用。Himmerich等[51]研究發(fā)現(xiàn)在健康對(duì)照組中，丙戊酸鹽可減少體外刺激的促炎細(xì)胞因子生產(chǎn)，Nassar等[50,52]在動(dòng)物和體外研究中發(fā)現(xiàn)，鋰、部分抗精神病藥和抗抑郁藥也能抑制促炎細(xì)胞因子的生產(chǎn)和/或合成。根據(jù)上述研究，免疫系統(tǒng)可能是BD藥物治療很有前途的潛在靶點(diǎn)。有研究發(fā)現(xiàn)，抗TNF-α單克隆抗體——英夫利昔單抗(infliximab)可以改善雙相躁狂癥狀[53-54]。Brietzke等[55]發(fā)現(xiàn)，IL-6受體拮抗劑也許有治療BD的作用。Nery等[56]研究顯示，常規(guī)治療聯(lián)合環(huán)氧合酶-2抑制劑——塞來昔布(celecoxib)，可以更快地改善雙相抑郁和雙相混合發(fā)作患者的抑郁癥狀，但聯(lián)合使用塞來昔布的利弊關(guān)系尚不明確。Arabzadeh等[57]的一項(xiàng)隨機(jī)對(duì)照試驗(yàn)發(fā)現(xiàn)，躁狂發(fā)作時(shí)，聯(lián)合使用塞來昔布的緩解率高于常規(guī)治療(43.5% vs. 87.0%)。Berk等[58-59]的隨機(jī)對(duì)照試驗(yàn)發(fā)現(xiàn)，聯(lián)合N-乙酰半胱氨酸(NAC)治療BD的抗抑郁療效更好。ω-3多不飽和脂肪酸(ω-3 polyunsaturated fatty acids，ω-3PUFA)是一種天然耐受性良好的抗炎劑，已有研究發(fā)現(xiàn)ω-3脂肪酸有改善BD抑郁癥狀的作用[60-61]。目前關(guān)于阿司匹林(aspirin)以及二甲胺四環(huán)素(minocycline)對(duì)BD療效的評(píng)估正處于研究階段[62]。上述研究表明，一些免疫抑制劑、抗炎藥物等具有改善BD患者情緒癥狀的潛在效果。需特別注意的是，BD和炎癥之間的關(guān)系似乎比單純的促炎癥狀態(tài)——循環(huán)細(xì)胞因子水平升高更復(fù)雜。一些臨床案例意外發(fā)現(xiàn)TNF抑制劑(依那西普和英夫利昔單抗)可誘導(dǎo)躁狂發(fā)生能說明這一點(diǎn)[53,63]。

4 小結(jié)與展望

越來越多的研究發(fā)現(xiàn)BD患者有免疫紊亂的情況，主要表現(xiàn)在各類炎癥因子、免疫標(biāo)志物的異常改變以及負(fù)責(zé)情感的腦區(qū)結(jié)構(gòu)改變。雖然各項(xiàng)研究中炎癥因子的研究一致性不強(qiáng)，炎癥因子在調(diào)節(jié)BD中的確切角色仍需進(jìn)一步確認(rèn)，但目前研究已為相關(guān)的病理生理學(xué)和心理學(xué)機(jī)制研究創(chuàng)立了新的觀點(diǎn)，同時(shí)上述免疫失衡的情況也為治療BD提供了更有效的潛在治療靶點(diǎn)或途徑。

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(本文編輯：唐雪莉)

Immunological research development of the bipolar disorder

ZhangLi,MengHuaqing*

(TheFirstAffiliatedHospitalofChongqingMedicalUniversity,Chongqing400016,China*Correspondingauthor:MengHuaqing,E-mail:mhq99666@126.com)

Bipolar disorder is a chronic psychiatric disease, associated with complex course, treatment-resistant and high disability rate. In the past decades, a certain amount of progress had been made in the study of bipolar disorder, but its exact etiology and pathogenesis remained poorly understood. In recent years, more and more studies showed that immune dysfunction may play a significant role in the pathogenesis of bipolar disorder. This review summarized the researches of the inflammation factors in peripheral and central nervous system among the bipolar patients, and discussed novel therapeutic strategies that emerged from these studies.

Bipolar disorder; Immune system; Cytokines; Microglia; Immunotherapy

R749.4

A

10.11886/j.issn.1007-3256.2017.01.020

2016-12-24)