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1、黏膜免疫黏膜免疫Mucosal ImmuneMucosal Immune黏膜免疫Mucosal Immune黏膜免疫系统（黏膜免疫系统（mucosal immune systemmucosal immune system）：）： 直接接触病原体的解剖部位并能够分泌粘液的直接接触病原体的解剖部位并能够分泌粘液的上皮细胞所覆盖，构成黏膜免疫系统。上皮细胞所覆盖，构成黏膜免疫系统。 广泛分布于广泛分布于呼吸道、胃肠道、泌尿生殖道黏膜呼吸道、胃肠道、泌尿生殖道黏膜下及一些外分泌腺体（唾液腺、泪腺、乳腺）处的下及一些外分泌腺体（唾液腺、泪腺、乳腺）处的淋巴组织。淋巴组织。 执行局部特异性免疫功能的主要场
2、所。执行局部特异性免疫功能的主要场所。黏膜免疫系统（mucosal immune system）：The mucosal immune system. The tissues of the mucosal immune system are the lymphoid organs associated with the intestine, respiratory tract, and urogenital tract, as well as the oral cavity and pharynx and the glands associated with these tissues, su
3、ch as the salivary glands and lachrymal glands. The lactating breast is also part of the mucosal immune system.黏膜免疫系统亦称黏膜相关淋巴组织（黏膜免疫系统亦称黏膜相关淋巴组织（mucosa-mucosa-associated lymphoid tissue, MALTassociated lymphoid tissue, MALT）。）。The mucosal immune system. The黏膜免疫系统与免疫应答黏膜免疫系统与免疫应答黏膜免疫系统中的固有免疫应答黏膜免疫系统中
4、的固有免疫应答黏膜免疫系统中的适应性免疫应答黏膜免疫系统中的适应性免疫应答黏膜免疫中的免疫耐受和免疫调节黏膜免疫中的免疫耐受和免疫调节黏膜免疫与疾病黏膜免疫与疾病主要内容黏膜免疫系统与免疫应答主要内容小肠黏膜免疫系统的各种细胞成分和器官化的淋巴组织小肠黏膜免疫系统的各种细胞成分和器官化的淋巴组织 肠腔固有层肠系膜粘膜上皮DCM细胞小肠上皮细胞上皮内淋巴细胞(IEL)绒毛共生菌粘液浆细胞隐窝杯状细胞IgA巨噬细胞肠腺嗜酸细胞B细胞T细胞抗菌肽DC输出淋巴管肥大细胞分立的 淋巴滤泡 派氏集合淋巴结滤泡T细胞肠系膜淋巴结Cross-sectional diagram of the mucous me
5、mbrane lining the intestine showing a nodule of lymphoid follicles that constitutes a Peyers patch in the submucosa. The intestinal lamina propria contains loose clusters of lymphoid cells and diffuse follicles.黏膜免疫系统与免疫应答黏膜免疫系统与免疫应答（结构和应答特点）（结构和应答特点）小肠黏膜免疫系统的各种细胞成分和器官化的淋巴组织 肠固肠黏膜免疫系统的特点黏膜免疫系统的特点 解剖
6、特征解剖特征 粘膜上皮和淋巴组织间因相互作用而联系紧密。粘膜上皮和淋巴组织间因相互作用而联系紧密。 由散在的淋巴组织和器官化的结构（如派氏集合淋巴由散在的淋巴组织和器官化的结构（如派氏集合淋巴结、结、 分立的淋巴滤泡和扁桃体）共同组成。分立的淋巴滤泡和扁桃体）共同组成。 启用抗原摄取机制，如出现派氏集合淋巴结和启用抗原摄取机制，如出现派氏集合淋巴结和M M细胞。细胞。 效应机制效应机制 在无感染发生的情况下拥有大量活化的在无感染发生的情况下拥有大量活化的T T细胞和记忆细胞。细胞和记忆细胞。 存在非特异性激活的存在非特异性激活的“天然天然”效应性效应性T T细胞和记忆性细胞和记忆性T T细胞。
7、细胞。 大量启用分泌型大量启用分泌型IgAIgA抗体。抗体。 涉及各种共生微生物菌丛。涉及各种共生微生物菌丛。 免疫调节免疫调节 可主动下调针对食物和其它共生性抗原的强势免疫应答。可主动下调针对食物和其它共生性抗原的强势免疫应答。 可激活抑制性巨噬细胞及诱导耐受的树突状细胞可激活抑制性巨噬细胞及诱导耐受的树突状细胞。* *黏膜覆盖面大；肠腔中充满各种微生物；防御病原体的入侵，维持对共生菌的耐受。黏膜覆盖面大；肠腔中充满各种微生物；防御病原体的入侵，维持对共生菌的耐受。黏膜免疫系统的特点*黏膜覆盖面大；肠腔中充满各种微生物；防一、组成肠相关淋巴组织的固有免疫细胞一、组成肠相关淋巴组织的固有免疫细
8、胞二、肠道粘膜相关的固有免疫应答二、肠道粘膜相关的固有免疫应答三、上皮内淋巴细胞杀伤入侵病毒和修复损伤组织三、上皮内淋巴细胞杀伤入侵病毒和修复损伤组织黏膜免疫中的固有免疫应答黏膜免疫中的固有免疫应答一、组成肠相关淋巴组织的固有免疫细胞黏膜免疫中的固有免疫应答Mucosal lymphoid tissue in Mucosal lymphoid tissue in the human intestine.the human intestine.Mucosal lymphoid tissue in the黏膜免疫研究生课件The lamina propria and epithelium of t
9、he intestinal The lamina propria and epithelium of the intestinal mucosa are discrete lymphoid compartments. mucosa are discrete lymphoid compartments. 组成肠相关淋巴组织的固有免疫细胞组成肠相关淋巴组织的固有免疫细胞The lamina propria and epithel lntraepithelial lntraepithelial lymphocytes express CCR9 lymphocytes express CCR9 and
10、 the integrin and the integrin E:E: 7 7, , which binds to E-cadherin which binds to E-cadherin on epithelial cells. on epithelial cells. They are mostly CD8 T They are mostly CD8 T cells, some of which cells, some of which express the conventional express the conventional : : form of CD8 and others
11、form of CD8 and others the CD8 the CD8 : : homodimer. homodimer. CD8 T cells predominate CD8 T cells predominate in the epitheliumin the epithelium, whereas , whereas CD8 T cells predominate in CD8 T cells predominate in the lamina propria. the lamina propria. lntraepithelial lymphocytes The lamina
12、propria The lamina propria contains contains lgA-producing plasma cellslgA-producing plasma cells, , lymphocyteslymphocytes, , effector T cellseffector T cells, , dendritic cellsdendritic cells, , macrophagesmacrophages, , and and mast cellsmast cells. . T cells in the lamina T cells in the lamina p
13、ropria of the small intestine propria of the small intestine express the integrin express the integrin 4:4: 7 7 and and the chemokine receptor the chemokine receptor CCR9CCR9, , which attracts them into the which attracts them into the tissue from the bloodstream. tissue from the bloodstream. The la
14、mina propria contains 黏膜淋巴细胞与上皮细胞相互作用：黏膜淋巴细胞与上皮细胞相互作用：黏膜淋巴细胞：黏膜淋巴细胞：位于黏膜上皮细胞间和上皮细胞基底层一位于黏膜上皮细胞间和上皮细胞基底层一侧的侧的T T 淋巴细胞，包括固有类淋巴细胞，包括固有类T T 淋巴细胞和淋巴细胞和NKNK细胞。细胞。 分布部位特殊、功能发挥受控于上皮细胞表面各类分布部位特殊、功能发挥受控于上皮细胞表面各类MHCMHC分分子与其受体分子间的相互作用。子与其受体分子间的相互作用。 除了经典的除了经典的MHC I MHC I 类和类和II II 类分子，上皮细胞还表达范围类分子，上皮细胞还表达范围广泛的各
15、种非经典广泛的各种非经典MHCMHC分子，包括分子，包括TLTL、HLA-EHLA-E、MIC-A/-BMIC-A/-B、MR1MR1和进化上与之高度同源的和进化上与之高度同源的CD1d CD1d 分子，激活多种黏膜淋分子，激活多种黏膜淋巴细胞。巴细胞。黏膜淋巴细胞与上皮细胞相互作用： TL MHC II MHC I TL MIC- MIC - HLA-E CD1d/ MR1 A/-B A/-B -GalCel CD8 CD4 CD8 CD8 NKG2D CD94/ TCR TCR TCR TCR TCR NKG2ATCR TCR TCR TCR NK NKT MAITCD8 CD4 T CD
16、8 T CD8 TGF- IFN-,IL-4 Pf,Gz,FasL IL-6, KGF TNF-, Pf, Gz, IFN-,IL-4 ? TNF- IFN- FasL 调节 Th1/Th2 毒性 炎症, 修复， 炎症 毒性 Th1/Th2 ？ 功能 毒性 抗炎 功能？BCRB受体上皮细胞配体粘膜淋巴细胞分泌因子功能 TL: 非经典MHC I 类分子 胸腺白血病抗原；MIC: MHC I 类链相关分子；CD1d/a-GalCel: 分化抗原CD1d分子提呈的 半乳糖神经 酰胺； MR1: MHC相关I 类分子；MAIT: MR1限制性粘膜相关恒定链T 细胞; Pf: 穿孔素；Gz: 颗粒酶。K
17、GF: 角朊细胞生长因子。 TL 物理免疫屏障功能物理免疫屏障功能 上皮细胞分泌的粘液防止微生物接近上皮细胞上皮细胞分泌的粘液防止微生物接近上皮细胞 上皮细胞产生的防御素具有抗菌活性上皮细胞产生的防御素具有抗菌活性 上皮细胞表达的上皮细胞表达的TLRTLR和和NLRNLR显示双重免疫功能显示双重免疫功能 固有层中的固有层中的DCDC和巨噬细胞具有炎症反应抑制作用和巨噬细胞具有炎症反应抑制作用和免疫调节作用和免疫调节作用肠道黏膜相关的固有免疫应答肠道黏膜相关的固有免疫应答 物理免疫屏障功能肠道黏膜相关的固有免疫应答免疫屏障功能免疫屏障功能免疫屏障功能肠腔固有层肠系膜粘膜上皮DCM细胞小肠上皮细胞
18、上皮内淋巴细胞(IEL)绒毛共生菌粘液浆细胞隐窝杯状细胞IgA巨噬细胞肠腺嗜酸细胞B细胞T细胞抗菌肽DC输出淋巴管肥大细胞分立的 淋巴滤泡 派氏集合淋巴结滤泡T细胞肠系膜淋巴结分泌的粘液防止微生物接近分泌的粘液防止微生物接近肠固肠粘DCM细胞小肠上皮细胞上皮内淋绒毛共生菌粘液浆细胞隐肠腔固有层肠系膜粘膜上皮DCM细胞小肠上皮细胞上皮内淋巴细胞(IEL)绒毛 共生菌粘液浆细胞隐窝杯状细胞IgA巨噬细胞肠腺嗜酸细胞B细胞T细胞抗菌肽DC输出淋巴管肥大细胞分立的 淋巴滤泡 派氏集合淋巴结滤泡T细胞肠系膜淋巴结产生的防御素具有抗菌活性产生的防御素具有抗菌活性 含有大量嗜含有大量嗜酸颗粒酸颗粒 分颗粒含
19、有防分颗粒含有防御素、溶菌酶御素、溶菌酶 对肠道微生物对肠道微生物有杀灭功能有杀灭功能肠固肠粘DCM细胞小肠上皮细胞上皮内淋绒毛共生菌粘液浆细胞隐Epithelial cells have a crucial role in innate defense against pathogens. TLRs are present in intracellular vesicles or on the basolateral or apical surfaces of epithelial cells, where they recognize different components of inv
20、ading bacteria. NOD1 and NOD2 pattern-recognition receptors are found in the cytoplasm and recognize cellwall peptides from bacteria. Both TLRs and NODs activate the NFB pathway leading to the generation of pro-inflammatory responses by epithelial cells. These include the production of chemokines su
21、ch as CXCL8, CXCL 1 (GROa), CCL 1, and CCL2, which attract neutrophils and macrophages, and CCL20 and -defensin, which attract immature dendritic cells in addition to possessing antimicrobial properties. The cytokines IL-1 and IL-6 are also produced and activate macrophages and other components of t
22、he acute inflammatory response表达的表达的TLRTLR和和NLRNLR显示双重免疫功能显示双重免疫功能Epithelial cells have a cruciaCommensal bacteria can prevent inflammatory responses in the intestine. The pro-Commensal bacteria can prevent inflammatory responses in the intestine. The pro-inflammatory transcription factor NFinflamma
23、tory transcription factor NF B pathway is activated in epithelial cells via B pathway is activated in epithelial cells via the ligation of TLRs by pathogens (first two panels). Commensal bacteria have been the ligation of TLRs by pathogens (first two panels). Commensal bacteria have been found to in
24、hibit this pathway and thus prevent inflammation. One way is by activation found to inhibit this pathway and thus prevent inflammation. One way is by activation of the nuclear receptor PPARof the nuclear receptor PPAR , leading to the export of NF, leading to the export of NF B from the nucleus B fr
25、om the nucleus (third panel). Another is by blocking the degradation of the inhibitor I(third panel). Another is by blocking the degradation of the inhibitor I B and thus B and thus retaining NFretaining NF B in the cytoplasm (fourth panel).B in the cytoplasm (fourth panel).Commensal bacteria can pr
26、event小肠上皮细胞及固有层中小肠上皮细胞及固有层中DCDC上上PRRPRR的的表达和功能可降低针对肠腔共生微生表达和功能可降低针对肠腔共生微生物的炎症反应。物的炎症反应。能识别细菌鞭毛的能识别细菌鞭毛的PRR(NLR:PRR(NLR:表达于胞表达于胞质中；质中；TLRTLR：表达于小肠上皮细胞基底：表达于小肠上皮细胞基底膜一侧膜一侧) )，对共生微生物的炎症反应只，对共生微生物的炎症反应只有当微生物进入或穿越上皮细胞后才有当微生物进入或穿越上皮细胞后才能产生。能产生。识别识别LPSLPS的的TLR4TLR4在小肠上皮细胞及固在小肠上皮细胞及固有层有层DCDC上的表达皆下调。上的表达皆下调。
27、能下调能下调TLRTLR信号转导的胞内调节蛋白信号转导的胞内调节蛋白（在固有层的（在固有层的DCDC中）可优势表达。中）可优势表达。TLRTLR4 DCNLR 细菌PAMP小肠上皮层固有层DCDC具有炎症反应抑制作用具有炎症反应抑制作用小肠上皮细胞及固有层中DC上PRR的表达和功能可降低针对肠腔IELIEL参与构筑黏膜防御屏障参与构筑黏膜防御屏障IELIEL对病原体的杀伤功能对病原体的杀伤功能IELIEL的维稳和保护功能的维稳和保护功能的功能的功能IELIEL杀伤入侵病毒和修复损伤组织杀伤入侵病毒和修复损伤组织IEL参与构筑黏膜防御屏障IEL杀伤入侵病毒和修复损伤组织黏膜免疫研究生课件病毒 食
28、物抗原 （谷朊肽）TCR MHC I类分子 MIC-A/-B NKG2D LT CD8 CD8 Fas FasL Gz (颗粒酶) Pf (穿孔素) a a型和型和b b型粘膜上皮细胞间淋巴细胞（型粘膜上皮细胞间淋巴细胞（IELIEL）的主要功能）的主要功能A. a型IEL。左：病毒感染粘膜上皮细胞；中：受感染细胞通过MHC I类分子向CD8 IEL展示病毒抗原肽，激活IEL；右：激活的IEL行使典型的CTL功能，通过分泌Pf和Gz，以及通过Fas/FasL途径杀伤病毒感染的上皮细胞；B. b型IEL。左：发生应急改变（感染、损伤、接触毒性肽）的上皮细胞表达非经典MHC分子MIC-A、MIC-
29、B和胸腺白血病抗原 (LT) ；中：IEL表达NKG2D和CD8分子，分别与MIC-A/-B以及LT结合，IEL被激活；右：激活的IEL杀伤受到应急损伤的上皮细胞，机制同上 。上皮细胞CD8 IELABa型IELb型IEL病毒 a型和b型粘膜上皮细胞间淋巴细胞（IEL）的主要功能上一、黏膜免疫系统器官化的淋巴组织一、黏膜免疫系统器官化的淋巴组织二、参与适应性黏膜免疫应答的免疫细胞二、参与适应性黏膜免疫应答的免疫细胞三、黏膜免疫中的抗体应答三、黏膜免疫中的抗体应答四、黏膜免疫中四、黏膜免疫中T T细胞介导的应答细胞介导的应答黏膜免疫中的适应性免疫应答黏膜免疫中的适应性免疫应答一、黏膜免疫系统器官
30、化的淋巴组织黏膜免疫中的适应性免疫应答黏膜免疫系统器官化的淋巴组织黏膜免疫系统器官化的淋巴组织派氏集合淋巴结与派氏集合淋巴结与M M细胞细胞散在性淋巴滤泡散在性淋巴滤泡肠系膜淋巴结肠系膜淋巴结黏膜免疫系统器官化的淋巴组织派氏集合淋巴结与M细胞派氏集合淋巴结（派氏集合淋巴结（Peyers Peyers 小结）小结）派氏集合淋巴结（Peyers 小结）肠系膜淋巴结肠系膜淋巴结（肿大）（肿大）肠系膜淋巴结肠系膜淋巴结肠系膜淋巴结（肿大）肠系膜淋巴结黏膜免疫系统含有大量效应淋巴细胞黏膜免疫系统含有大量效应淋巴细胞黏膜免疫系统中独特的树突状细胞黏膜免疫系统中独特的树突状细胞黏膜固有层中黏膜固有层中T T
31、细胞的致敏和归巢细胞的致敏和归巢参与适应性黏膜免疫应答的免疫细胞参与适应性黏膜免疫应答的免疫细胞黏膜免疫系统含有大量效应淋巴细胞参与适应性黏膜免疫应答的免疫肠道中肠道中T T细胞依赖的细胞依赖的IgA IgA 抗体类别转换机制抗体类别转换机制派氏集合淋巴结圆丘状隆起部位的DC 获取由M 细胞提交的肠腔抗原并迁移至滤泡区近旁后，将抗原提呈给初始CD4 T 细胞并使之激活和分化成Th。Th与借助其BCR识别了抗原的B细胞发生相互作用，通过T-B间CD40L-CD40的结合，B细胞分化成产生IgA的浆细胞。该过程受DC产生的一氧化氮及TGF-的促进。由此产生的浆细胞经由血循环再归槽至固有层，所分泌的
32、高亲和力IgA抗体，经过上皮细胞胞吞转换进入肠腔，与当初致敏的肠腔抗原结合。 CD40L CD40DC初始T激活的ThNOB浆母细胞TGF-经过血流派氏集合淋巴结淋巴滤泡固有层肠腔基底膜上皮细胞肠腔抗原IgAIgA分泌IgA浆细胞DC B7 CD28M 细胞肠道中T细胞依赖的IgA 抗体类别转换机制 CD40L CDCapture of antigens from the intestinal lumen by mononuclear cells in the lamina propriaCapture of antigens from the intestinal lumen by mono
33、nuclear cells in the lamina propria. First panel: soluble antigens such as food proteins might be transported directly across or between enterocytes, or there might be M cells in the surface epithelium outside Peyers patches. Second panel: enterocytes can capture and internalize antigen:antibody com
34、plexes by means of the FeRn on their surface and transport them across the epithelium by transcytosis. At the basal face of the epithelium, lamina propria dendritic cells expressing FeRn and other Fe receptors pick up and internalize the complexes. Third panel: an enterocyte infected with an intrace
35、llular pathogen undergoes apoptosis and its remains are phagocytosed by the dendritic cell. Fourth panel: mononuclear cells have been seen extending processes between the cells of the epithelium without disturbing its integrity. The cell process could pick up and internalize antigen from the gut lum
36、en and then retract. The micrograph shows mononuclear cells, which may be dendritic cells or macrophages, (stained green with a fluorescent tag on the CD11 c molecule) in the lamina propria of a villus of mouse small intestine. The epithelium is not stained and appears black, but its luminal (outer)
37、 surface is shown by the white line. A cell process has squeezed between two epithelial cells and its tip is present in the lumen of the intestine. Magnification x200. Micrograph from Niess, J.H., eta/.: Science 2005, 307:254-258.Capture of antigens from the intestinal lumenCapture of antigens from
38、the intestinal lumenCapture of antigens from the i参见图参见图9-9-7 7黏膜免疫系统中独特的树突状细胞黏膜免疫系统中独特的树突状细胞参见图9-7黏膜免疫系统中独特的树突状细胞CCR9CCL2547DCCCR947 TSLPRC T肠系膜淋巴结微静脉MadCAM-1E-钙粘素E7固有层肠系膜M细胞固有层上皮细胞TT上皮细胞小肠淋巴细胞的激活和归巢小肠淋巴细胞的激活和归巢肠系膜淋巴结和派氏集合肠系膜淋巴结和派氏集合淋巴结中的淋巴结中的DCDC，在，在胸腺基胸腺基质淋巴生成素质淋巴生成素 (TSLP) (TSLP) 和和其它因子的作用下表达其它因
39、子的作用下表达视视黄醇脱氢酶黄醇脱氢酶 (RALDH)(RALDH)，后，后者将维生素者将维生素A A转化转化成视黄酸成视黄酸 (RC)(RC)。RCRC诱导，诱导，已被抗原活化的效应已被抗原活化的效应T T细胞细胞（及（及B B细胞）表达趋化因子细胞）表达趋化因子受体受体CCR9CCR9和整合素和整合素 4 4 7 7，并进入血循环。并进入血循环。CCR9CCL2547DCCCR947 TSLCCR9CCL2547DCCCR947 TSLPRC T肠系膜淋巴结微静脉MadCAM-1E-钙粘素E7固有层肠系膜M细胞固有层上皮细胞TT上皮细胞小肠淋巴细胞的激活和归巢小肠淋巴细胞的激活和归巢分布在
40、黏膜固有层中的后毛细血管分布在黏膜固有层中的后毛细血管微静脉的内皮细胞表达微静脉的内皮细胞表达MadCAM-1 MadCAM-1 ( ( 4 4 7 7 配体配体) )，使，使CCR9CCR9+ + 4 4 7 7+ +T T细胞细胞停留于该处并穿越微静脉到达固有停留于该处并穿越微静脉到达固有层层, , 并变更其表型为并变更其表型为CCR9CCR9+ + E E 7 7+ +T T。固有层上皮细胞表达固有层上皮细胞表达CCL25 (CCR9CCL25 (CCR9配配体体) )和和E-E-钙粘素（钙粘素（ E E 7 7配体），使配体），使效应性淋巴细胞选择性地归巢和停效应性淋巴细胞选择性地归巢
41、和停于黏膜固有层。于黏膜固有层。 CCR9CCL2547DCCCR947 TSL黏膜免疫研究生课件Molecular control of intestine-specific homing of lymphocytes. Left panel: T and B lymphocytes primed by antigen in the Peyers patches or mesenteric lymph nodes arrive as effector lymphocytes in the bloodstream supplying the intestinal wall). The lymp
42、hocytes express the integrin 4:7, which binds specifically to MAdCAM-1 expressed selectively on the endothelium of blood vessels in mucosal tissues. This provides the adhesion signal needed for the emigration of cells into the lamina propria. Right panel: if primed in the small intestine, the effect
43、or lymphocytes also express the chemokine receptor CCR9, which allows them to respond to CCL25 (green circles) produced by epithelial cells of the small intestine; this enhances selective recruitment. Effector lymphocytes that have been primed in the large intestine do not express CCR9 but do expres
44、s CCR10. This may respond to CCL28 (blue circles) produced by colon epithelial cells to fulfill a similar function. Lymphocytes that will enter the epithelial layer stop expressing the 4:7 integrin and instead express the E:7 integrin. The receptor for this is E-cadherin on the epithelial cells. The
45、se interactions may help keep lymphocytes in the epithelium once they have entered it.Molecular control of intestine分泌型分泌型IgAIgA的特征的特征影响分泌型影响分泌型IgAIgA抗体类别转换的因素抗体类别转换的因素分泌型分泌型IgAIgA的转运的转运分泌型分泌型IgAIgA的意义的意义分泌型分泌型IgMIgM可以代偿有缺陷的可以代偿有缺陷的IgAIgA 黏膜免疫中的抗体应答黏膜免疫中的抗体应答分泌型IgA的特征黏膜免疫中的抗体应答参见图9-6参见图9-6黏膜免疫研究生课件分
46、泌型分泌型IgAIgA的特征的特征影响分泌型影响分泌型IgAIgA抗体类别转换的因素抗体类别转换的因素分泌型分泌型IgAIgA的转运的转运分泌型分泌型IgAIgA的意义的意义分泌型分泌型IgMIgM可以代偿有缺陷的可以代偿有缺陷的IgAIgA 黏膜免疫中的抗体应答黏膜免疫中的抗体应答分泌型IgA的特征黏膜免疫中的抗体应答黏膜黏膜DCDC与炎症反应与炎症反应Th17Th17与黏膜免疫屏障与黏膜免疫屏障肠道蠕虫感染与肠道蠕虫感染与Th2Th2型免疫应答型免疫应答黏膜免疫中黏膜免疫中T T细胞介导的应答细胞介导的应答黏膜DC与炎症反应黏膜免疫中T细胞介导的应答黏膜免疫研究生课件对肠道蠕虫感染的保护性
47、应答和病理性应答对肠道蠕虫感染的保护性应答和病理性应答大部分肠道蠕虫即可启动CD4 T 细胞介导的保护性应答也可诱导病理性应答。其中Th2相关应答有利于清除寄生虫，属保护性应答；当DC接触抗原时产生IL-12，则产生Th1型应答。通常两种应答并存，若Th2介导的保护性应答不能处于优势地位，Th1型应答将使感染持续，并造成小肠的慢性病理性损伤。置换被寄生的上皮细胞，用粘液阻止寄生虫粘附，促其脱落。肥大细胞产生TNF, 组胺等介质，募集炎症细胞, 重塑粘膜。产生能固定补体的抗体IgG2a。活化的巨噬细胞以其产物引起组织损伤，诱导组织重塑。IgE激活肥大细胞，介导ADCC。嗜酸粒细胞通过主要碱性蛋白
48、 (MBP) 杀伤寄生虫。激活巨噬细胞招募和激活嗜酸粒细胞驱动 B 淋巴细胞产生 IgE招募肥大细胞，抗蠕虫驱动B淋巴细胞产生IgG2aIL-13IL-5IL-4IL-9IL-3IFN-诱导上皮细胞修复,分泌粘液. .Th-2Th-1DC 初始CD4 T保护效应宿主损伤对肠道蠕虫感染的保护性应答和病理性应答置换被寄生的上皮细肥大一、黏膜一、黏膜DCDC与免疫耐受与免疫耐受二、正常肠道的大量共生菌不引发有害的免疫反应二、正常肠道的大量共生菌不引发有害的免疫反应三、黏膜耐受的诱导三、黏膜耐受的诱导黏膜免疫中的免疫耐受和免疫调节黏膜免疫中的免疫耐受和免疫调节一、黏膜DC与免疫耐受黏膜免疫中的免疫耐受
49、和免疫调节黏膜黏膜DCDC-CD103-CD103+ +DCDCiTregiTreg黏膜DC-CD103+DCiTreg正常肠道的大量共生菌不引发有害的免疫反应正常肠道的大量共生菌不引发有害的免疫反应肠道共生菌对维持人体的健康发挥着重要的作用。肠道共生菌对维持人体的健康发挥着重要的作用。能够促进食物如纤维素的代谢；能够促进食物如纤维素的代谢；能分解毒素；能产生重要的辅助因子如维生素能分解毒素；能产生重要的辅助因子如维生素K1K1和短链和短链脂肪酸。脂肪酸。通过竞争空间和营养成份可以抑制病原体在肠道的繁殖和通过竞争空间和营养成份可以抑制病原体在肠道的繁殖和入侵共生菌能够直接作用于黏膜上皮细胞，对
50、维持黏膜的入侵共生菌能够直接作用于黏膜上皮细胞，对维持黏膜的屏障功能有重要作用。屏障功能有重要作用。共生菌和其产物对于免疫系统的发展和功能有重要作用。共生菌和其产物对于免疫系统的发展和功能有重要作用。 正常肠道的大量共生菌不引发有害的免疫反应肠道共生菌对维持人体Local responses to commensalsLocal responses to commensals. Several local processes ensure peaceful coexistence between the microbiota and the host, allowing the commens
51、al organisms to be recognized by the immune system without inducing inflammation or an immune response that would eliminate them. Commensal bacteria in the lumen gain access to the immune system via M cells in Peyers patches and isolated follicles (left panel). Uptake and presentation of these nonin
52、vasive organisms by resting dendritic cells generates lgA-switched B cells that localize in the lamina propria as lgA-producing plasma cells (right panel). The secretory lgA that is produced limits the access of commensals to the epithelium and helps prevent their penetration. This is assisted furth
53、er by the presence of thick layers of mucus, which also contain mucin glycoproteins that have antibacterial properties. In addition, stimulation of pattern-recognition receptors on epithelial cells and local leukocytes induces the production of antimicrobial peptides such as defensins.Local response
54、s to commensals.A. A. 健康小鼠饲以卵清蛋白，健康小鼠饲以卵清蛋白，7 7天后，用同一抗原加佐剂作皮下免疫，天后，用同一抗原加佐剂作皮下免疫，1414天后测定小鼠针对卵清蛋白的血清抗体和天后测定小鼠针对卵清蛋白的血清抗体和T T细胞应答水平。细胞应答水平。B. B. 同一品系的对照小鼠，喂饲无关蛋白，而同一品系的对照小鼠，喂饲无关蛋白，而7 7天后注射的卵清蛋白属首次免疫，诱导出的典型保护性免疫针对卵清蛋白。天后注射的卵清蛋白属首次免疫，诱导出的典型保护性免疫针对卵清蛋白。C. BC. B组小鼠以无关蛋白喂饲后若注射同一无关蛋白，同样可诱导针对该无关蛋白的粘膜耐受。组小鼠以
55、无关蛋白喂饲后若注射同一无关蛋白，同样可诱导针对该无关蛋白的粘膜耐受。特异应答 7d7d14d14dAB特异应答 黏膜耐受保护性 免疫 7d14dC特异应答 黏膜 耐受黏膜耐受的诱导黏膜耐受的诱导特异 7d7d14d14dAB特异黏膜保护性 一、病原体感染与宿主免疫反应之间的消长一、病原体感染与宿主免疫反应之间的消长 决定了感染的结局决定了感染的结局二、针对共生菌的免疫应答与肠道疾病二、针对共生菌的免疫应答与肠道疾病三、肠道中与免疫应答相关的一些临床疾病三、肠道中与免疫应答相关的一些临床疾病黏膜免疫与疾病黏膜免疫与疾病一、病原体感染与宿主免疫反应之间的消长 决定了感染的结Mucosal Muc
56、osal infections infections are are one one of of the the biggest biggest health health problems problems worldwide. worldwide. Most of the pathogens that cause the deaths of large numbers of people are those of mucosal surfaces or enter the body through these routes. Respiratory infections are cause
57、d by numerous bacteria (such as Streptococcus pneumoniae and Haemophilus influenzae, which cause pneumonia, and Bordetella pertussis, the cause of whooping cough) and viruses (such as influenza and respiratory syncytial virus). Diarrheal diseases are caused by both bacteria (such as the cholera bact
58、erium Cholera vibrio) and viruses (such as rotaviruses). The human immunodeficiency virus (HIV) that causes AIDS enters through the mucosa of the urogenital tract or is secreted into breast milk and is passed from mother to child in this way. The bacterium Mycobacterium tuberculosis, which causes tu
59、berculosis, also enters through the respiratory tract. Measles manifests itself as a systemic disease, but it originally enters via the oral/respiratory route. Hepatitis B is also a sexually transmitted virus. Finally, parasitic worms inhabiting the intestine cause chronic debilitating disease and p
60、remature death. Most of these deaths, especially those from acute respiratory and diarrheal diseases, occur in children under 5 years old in the developing world, and there are still no effective vaccines against many of these pathogens. Numbers shown are the most recent estimated figures available
61、(The Global Burden of Disease: 2004 Update. World Health Organization, 2008). *Does not include deaths from liver cancer or cirrhosis resulting from chronic infection.Mucosal infections are one of Infection by Infection by Clostridium difficileClostridium difficile. Treatment with antibiotics causes
62、 massive death of the commensal bacteria that normally colonize thecolon. This allows pathogenic bacteria to proliferate and to occupy an ecological niche that is normally occupied by harmless commensal bacteria. Clostridium difficile is an example of a pathogen producing toxins that can cause sever
63、e bloody diarrhea in patients treated with antibiotics.病原体感染与宿主免疫反应之间的消长病原体感染与宿主免疫反应之间的消长决定了感染的结局决定了感染的结局Infection by Clostridium diffiShigella flexneri, a cause of bacterial dysentery, infects intestinal epithelial cells, triggering activation of the NFB pathway. Shigella flexneri binds to M cells
64、and is translocated beneath the gut epithelium (first panel). The bacteria infect intestinal epithelial cells from their basal surface and are released into the cytoplasm (second panel). Muramyl tripeptides containing diaminopimelic acid in the cell walls of the shigellae bind to and oligomerize the
65、 protein NOD1. Oligomerized NOD1 binds the serine/ threonine kinase RIPK2, which triggers activation of the NFB pathway , leading to the transcription of genes for chemokines and cytokines (third panel). Activated epithelial cells release the chemokine CXCL8, which acts as a neutrophil chemoattracta
66、nt (fourth panel). IB, inhibitor of NFB; IK, IB kinase.Shigella flexneri, a cause of 针对共生菌的免疫应答与肠道疾病针对共生菌的免疫应答与肠道疾病针对共生菌的免疫应答与肠道疾病Mucosal Mucosal dendritic dendritic cells cells regulate regulate the the induction induction of of tolerance tolerance and and immunity immunity in in the the intestine.
67、 intestine. Under normal conditions (left panels), dendritic cells are present in the mucosa underlying the epithelium and can acquire antigens from foods or commensal organisms. They take these antigens to the draining mesenteric lymph node, where they present them to naive CD4 T cells. There is, h
68、owever, constitutive production by epithelial cells and mesenchymal cells of molecules such as TGF-, thymic stromal lymphopoietin (TSLP), and prostaglandin E2 (PGE2), which maintain the local dendritic cells in a quiescent state with low levels of co-stimulatory molecules, so that when they present
69、antigen to naive CD4 T cells, anti-inflammatory or regulatory T cells are generated. These recirculate back to the intestinal wall and maintain tolerance to the harmless antigens. Invasion by pathogens or a massive influx of commensal bacteria (right panels) overcomes these homeostatic mechanisms, r
70、esulting in full activation of local dendritic cells and their expression of co-stimulatory molecules and pro-inflammatory cytokines such as I L -12. Presentation of antigen to naive CD4 T cells in the mesenteric lymph node by these dendritic cells causes differentiation into cells, leading to a ful
71、l immune response.Mucosal dendritic cells regula炎症性肠炎炎症性肠炎乳糜泻乳糜泻食物过敏（食物过敏（I I型超敏反应）型超敏反应）微生物的持续感染与肿瘤微生物的持续感染与肿瘤肠道中与免疫应答相关的一些临床疾病肠道中与免疫应答相关的一些临床疾病炎症性肠炎肠道中与免疫应答相关的一些临床疾病Inflammatory bowel disease（炎症性肠（炎症性肠炎）炎） 一种特殊的慢性肠道炎症性疾病。一种特殊的慢性肠道炎症性疾病。 临床上，患者会表现为反复的腹痛、腹泻、粘液血便，临床上，患者会表现为反复的腹痛、腹泻、粘液血便，甚至出现各种全身并发症如视
72、物模糊、关节疼痛、皮疹甚至出现各种全身并发症如视物模糊、关节疼痛、皮疹等。等。 患者肠道不能正常吸收进食的碳水化合物、蛋白质、脂患者肠道不能正常吸收进食的碳水化合物、蛋白质、脂肪、维生素及多种微量元素，加上肠道炎症或服用的药肪、维生素及多种微量元素，加上肠道炎症或服用的药物可能造成食欲不佳，因此炎性肠病常伴随着不同程度物可能造成食欲不佳，因此炎性肠病常伴随着不同程度的营养不良，甚至影响小孩正常的生长发育。的营养不良，甚至影响小孩正常的生长发育。Inflammatory bowel disease（炎症性Celiac disease（乳糜泻）乳糜泻） 炎症性小肠黏膜疾病炎症性小肠黏膜疾病 小肠绒
73、毛萎缩、吸收不良，营养缺陷小肠绒毛萎缩、吸收不良，营养缺陷 患者有遗传倾向（患者有遗传倾向（HLA-DQA1*0501-HLA-DQB1*0301HLA-DQA1*0501-HLA-DQB1*0301） 患者对谷脘蛋白异常敏感患者对谷脘蛋白异常敏感 正常人小肠黏膜细胞内有多肽分解酶，可将其分解正常人小肠黏膜细胞内有多肽分解酶，可将其分解为更小分子的无毒物质，但在活动性乳糜泻病人，肠为更小分子的无毒物质，但在活动性乳糜泻病人，肠黏膜细胞酶活性不足，不能将其分解而致病。黏膜细胞酶活性不足，不能将其分解而致病。Celiac disease（乳糜泻） 炎症性小肠黏膜疾病A hypothesis to
74、explain antibody production against tissue transglutaminase (tTG) in the absence of T cells specific for tTG in celiac patients. tTG-reactive B cells endocytose gluten-tTG complexes and present gluten peptides to the gluten-specific T cells. The stimulated T cells can now provide help to these B cel
75、ls, which produce autoantibodies against tTG.The activation of cytotoxicT cells by the innate immune system in celiac disease. Gluten peptides can induce the expression of the MHC class lb molecules MIC-A and MIC-B on gut epithelial cells. lntraepithelial lymphocytes (IELs), many of which are CD8 cy
76、totoxic T cells, recognize these proteins via the receptor NKG2D, which activates the IELs to kill the MIC-bearing cells, leading to destruction of the gut epithelium.A hypothesis to explain antibo食物过敏（食物过敏（I I型超敏反应）型超敏反应）食物过敏（I型超敏反应）微生物的持续感染与肿瘤微生物的持续感染与肿瘤微生物的持续感染与肿瘤黏膜免疫系统与免疫应答黏膜免疫系统与免疫应答黏膜免疫系统中的固有免
77、疫应答黏膜免疫系统中的固有免疫应答黏膜免疫系统中的适应性免疫应答黏膜免疫系统中的适应性免疫应答黏膜免疫中的免疫耐受和免疫调节黏膜免疫中的免疫耐受和免疫调节黏膜免疫与疾病黏膜免疫与疾病主要内容黏膜免疫系统与免疫应答主要内容1.1.PAMPPAMP、DAMPDAMP和和PRRPRR概念和特点概念和特点2.2.TLRTLR、NLRNLR的特性、信号转导途径和生物学功能的特性、信号转导途径和生物学功能3.3.急性炎症性应答中的局部反应和全身急性相反应急性炎症性应答中的局部反应和全身急性相反应4.4.黏膜固有和适应性免疫应答的结构和特点黏膜固有和适应性免疫应答的结构和特点 （激活和应答以及耐受和调节）。（激活和应答以及耐受和调节）。5. 5. 炎症性肠炎（炎症性肠炎（inflammatory bowel diseaseinflammatory bowel disease） 与乳糜泻与乳糜泻(celiac disease)(celiac disease)的发病机制的发病机制 复习思考题复习思考题PAMP、DAMP和PRR概念和特点复习思考题谢 谢！谢 谢！
