2018, Vol. 13
皮肤黏膜作为机体最大的器官，是隔离机体与外环境和防御病原微生物入侵的第一道防线，其以形成的物理、生化和免疫屏障来共同发挥防御作用[1]。皮肤黏膜免疫屏障的形成依赖一系列位于表皮和真皮中的树突细胞(dendritic cell，DC)[2]。其中，朗格汉斯细胞(Langerhans cell，LC)属于DC家族一员，位于皮肤分层鳞状上皮和黏膜状组织中，也是第1个被认识的专职抗原呈递细胞(antigen-presenting cell，APC)[3]。本文对LC在病毒感染中的作用进行综述。
1 LC1868年，德国医学家Paul Langerhans在研究人皮肤表层时首次报道了长树突状的细胞[4]，随后人们将这种细胞命名为朗格汉斯细胞；但直到一个多世纪后，诺贝尔奖得主Ralph Steinman才证明它们是DC家族中的一个特异性亚群[5]。通过对人和小鼠LC进行大量研究，发现机体在稳定条件下，非成熟的LC是位于表皮中的唯一DC，占表皮细胞的1%~3%[6]。LC的直接前体细胞是一种高表达Gr-1分子的单核细胞，且集落刺激因子1受体(colony-stimulating factor 1 receptor，CSF-1R)在LC的迁移、发育过程中发挥关键作用。此外，LC的发生、发育还依赖生长转化因子β(transforming growth factor β，TGF-β)、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony stimulating factor，GM-CSF)等一系列可溶性细胞因子[7-9]。有研究发现，表皮LC表达识别捕获抗原的模式识别受体，如Toll样受体(Toll-like receptor，TLR)1、2、3、6、7、8和C型凝集素受体(C-type lectin receptor，CLR)Langerin，但缺乏TLR-4、TLR-5、TLR-9。此外，LC还表达高水平的白细胞介素8(interleukin 8，IL-8)、肿瘤坏死因子α(tumor necrosis factor α，TNF-α)、CXC趋化因子配体10 [motif chemokine (C-X-C) ligand 10，CXCL10]，但几乎不产生IL-1β、IL-6和IL-10[10-12]。LC表达的这些分子在其功能正常发挥中起重要作用。通常，LC的分离和鉴定是通过其表达的HLA-DR、CD1a及Langerin(CD207)来综合确定。LC还具有一种特异性的名为伯贝克颗粒(Birbeck granule)呈网球拍状的细胞器[13]，主要用来储存合成Langerin和加工降解吞入胞内的病原体[14]，也可以此来区分鉴定LC。
由于LC位于机体皮肤黏膜表层，而皮肤黏膜正是一些病毒如人类免疫缺陷病毒(human immunodeficiency virus，HIV)、疱疹病毒包括单纯疱疹病毒(herpes simplex virus，HSV)和水痘-带状疱疹病毒(varicella-zoster virus，VZV)、人乳头瘤病毒(human papillomavirus，HPV)的侵入靶点，所以LC在皮肤黏膜的病毒感染中具有重要作用。LC能通过黏附分子E-钙黏蛋白在彼此之间以及与周围的角质之间形成紧密的网络结构，以抵御和监视病原微生物的入侵[7]。一旦有外来抗原和病原体突破机体的物理和生化屏障接触到LC的树突，LC将迅速走向成熟并伴随一系列表型变化，如LC表面的主要组织相容性复合体(major histocompatibility complex，MHC)Ⅰ和Ⅱ类分子，以及共刺激分子CD80、CD86、CD40表达上调；CD83的获得性表达；细胞表面Langerin和E-钙黏蛋白表达下调等[8]。淋巴细胞归巢受体CCR7的上调表达介导LC通过输入淋巴管向局部引流淋巴结迁移，并不断走向成熟[2]，活化的LC分泌相应的趋化因子、细胞因子，其抗原呈递能力也不断增强。因此，LC在防御病原微生物感染中不仅发挥“哨兵”细胞的作用，也是连接天然免疫与适应性免疫的重要桥梁[15]。
2 LC与HIV感染HIV作为一种性传播病毒，感染机体后可损伤人体免疫系统，最终并发各种致死性的机会性感染和恶性肿瘤，其感染已成为全球重要的公共卫生问题之一。大量研究表明，跨生殖器黏膜的性传播是HIV最常见感染途径，而黏膜组织中的DC亚群通过特定受体参与HIV传递[16-19]。LC存在于皮肤表皮和大多数黏膜分层上皮，如宫颈外膜、阴道和包皮等，且特征性地表达Langerin[18]及HIV结合受体CD4和CCR5[20]。很多研究发现，LC能被HIV感染，并有效将HIV传递给T细胞导致T细胞感染[21-23]，成为HIV通过性传播途径感染过程中遇到的第1个DC。
关于LC在HIV传播过程中的具体作用存在争议。de Witte及其同事认为，表皮未成熟LC表达的Langerin是防御HIV传播的自然保护性屏障[24]。LC的Langerin可有效捕获HIV，导致HIV内化进入细胞，并随后将HIV靶向运输至Birbeck颗粒进行降解，因此LC抑制HIV感染和传播。20世纪有科学家通过皮肤移植物[25-26]或表皮层与T细胞共培养模型[27]发现，LC可将HIV转移至CD4+ T细胞，并迅速提高HIV增殖和感染能力。2014年，Nasr及其同事使用胶原酶消化分离的人LC，对de Witte等的研究结果提出质疑[28]。该研究表明，LC对HIV感染和传播存在两个阶段的转移：第一阶段显示LC在接触HIV 2 h内确实能通过Langerin将HIV转移至T细胞，该阶段的转移可直接被中和Langerin的单克隆抗体阻断，暗示了Langerin的作用，并且该观察结果类似于来自单核细胞的DC[17]；第二阶段的转移可被阻断HIV复制的药物齐多夫定(zidovudine，AZT)抑制，表明该阶段转移的病毒是增殖后的病毒，即HIV进入LC后增殖并将新生子代病毒转移给了T细胞。Ganor等的研究结果[29]与Nasr等的一致，他们指出人类包皮LC结合HIV后可改变其分布，并在1 h内转移HIV给T细胞，阴道LC也有类似功能。最近，van den Berg等也证明Langerin促进HIV转移并引发LC及其他DC成熟，刺激CD8+ T细胞的活化[30]。Harman等也发现，HIV激活LC后，足以使其成熟并从上皮组织迁移至黏膜下层或下游引流淋巴结，在那里LC可有效地与CD4+ T细胞相互作用并将病毒转移至CD4+ T细胞，但同时抑制其溶酶体功能以防止自身凋亡和降解[31]。
此外，流行病学研究表明，性传播感染(sexually transmitted infection，STI)可直接和间接影响LC，从而增加HIV的易感性[32-35]。女性阴道和男性包皮生殖器黏膜组织中的LC不仅可与HIV相互作用，还受STI病原的影响。最新研究发现，一些STI病原与LC直接相互作用，与HIV竞争结合Langerin或降低Langerin表达量，从另一方面提高了LC进入受体CD4和辅助性受体CCR5捕获HIV的能力，还增强了LC的增殖性感染能力，从而促进HIV传播。HSV-2是最常见的STI病原体，预先感染了HSV-2的个体HIV易感概率比未感染HSV-2者提高3倍以上[36-38]。据估计，在某些地区如撒哈拉以南非洲，HSV-2感染可能与30%~50%的新发HIV感染有关[39]。STI诱导产生的促炎细胞因子也能影响LC对HIV传播的易感性[40]，目前已证明TNF-α能通过激活核因子κB(nuclear factor κB，NF-κB)信号通路来增强HIV复制[41-42]。
总之，LC对HIV的感染和传播受不同因素的影响。LC的激活状态似乎是HIV易感性的重要决定因素，尽管未成熟的LC可形成对HIV感染的保护性屏障[24]，但活化的LC促进HIV感染和传播[28]。
3 LC与疱疹病毒的相互作用HSV和VZV是能感染角质形成细胞和LC的典型嗜上皮性病毒[43-44]，急性皮肤黏膜感染后可在感觉神经节中建立终身潜伏感染。尽管表皮LC是与疱疹病毒相互作用的第1个DC，但直到最近疱疹病毒的免疫机制才逐渐被人们解开。
关于LC在抗HSV应答中作用的最早研究之一表明，在HSV-1感染脚垫之前从小鼠皮肤消除LC可导致HSV-1毒力增加[45]。随后又有报道表明，在小鼠皮下注射HSV-1后会引起LC在下游淋巴结中累积，其数量在感染后第3天达到峰值；结果还表明HSV-1免疫后小鼠淋巴结中的T细胞在体外对HSV-1抗原有免疫反应，但这些反应在预先从皮肤敲除LC后减弱[46]。这些研究表明，LC在诱导对HSV的细胞免疫中具有重要作用[47]。在人类复发性疱疹病变中，CD4+ T细胞首先浸润至病灶部位，然后行使杀伤功能并清除感染的CD8+ T细胞[43, 48]。小鼠模型研究发现，HSV可感染LC[49]，但这些LC并不是呈递HSV抗原至淋巴结中T细胞的DC，相反，该功能是由真皮层DC来完成的[50]。此外，在小鼠研究中也发现，LC不是引发病毒特异性细胞毒性T细胞反应的APC[51]。最近，Kim等使用人类包皮移植物等3种不同系统揭示了原因[52]。他们发现LC与HSV-2相互作用导致LC增殖性感染，最终诱导LC发生细胞凋亡并迁移至真皮层；在真皮层，CD141+ DC和CD14+ DC吞噬垂死的HSV感染的LC，并将抗原呈递给淋巴结中的T细胞，启动细胞免疫。由于CD141+ DC属于交叉呈递细胞，可特异性地将抗原交叉呈递给CD8+ T细胞，这就解释了为什么CD8+ T细胞能被激活并随后渗入疱疹病灶而清除感染，然后转化为组织驻留记忆性T细胞[53]。因此，LC起呈递HSV抗原给黏膜下DC的作用，这与HIV感染中LC的作用及最终命运有所不同。
研究表明，呼吸道黏膜DC可能是VZV初次感染期间遇到的第1批细胞，且能将病毒转运至人类扁桃体CD4+ T细胞，这些T细胞表达皮肤归巢标记，可在原发病毒血症期间直接从淋巴结向皮肤转运VZV[54-55]。病毒一旦到达皮肤，会感染皮肤上皮细胞，导致独特的脓包性病变[56-58]。此外，最近有研究报道了患有水痘或带状疱疹的人类皮肤中DC亚群类型和分布发生的变化，并与单纯疱疹病变进行比较，发现在HSV、VZV感染病变皮肤中DC-SIGN+ DC的比例没有显著改变，但与HSV感染不同的是，表皮LC显著减少；存在于LC中的VZV结构和非结构蛋白与复制病毒一致，表明这些细胞在体内被感染；VZV感染期间表皮LC显著减少不是LC的标记CD1a和Langerin在皮肤LC中表达减少导致的，VZV感染的LC也没有发生显著的细胞凋亡[59]。因此，皮肤和呼吸道黏膜中的LC可能参与VZV感染的早期阶段[55]。总之，通过以上研究可推测，存在于呼吸道黏膜中的LC可能是最早感染VZV并传播VZV到淋巴结的细胞，然后VZV感染淋巴结T细胞，感染的T细胞作为炎症浸润的一部分迁移到皮肤[59-61]，因此LC是负责将VZV扩散到皮肤细胞的细胞。在皮肤病灶VZV又可感染表皮内LC，感染的表皮内LC作为专职APC可迁移到下游引流淋巴结感染另外的T细胞，新感染的T细胞又作为炎症浸润的一部分迁移回皮肤，引起额外的皮肤损伤。
4 LC在麻疹病毒(measles virus，MV)感染中的作用MV是一种高度传染性的嗜淋巴细胞和骨髓细胞病毒，通过呼吸道传播。因此，病毒入侵的最初靶点必须存在于呼吸道黏膜表面，而表达Langerin的LC大量存在于上呼吸道上皮中[62-64]。目前，有关LC在MV感染中的作用报道较少。van der Vlist及其团队发现人LC能通过Langerin捕获MV抗原，且未成熟和成熟的LC均能通过HLA-Ⅱ类分子将MV抗原呈递给特异性CD4+ T细胞。MV不能在未成熟的LC中完成其增殖性感染，因此细胞不存在通过HLA-Ⅰ类分子呈递内源性MV抗原；相反，MV能在成熟的LC中完成其增殖性感染，细胞可将新合成的病毒抗原呈递给MV特异性CD8+ T细胞。他们还发现，未成熟和成熟的LC均不能交叉呈递外源紫外线灭活的MV或MV感染后的凋亡细胞至淋巴细胞。通过这些结果推测，人LC的免疫激活似乎是LC中的MV增殖性感染和通过内源性抗原呈递途径启动CD8+ T细胞的先决条件[65]。
5 结语LC是机体免疫系统的重要组成部分，其作为DC家族中的一种独特类型成员，已成为病毒通过皮肤黏膜初次感染机体和维持机体自身稳定的研究重点，尤其是其在病毒感染中作为专职APC摄取、加工处理和呈递病毒抗原及诱导T细胞反应等方面。
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