双相障碍的免疫学研究进展

张 丽，蒙华庆

(重庆医科大学附属第一医院，重庆 400016*通信作者：蒙华庆，E-mail：mhq99666@126.com)



综 述

双相障碍的免疫学研究进展

张 丽，蒙华庆*

(重庆医科大学附属第一医院，重庆 400016*通信作者：蒙华庆，E-mail：mhq99666@126.com)

双相障碍是一类病程复杂、治疗难度大、致残率高的慢性精神疾病。在过去的几十年中，虽然对双相障碍的研究取得了一定进展，但其确切的病因及发病机制仍不明确。近年来，越来越多的研究显示免疫系统失调可能是双相障碍的一个发病机制。本文总结了双相障碍患者外周血及中枢神经系统炎症因子的研究，并探讨了以炎症因子为靶点的免疫治疗方法在双相障碍治疗中的研究进展。

双相障碍；免疫系统；细胞因子；小胶质细胞；免疫治疗

1 概 述

双相障碍(Bipolar disorder，BD)是具有心境变高和变低的两极性，包括1次及以上的躁狂、轻躁狂或混合发作的一类精神疾病。其临床表现多变，包括躁狂、轻躁狂、抑郁、混合状态或维持阶段。BD患者发病年龄较小，发作次数频繁，且治疗难度较单相抑郁更大。在长期随访中发现仅7%的患者在首次发病后不再复发，而45%的患者首次发病后会出现1次及以上的复发可能[1]。2004年，BD被WHO列为所有年龄段第十二种最常见的中重度致残性疾病。2011年，全球范围内BD的终生患病率达2.4%，该病无性别、人种或种族易患性。其致残作用不仅局限于有症状的阶段，也发生在维持阶段[2]。截至目前，大量研究表明该类疾病的病因和发病机制十分复杂，涉及全身多个系统，与遗传、环境及心理状况等多方面因素密切相关，同时越来越多的研究发现免疫系统失调可能是该类疾病重要的发病机制之一[3]。

细胞因子是一类由免疫细胞分泌的具有生物活性的蛋白分子，在细胞之间充当信息传递的角色，它们不仅可以协调免疫反应，还能参与调节神经化学和神经内分泌过程，包括白细胞介素(interleukin，IL)、肿瘤坏死因子(tumor necrosis factor，TNF)、干扰素(interferon，IFN)、生长因子(growth factor，GF)等几大类，根据其在炎症反应中的不同作用又分为抗炎性细胞因子(如IL-3、 IL-4、IL-10等)和致炎性细胞因子(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又称为前炎性细胞因子，是炎症反应启动的关键细胞因子)。免疫系统与神经和内分泌系统一起形成了神经-内分泌-免疫网络，在调节整个机体内环境的稳定中发挥重要作用[4]。大量研究表明炎症介质和免疫调节异常在精神疾病如精神分裂症、抑郁症和阿尔茨海默病的发病机制中起作用[5-8]。最近，越来越多的证据表明，炎症和免疫调节异常在BD中发挥重要作用[9]。

2 BD的免疫学研究

2.1 BD血清炎症因子水平的研究

细胞免疫是BD相关研究的焦点，通过测量血清中炎症标记物和细胞因子，达到反应细胞因子水平的目的[10]。一项荟萃分析显示，与健康对照组和BD心境愉快患者组相比，双相躁狂患者组的TNF-α、可溶性肿瘤坏死因子受体1型(sTNFR1)和可溶性白介素2受体(sIL2R)水平升高；与健康对照组相比，BD心境愉快患者组的sTNFR1水平升高[11]。BD患者的细胞因子水平似乎有阶段性差异，双相躁狂患者血清TNF-α、IL-2、IL-4水平升高[12]，双相抑郁患者血清IL-8、IL-6水平升高[13]。有研究表明BD的不同阶段细胞因子的异常有差异，疾病早期，所有白细胞介素和TNF-α水平升高，而在疾病的后期，TNF-α和IL-6水平继续升高，IL-10却不再升高。因此，这些细胞因子可以作为BD进展的重要标志之一[14]。Berk等[9]推测，炎症介质与BD患者的认知功能减退有关。BD心境愉快状态患者趋化因子水平存在异常，诱导趋化作用(即白细胞向炎症部位移动)，这表明在疾病的临床静止期仍有持续性的炎症[13]。少有研究比较BD和其他精神疾病患者血浆中细胞因子的变化水平，现有研究发现，不管何种心境状态，BD患者与精神分裂症患者外周血sTNFR1、IL-1ra、IL-6、IL-10和IL-12水平差异均无统计学意义[15-18]，与重性抑郁症患者的TNF-α、IL-6和IL-12水平差异也无统计学意义[17,19-21]。Mota等[22]研究发现，与重性抑郁症患者相比，BD患者在心境障碍发作时(抑郁相或躁狂相)IL-1β水平降低。

2.2 BD中枢神经系统炎症水平的研究

神经炎症是中枢神经系统免疫反应的结果，涉及中枢神经系统先天免疫系统、血脑屏障和外周免疫系统之间复杂的相互作用[10]。有研究发现BD存在神经炎症。Söderlund等[23]的一项研究发现，BD患者的IL-1β水平在外周及中枢神经系统均较高。同时，在BD患者前额叶皮质发现IL-1β及其受体的mRNA和蛋白水平均有显著增加[24]。尸检发现，相对于健康对照组，BD患者前额叶皮质存在炎性改变，主要表现为抗炎因子水平下降而炎症因子水平升高[25]。Dean等[26]研究发现，BD患者背外侧前额叶皮质的TNFR2蛋白水平降低，而前扣带回区的TNF-α蛋白水平上调。已知背外侧前额叶和前扣带回皮质是情绪调节和认知功能疾病常涉及的脑区，故上述研究结果支持了炎症反应在BD中发挥重要作用的观点。小胶质细胞是一种神经胶质细胞，在中枢神经系统发挥巨噬细胞的作用，是中枢神经系统的第一道免疫防线，同时也是最主要的防线。神经损伤、感染或缺血时，可以通过小胶质细胞表面的模式识别受体激活小胶质细胞。小胶质细胞被激活，随后激活核转录因子κB(nuclear factor kappa B，NF-κB)和丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)，进而释放炎症细胞因子(如IL-1β，TNF-α，IL-6)和趋化因子。虽然小胶质细胞的激活是先天免疫的重要组成部分，可保护中枢神经系统免遭有害刺激，但小胶质细胞过度激活可导致神经毒性和神经变性[27-28]。已有文献报道在BD中，小胶质细胞在过度激活状态通过释放TNF-α、IL-1、IL- 6和NO而导致神经炎症[29]，加速神经元损伤和损失[30]。TNF-α作用于TNFR1，通过激活凋亡蛋白酶启动凋亡机制，从而参与神经细胞凋亡[31-32]，上述过程最终可能使BD患者额叶的体积减少和活性降低，而已有研究表明TNF-α介导的BD患者额叶的改变可能与边缘系统的脱抑制有关[33-34]。

细胞因子IL-1β可增加N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptors，NMDAR)，参与谷氨酸所致神经毒性[35]。Kaindl等[36]研究表明，小胶质细胞NMDAR的激活触发炎症和细胞死亡，这又可以反过来进一步激活小胶质细胞并形成一个反馈环。细胞因子如IL-6和TNF-α激活肾上腺轴使皮质醇水平增加，从而毒害神经，也可能是抑郁症状和认知减退的核心发病机制[37-38]；皮质醇水平升高可减少突触后膜5-羟色胺(5-HT)受体，降低5-HT反应性水平和脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)水平，从而影响神经递质调节和神经可塑性[39]。IFN-α水平与广泛双侧皮质下区域的葡萄糖代谢增加有关，这些皮质下区域包括基底核和前扣带回，二者分别与疲劳和认知效应有关[40-41]。

小胶质细胞与其他神经胶质细胞(即星形胶质细胞和少突胶质细胞)有密切的相互作用，这在神经、认知和行为功能方面起重要作用[42]。星形胶质细胞维持血脑屏障的完整性、调节突触传递，并且负责抑制小胶质细胞引起的有害炎症。星形胶质细胞表达Toll样受体(Toll-like receptor，TLR，一种模式识别受体)，并可通过分泌补体成分和趋化因子增强中枢神经系统的先天免疫反应。星形胶质细胞能减少毒性谷氨酸的影响，但中枢神经系统炎症反应能减弱星形胶质细胞功能，从而加重中枢神经系统的毒性[43-44]。少突胶质细胞参与髓鞘形成过程，可通过分泌抗炎细胞因子抑制小胶质细胞的炎性反应[42,45]。TNF-α对少突胶质细胞有直接的毒性作用，可能导致细胞凋亡和髓鞘脱失[46]，TNF-α水平与BDNF的浓度呈负相关，BD患者中BDNF水平降低[47-48]。总之，小胶质细胞激活导致的炎症级联激活产生一系列下游介质，可导致少突胶质细胞凋亡、血脑屏障损伤、线粒体功能障碍和神经损伤[10]。然而，BD的小胶质细胞过度活化的机制尚不明确。

3 BD免疫治疗的研究

目前BD的药物治疗是基于神经递质功能障碍。现有的药物治疗在控制躁狂发作及预防其复发方面效果好，但双相抑郁的治疗仍面临巨大的挑战[49]。此外，目前的治疗药物没有找到特定的治疗靶点，甚至可能加重BD相关的并发症，如肥胖和胰岛素抵抗[50]。值得注意的是，治疗BD使用的心境稳定剂和其他药物的作用机制并不完全清楚。临床前和临床证据表明这些药物也在调节细胞因子和促炎通路中发挥作用。Himmerich等[51]研究发现在健康对照组中，丙戊酸盐可减少体外刺激的促炎细胞因子生产，Nassar等[50,52]在动物和体外研究中发现，锂、部分抗精神病药和抗抑郁药也能抑制促炎细胞因子的生产和/或合成。根据上述研究，免疫系统可能是BD药物治疗很有前途的潜在靶点。有研究发现，抗TNF-α单克隆抗体——英夫利昔单抗(infliximab)可以改善双相躁狂症状[53-54]。Brietzke等[55]发现，IL-6受体拮抗剂也许有治疗BD的作用。Nery等[56]研究显示，常规治疗联合环氧合酶-2抑制剂——塞来昔布(celecoxib)，可以更快地改善双相抑郁和双相混合发作患者的抑郁症状，但联合使用塞来昔布的利弊关系尚不明确。Arabzadeh等[57]的一项随机对照试验发现，躁狂发作时，联合使用塞来昔布的缓解率高于常规治疗(43.5% vs. 87.0%)。Berk等[58-59]的随机对照试验发现，联合N-乙酰半胱氨酸(NAC)治疗BD的抗抑郁疗效更好。ω-3多不饱和脂肪酸(ω-3 polyunsaturated fatty acids，ω-3PUFA)是一种天然耐受性良好的抗炎剂，已有研究发现ω-3脂肪酸有改善BD抑郁症状的作用[60-61]。目前关于阿司匹林(aspirin)以及二甲胺四环素(minocycline)对BD疗效的评估正处于研究阶段[62]。上述研究表明，一些免疫抑制剂、抗炎药物等具有改善BD患者情绪症状的潜在效果。需特别注意的是，BD和炎症之间的关系似乎比单纯的促炎症状态——循环细胞因子水平升高更复杂。一些临床案例意外发现TNF抑制剂(依那西普和英夫利昔单抗)可诱导躁狂发生能说明这一点[53,63]。

4 小结与展望

越来越多的研究发现BD患者有免疫紊乱的情况，主要表现在各类炎症因子、免疫标志物的异常改变以及负责情感的脑区结构改变。虽然各项研究中炎症因子的研究一致性不强，炎症因子在调节BD中的确切角色仍需进一步确认，但目前研究已为相关的病理生理学和心理学机制研究创立了新的观点，同时上述免疫失衡的情况也为治疗BD提供了更有效的潜在治疗靶点或途径。

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(本文编辑：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)