修回日期: 2002-11-10
接受日期: 2002-11-16
在线出版日期: 2003-05-15
肠黏膜屏障是机体屏障系统的重要组成部分. 肠黏膜屏障由肠黏膜机械屏障、化学屏障、生物屏障和免疫屏障组成, 各自具有不同的结构、不同的分子调控机制和不同的生物学功能, 同时又通过各自的信号通路有机地结合在一起, 共同防御外来抗原物质对机体的侵袭, 消化系统疾病和一些非消化系统疾病常导致肠黏膜屏障功能障碍, 肠黏膜屏障功能障碍可以进一步加重原发疾病的病情, 甚至诱发多脏器功能不全、全身炎症反应综合征, 形成恶性循环, 危及生命. 因而深入研究肠黏膜屏障必将有助于通过对这些分子调控信号通路进行干预, 从而达到防治肠道相关性疾病, 筛选有效的黏膜疫苗, 为开发新药物提供特异的作用靶点.
引文著录: 武金宝, 王继德, 张亚历. 肠黏膜屏障研究进展. 世界华人消化杂志 2003; 11(5): 619-623
Revised: November 10, 2002
Accepted: November 16, 2002
Published online: May 15, 2003
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11(5): 619-623
- URL: https://www.wjgnet.com/1009-3079/full/v11/i5/619.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v11.i5.619
近年来, 随着对炎症性肠病、多脏器功能衰竭、细菌移位、肠源性感染等研究的深入, 人们对肠道复杂生理功能有了新的认识, 注意到肠道不仅是消化和吸收营养物质的重要脏器, 而且肠道的其他功能如免疫调节、内分泌功能、黏膜屏障功能, 逐渐被重视. 不论肠道的原发性病变, 还是继发性损害, 均会造成肠功能不同程度的损伤. 当前临床研究的热点主要是肠黏膜屏障功能(gut barrier function). 肠道屏障是存在于肠道内的具有高效选择性功能的屏障系统[1], 由肠黏膜非特异免疫屏障和肠黏膜特异性免疫屏障组成[2]. 肠黏膜屏障在保护机体免受食物抗原、微生物极其产生的有害代谢产物的损害, 保持机体内环境的稳定方面起重要作用[3,4].
肠黏膜非特异免疫屏障由肠黏膜机械屏障、化学屏障、生物屏障组成.
机械屏障由肠道黏膜上皮细胞、细胞间紧密连接与菌膜三者构成, 能有效阻止细菌穿透黏膜进入深部组织, 是肠黏膜屏障的结构基础. 肠上皮为单层柱状上皮细胞, 由吸收细胞、杯状细胞及潘氏细胞(paneth cell)等组成. 吸收细胞侧面和质膜在近肠腔侧与相邻的细胞连接形成紧密连接复合体, 包括两类: (1)绒毛上皮间紧密连接, 孔径较小, 结构层次复杂, 只允许水分子和小分子水溶性物质有选择性通过; (2)腺管细胞间紧密连接孔径较大而层次较简单, 可容许较大的分子通过[5]. 上皮细胞间的紧密连接由多种功能各异的蛋白质组成, 开放和关闭具有可控性, 受肠腔内容物成分和细胞因子、黏附素的调控[6,7]; 潘氏细胞具有一定的吞噬细菌的能力, 并可分泌非特异性的溶菌酶, 调节肠道菌群. 近年研究发现, 潘氏细胞还分泌天然抗生素肽(Antibiotic peptide)人类防御素5(human defensin 5, HD-5)和人类防御素6(human defensin 6, HD-6), 都是由32-36个氨基酸残基组成的小分子肽, 其抗菌谱广, 杀灭微生物作用强大[8-10], 在抑制细菌移位、防治肠源性感染方面日益受到重视[10,11] 杯状细胞分泌的黏液在黏膜表面形成疏水的黏液凝胶层, 主要成分是黏液糖蛋白. 他覆盖肠上皮表面, 可阻抑消化道中的消化酶和有害物质对上皮细胞的损害. 研究表明, 黏液糖蛋白本身的结构和带有负电荷的特性, 有利于包裹细菌; 黏液糖蛋白暴露的化学基团与肠上皮表面结构类似, 易于细菌识别和黏附[12]; 黏液糖蛋白还与病原微生物竞争抑制肠上皮细胞上的黏附素受体, 抑制病菌在肠道的黏附定植[13]; 黏液糖蛋白协同分泌型IgA在黏膜表面形成一个抗感染的抗体黏膜屏障, 通过肠的蠕动将捕获在黏液层中的细菌和毒素清除出体外[14].
肠道是人体内最大的储菌库, 细菌种类多达400种以上, 99%左右为专性厌氧菌. 肠道常驻菌群是一个相互依赖又相互作用的微生态系统, 这种微生态平衡构成了肠生物屏障[15], 其中深层主要寄居着厌氧菌, 中层为类杆菌、消化链球菌, 表层是大肠杆菌、肠球菌等. 表层的需氧菌(主要为大肠杆菌)可游动在肠腔中, 而深层的专性厌氧菌紧贴在肠黏膜表面, 被糖衣包被, 比较稳定, 形成膜菌群, 能阻止表层具有潜在致病性的需氧菌或外来菌直接黏附于肠黏膜细胞. 兼性厌氧肠杆菌可以消耗肠道中的游离氧, 并可以在肠道中形成厌氧菌必需的-350 mV的氧化还原电势, 因而对维持肠道的厌氧环境和厌氧菌的定植起重要的作用[15,16]. 专性厌氧菌(主要是双歧杆菌等)通过黏附作用与肠上皮紧密结合, 形成菌膜屏障, 可以竞争抑制肠道中条件致病菌-革兰氏阴性杆菌, 主要是兼性厌氧菌和需氧菌黏附肠上皮细胞[15,16], 其次专性厌氧菌可分泌短链脂肪酸来降低肠道的pH值以及抑菌肽均可抑制肠道兼性厌氧菌和外来菌的定植和生长. 另外, 许多研究证实双歧杆菌除了具有维持肠道正常微生物群平衡、抗感染的作用外, 还具有抗肿瘤、抗衰老等生理作用[15-20].
胃肠道分泌的胃酸、胆汁、各种消化酶、溶菌酶、黏多糖、糖蛋白和糖脂等化学物质组成肠黏膜的化学屏障. 胃酸能杀灭进入胃肠道的细菌, 抑制细菌在胃肠道上皮的黏附和定植. 溶菌酶能破坏细菌的细胞壁, 使细菌裂解. 黏液中含有的补体成分可增加溶菌酶及免疫球蛋白的抗菌作用. 其中, 肠道分泌的大量消化液可稀释毒素, 冲洗清洁肠腔, 使潜在的条件致病菌难以黏附到肠上皮上.
肠道黏膜免疫屏障是区别于系统性免疫的功能发达的局部免疫系统. 根据功能和分布, 可将肠道黏膜免疫系统分成肠相关淋巴组织(gut-associated lymphoid tissue, GALT)和弥散免疫细胞. 肠相关淋巴组织主要指分布于肠道的集合淋巴小结, 即Peyer结(peyer's patches), 是免疫应答的诱导和活化部位; 弥散免疫细胞则是肠黏膜免疫的效应部位[21]. 最近几年, 发现多种细胞和细胞因子参与肠黏膜免疫应答, 为进一步阐明肠黏膜免疫的机制奠定了基础[22].
M细胞为一种特化的扁平上皮细胞, 是位于黏膜淋巴结的滤泡上皮中的抗原递呈细胞[22,23]. 这些细胞在扫描电镜下因具有特征性的微折叠现象, 最初被称作微折叠细胞(microfold cell), 后据其有膜样结构而称作膜样细胞(membranous cell)或膜性细胞(membrane cell), 简称M细胞[24]. Ｍ细胞与邻近上皮细胞间可通过桥粒紧密连接, 形成上皮障碍, 将肠道内抗原物质与上皮下淋巴组织隔开. 研究发现Ｍ细胞是大分子颗粒抗原进入上皮下淋巴组织的主要途径[25]. 与肠上皮不同的是, M细胞能摄取和运输多种大分子物质, 如微生物和微粒等颗粒性抗原, 把他们传递给黏膜下的淋巴组织应答[26]. 当黏膜表面的抗原与Ｍ细胞膜结合后, Ｍ细胞便将其吞入形成吞饮小泡, 但抗原很少或完全不在Ｍ细胞溶酶体中停留, 因而微生物抗原一般仍以完整的活性形式跨过Ｍ细胞, 直接迅速被转运至上皮下淋巴组织[27]. Ｍ细胞上皮下淋巴滤泡生发中心的上皮内专有抗原递呈细胞如巨噬细胞、树突状细胞, 处理经Ｍ细胞转运来的抗原然后呈递给T、B淋巴细胞, 产生抗原特异性Ｂ淋巴母细胞, 在生发中心繁殖后, 通过血流迁移到远处的黏膜和腺体组织, 进一步分化成熟为浆细胞, 产生分泌型IgA[28,29]. 可以看出, 跨越Ｍ细胞转运抗原为启动肠黏膜免疫应答的最重要的第一步, 因而, M细胞起"第一信息通道"(first information conduct)的作用[27,30].
IEL是一组CD8+细胞[31,32], 主要位于肠道上皮之间和绒毛顶端, 被激活后可释放IL-2, 3, 4, 5, 10、IFN-α、IFN-γ, TGF-β等多种细胞因子, 因此在防御肠道病原体入侵方面发挥重要的作用[33,34]. 研究表明, IEL有与细胞毒T细胞及NK相似的胞内颗粒, 如穿孔素、端粒酶和丝氨酸酯酶, 故IEL的主要功能是细胞杀伤作用[35]. 另外, IEL可抑制黏膜部位的过敏反应[35,36].
LPL位于黏膜固有层, T、B细胞均很丰富. 已发现在黏膜部位的免疫应答以TH2型为主, 定居在固有层的CD4+Th2细胞可分泌多种Th2型细胞因子如TGF-β、IL-4、IL-5、IL-6及IL-10[37]. Husband研究了各种Th2型细胞因子在黏膜免疫中的作用, 发现由于IL-4可激活静止期B细胞, 故在诱导局部及全身抗体应答中均起关键作用, 而IL-5和IL-6则主要在黏膜部位发挥特殊作用[38]. IL-6在促进肠道和呼吸道IgA应答方面起重要作用, 这已通过用基因敲除技术(knockout)灭活IL-6基因得到证实[39]. IL-4、IL-5、IL-6可协同诱导SIgA+B细胞分化成为IgA+浆细胞[40,41]. 因此, 固有层是黏膜免疫应答的主要效应场所, 浆细胞所分泌的大量IgA可通过分泌片的介导进入黏膜表面, 中和抗原物质, 起到清除外来抗原, 保护机体的作用[12,42,43].
分泌型IgA(secretory immunoglobulin A, SIgA)是机体内分泌量最多的免疫球蛋白, 是胃肠道和黏膜表面主要免疫球蛋白, 对消化道黏膜防御起着重要作用, 其中以SIgA为主的体液免疫起主导作用, 他是防御病菌在肠道黏膜黏附和定植的第一道防线[44-47].目前, 对SIgA的表达及其调节、黏膜神经内分泌免疫网络的调节机制等研究已经有了较大的进展, 但还有些问题等待解决.肠道中的SIgA可阻止病原体在肠黏膜表面的黏附, 可中和细菌产生的毒素, 中和病毒, 可以增强具有FC受体(FCR)细胞的吞噬功能, 并与补体和溶菌酶协同抗菌[48,49]; 其次, SIgA可作为封闭抗体抑制由IgM免疫复合物介导的抗体依赖式细胞毒作用(ADCC作用)对肠道局部的免疫炎症损伤[50]. 如果因为使用糖皮质激素、胃肠外营养(TPM)等干扰了SIgA的合成过程, 将导致SIgA减少而削弱肠道的免疫功能, 可引起肠道菌群失调, 发生以脂肪痢为特征的消化吸收障碍, 甚至引起肠道细菌的易位而发生肠源性全身感染[51]. 体内实验表明, IL-5能增强特异性IgA的反应; IL-6对分泌IgA的浆细胞在黏膜效应位点的定位、终末分化和增生起关键作用[52,53].
多形核中性粒细胞(polymo-rphonuclear neutrophils, PMN)在炎症部位募集、浸润是炎症反应的基本组织病理表现之一, 也是导致肠黏膜屏损伤的重要因素, 而白细胞-内皮细胞(PMN-EC)黏附是其发生的分子基础. 细胞黏附包括PMN沿EC滚动、PMN-EC紧密黏附及PMN穿越内皮细胞游出三个阶段, 各阶段均需多种黏附分子的参与[54,55]. 最近, 对黏附分子ICAM-1, ICAM-2及β2整合素(β2-integrins, CD11/CD18)的研究提示, 炎症性肠病和其他多种肠炎模型中白细胞的浸润是白细胞与内皮细胞黏附分子相互作用的结果[56,57]. ICAM-1(intercellular adhesion molecule-1, ICAM-1), ICAM-2(inter -cellular adhesion molecule-2, ICAM-2)均为内皮细胞的黏附分子, 是免疫球蛋白超家族(super-gene family)的成员. ICAM-1含有5个免疫球蛋白样的细胞外区域, 第1个以氨基端的IgA样区域识辨CD11a/CD18, 第3个则识辨CD11b/CD18分子, 在Th1源性细胞因子和细菌产物的刺激下, 随着内皮细胞的激活而表达. 存在于PMN表面上的?2整合素的结构是杂二聚体, 一个共同的亚基CD18和另外三个免疫学特性相异的亚基CD11a或CD11b或CD11c结合而成三种抗原成分: 淋巴细胞功能相关抗原-1(LFA-1, CD11a/CD18)、巨噬细胞分化抗原-1(Mac-1, CD11b/CD18)和GP150/95(CD11c/CD18)[54,58]. PMN通过改变细胞表面整合素的结构和功能来调控与其他细胞的相互作用[54,59,60]. 当PMN被激活后, CD11a/CD18和CD11b/CD18被动员到表面上, 与受到细胞因子刺激的内皮上的ICAM-1和ICAM-2相互作用, 促使PMN淋巴细胞与内皮细胞的黏附[61,62]. 实验证实, 抗CD11a/CD18和ICAM-1的单克隆抗体可抑制ICAM-1和ICAM-2的黏附作用[61,63]; 肠道炎症活动时的组织损伤和功能失调也可抑制这种黏附作用, 这也有力地例证了CD11/CD18和ICAM-1, ICAM-2对肠道组织损伤和肠黏膜屏障稳定的重要意义[64-67].
正常情况下肠黏膜淋巴细胞进入血循环参加淋巴循环, 记忆淋巴细胞可通过肠黏膜的高内皮静脉(high endothelial vein, HEV)重新回到原来所在的肠黏膜和肠系膜淋巴结的现象叫淋巴细胞的归巢(homing). 淋巴细胞的归巢则主要取决于淋巴细胞上的黏附分子与靶器官血管内皮细胞上配体之间的相互作用. 淋巴细胞归巢到黏膜是由淋巴细胞表达的黏附分子与黏膜血管内皮表达的组织特异性配体相互作用而启动的[68,69]. 近几年已发现多种黏附分子参与了淋巴细胞的归巢与定居, 其中最主要的是整合素分子. 整合素由α、β亚基组成, 属于是Ⅰ型跨膜糖蛋白. 因为β亚基可与几个不同的α亚基结合, 据此可将整合素分成不同的亚家族[70,71]. 其中研究较多的有: (1)整合素α4 β7及配体MAdCAM-1已知α4 β7是小鼠淋巴细胞归巢到黏膜组织的主要受体. Berlin et al[72]发现, 表达α4 β7及CD44high的记忆T细胞可以非常有效地归巢到Peyer结. α4β7的主要配体为内皮细胞上的黏膜地址素细胞黏附分子1(mucosal address in cell adhension molecule 1, MAdCAM-1), 属于免疫球蛋白超家族, 为50 KD的跨膜糖蛋白. MAdCAM-1主要在肠Peyer结、肠系膜淋巴结的HEV及肠固有层小静脉表达, 因此α4 β7主要介导淋巴细胞归巢到这些黏膜淋巴组织[70,72]. (2)整合素αE β7及其配体E-钙依赖黏附素(E-Cadherin) αE β7主要在IEL及LPL中高水平表达, 其中B细胞表达水平高于T细胞. 关于αE β7的功能, 在体外实证表明抗αEβ7单抗可阻断T细胞黏附于上皮细胞, 因此推测他主要介导上皮内淋巴细胞(IEL)黏附及定居于肠上皮.αE β7的配体是上皮细胞表达的E-钙依赖黏附, 钙依赖黏附素是另一类黏附分子, 有5个细胞外区, 尾部及连环蛋白(catenin)及肌动蛋白相连. 在固体组织形成过程中, 钙依赖黏附素可介导钙离子依赖的同型细胞黏附, 具有严格的组织特异性[72]. E-钙依赖黏附素主要在上皮细胞基底面表达, 可识别IEL上的αE β7, 介导IEL与上皮细胞黏附, 有助于淋巴细胞归巢到黏膜部位[72-74] .
总之, 肠道是人体最大且功能复杂的免疫器官, 由众多功能复杂的细胞和生物分子成分构成了多层次的防御体系和调控体系[75]. 一般生理状况下, 肠黏膜免疫系统处于巨量抗原的包围中, 既要维持肠黏膜重要的生理功能, 即对外来食物抗原产生免疫耐受, 保障机体对营养物质的消化和吸收; 又要发挥黏膜防御功能, 对肠道内条件致病菌、外来菌进行免疫监视和清除[75]. 肠黏膜免疫系统如何调节和平衡这两种免疫反应尚待进一步研究, 但临床和实验研究观测到, 再许多病理状况下, 相关生物分子的表达上调和下调, 后者的作用可被放大, 造成和加剧肠黏膜屏障损害. 肠黏膜屏障损害可引起肠黏膜通透性增加, 肠道内细菌移位, 引发肠源性感染, 加重原发疾病[76,77]. 现在普遍认为, 肠道不仅是MODS的靶器官, 更是MODS的启动者[77-80]. 因而, 加强肠黏膜屏障的深入研究, 阐明肠黏膜屏障的分子和免疫机制, 可为创伤、烧伤、胰腺炎、休克及MODS、SIRS的防治提供新的手段, 可为治疗炎症性肠病和抗肿瘤药物的开发提供新的靶点, 为高效安全的黏膜疫苗研制提供新思路[78-81].
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