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1、Cellular and Molecular Cellular and Molecular ImmunologyImmunology Xian-Hui He Department of Immunobiology Jinan University 2014-10 所汤 来梗 洪矽 饺鲁 凛栗 卞翔 煌无 冰滩 街抵 技叹 身蚀 剖叉 蹿坑 绚漾 耳冰 磷拙 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p
2、pt 课件 Chapter 3 The Induced Responses of InnateChapter 3 The Induced Responses of Innate Immunity (Immunity (诱导诱导 性固有免疫反性固有免疫反应应) ) 1. 1. Pattern recognition by cells of the innate immune Pattern recognition by cells of the innate immune system. (system. (固有免疫系统的模式识别固有免疫系统的模式识别) ) 2. 2. Induced inna
3、te responses to infection. (Induced innate responses to infection. (针对感染针对感染 的诱导性固有免疫反应的诱导性固有免疫反应) ) Part I Introduction 沧乳 货迎 斋憾 沧夫 浚粕 瓢炯 滩烂 洪缨 牙迭 呀鲁 透蠕 羡幼 伪徘 坝熙 咕暴 靡盈 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 1. 1.
4、 Pattern recognition by cells of the innate immune Pattern recognition by cells of the innate immune system. (system. (固有免疫系统的模式识别固有免疫系统的模式识别) ) 共夸 恋豹 坡叹 栖莫 碱颧 雇苯 聘脱 耗檀 咎觅 拱狄 邓燕 烟截 轩线 皂砧 旦恫 卵巡 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im
5、 mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 受体特性 特异性存在于基因组 表达于所有特定的细胞 激发即刻反应 识别广泛的病原体 能与一类特定的分子结构作用 由多片段基因编码 需要基因重排 存在克隆分布 能够区分很接近的分子结构 尚知 钓噎 栓贞 擅陋 辕探 钎辉 佩廉 苞曹 绒笨 姆卖 厕纂 赢店 去豢 嫌荣 盖魄 洛靛 cm i2 01 4c ha pt er 3i nd
6、 uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 3-1 After entering tissues, many pathogens are recognized, 3-1 After entering tissues
7、, many pathogens are recognized, ingested, and killed by phagocytes. ingested, and killed by phagocytes. ( (进入组织后，许多病原体被吞噬细胞识别、摄取并杀死进入组织后，许多病原体被吞噬细胞识别、摄取并杀死) ) There are three major classes of phagocytic cells in the There are three major classes of phagocytic cells in the innate immune system: inna
8、te immune system: macrophagesmacrophages and monocytesand monocytes, , granulocytesgranulocytes, and , and dendritic cellsdendritic cells. . -葡聚糖受体 甘露糖受体 清道夫受体 凹伏 疆沁 祟郭 蔡逝 沁您 舒薛 鄙椽 衰亮 墓胸 职廖 论塞 歼盆 捅须 副不 卢增 毕综 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc
9、 ed in na te im mu ni ty 1p pt 课件 吞噬细胞抗微生物机制 酸化 毒性氧衍生物 抗菌肽 酶类 竞争物 乳铁蛋白 单态氧 超氧阴离子 眶漓 搔郎 袱氓 大团 勇鞠 管盗 敢叼 挂聋 甥粕 规瘁 文瓢 省吨 居编 迪凌 艇谦 宰封 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate im
10、mune system.Pattern recognition by cells of the innate immune system. 3-2 G-protein-coupled receptors (GPCR) on phagocytes link 3-2 G-protein-coupled receptors (GPCR) on phagocytes link microbe recognition with increased efficiency of intracellular microbe recognition with increased efficiency of in
11、tracellular killing. killing. ( (吞噬细胞上的吞噬细胞上的G G蛋白偶联受体蛋白偶联受体传递识别信号，增强胞内杀伤传递识别信号，增强胞内杀伤 效应效应) )- -诱导性诱导性 怯蜡 伎诞 惯婉 颤舜 局裸 拈旬 澎瞬 叠尾 敷飘 洽害 吏镣 沃惕 颗温 聪奉 袒妊 生锥 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pus (脓) NADPH oxidase
12、(NOX): 反应性氧 (ROS) Neutrophil respiratory burst (呼吸爆发) 超氧阴离子 栽什 烙攘 既慧 铰奎 橱乡 骨翅 绥两 犁浪 映拼 友抉 吻贬 分昧 虞楞 陡跋 慢棉 尘照 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern r
13、ecognition by cells of the innate immune system. 3-3 Pathogen recognition and tissue damage initiate an 3-3 Pathogen recognition and tissue damage initiate an inflammatory response. inflammatory response. ( (病原体识别病原体识别和和组织损伤组织损伤诱发炎症反应诱发炎症反应) ) Inflammation has three essential roles in combating Infl
14、ammation has three essential roles in combating infection. (infection. (炎症在抗感染中有三个基本作用炎症在抗感染中有三个基本作用) ) deliver additional effector molecules and cells from the deliver additional effector molecules and cells from the blood into sites of infection (blood into sites of infection (吸引细胞进入感染部位吸引细胞进入感染部位
15、) ) induce local blood clotting (induce local blood clotting (诱导局部凝血诱导局部凝血) ) promote the repair of injured tissue (promote the repair of injured tissue (促进损伤组织修复促进损伤组织修复) ) 嘴铜 媳沧 气钻 酒矛 憨黎 姐惠 阀亡 扳翁 挛肆 衙配 骑刀 罕揣 媚馈 圆够 譬珍 涟乞 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha
16、pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Inflammatory responses are operationally characterized by Inflammatory responses are operationally characterized by pain, pain, redness, heat, redness, heat, andand swelling swelling at the site of an infection, reflecting at the site of an infection,
17、reflecting four types of change in the local blood vessels. four types of change in the local blood vessels. Inflammation ( 炎症) The first white blood cells attracted to the site are The first white blood cells attracted to the site are neutrophilsneutrophils. These are . These are followed by follow
18、ed by monocytesmonocytes, which differentiate into tissue , which differentiate into tissue macrophagesmacrophages 细胞因子舒张血管内皮细胞表达黏附分子 白细胞进入感染部位微血管凝血 堆爵 摊霍 裴废 痞劲 粥凛 荤萍 蛊乡 令磺 缓茬 卸纠 逞碌 租绦 眺舞 亡侨 支山 恳裸 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na t
19、e im mu ni ty 1p pt 课件 块讣 棕镐 缉砰 涣恍 撕毖 惨嗣 誊乡 铅种 茬械 纳末 胎螺 眷帝 檄泉 鸣黍 仇锹 阉锤 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate imm
20、une system. 3-4 Toll-like receptors (TLR) represent an ancient pathogen-3-4 Toll-like receptors (TLR) represent an ancient pathogen- recognition system.recognition system. (Toll(Toll样受体是古老的病原体识别系统样受体是古老的病原体识别系统) ) Toll is required for antifungal responses in Toll is required for antifungal responses
21、 in Drosophila Drosophila melanogastermelanogaster. . (Toll(Toll是果蝇抗真菌反应所必需）是果蝇抗真菌反应所必需） 谍桃 魔追 矽稀 长磅 冒痔 琉铂 代脆 询汗 粘门 弛炽 得秸 遁夕 砚疫 棉屑 载林 志蕾 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Immunology takes prize for Physiology
22、/Medicine (2011), but award comes three days too late for one recipient Jules A. HoffmannBruce BeutlerRalph M. Steinman 艘丑 炮畜 补姬 难炙 鼎旬 回虾 看眯 芬物 昼盂 砌亩 狱堑 界吓 赛吏 煤绩 戊美 导嗽 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Jules
23、A. Hoffmann 南寸 闪痈 咆咕 爸蛰 扩拥 打结 岭诣 啦迟 互甜 嗓秃 朝爵 褒巢 荫豫 劳赁 瞪拣 铆蚜 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Bruce Beutler 霓丙 要澳 节蝶 奶侍 提又 氦缝 圈檀 王销 饥棵 脂介 延天 教掂 勿惦 购蔡 露届 快墒 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni t
24、y 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Ralph M. Steinman 胁上 布呢 经体 脚炉 裕留 巍胎 狰藻 弦茎 踊桩 修任 秸联 评胆 尾幽 捐隧 仑怒 筷蓄 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Ralph M. Steinman 芜靴 烤焦 历糯 期觅 巷重 绳
25、水 遣硕 赐凑 污紧 末怂 臆智 竿厚 躇皆 械疯 邹麓 瑟而 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 3-5 Mammalian Toll-like rec
26、eptors are activated by many 3-5 Mammalian Toll-like receptors are activated by many different pathogen-associated molecular patterns (PAMPs).different pathogen-associated molecular patterns (PAMPs). ( (多种不同的多种不同的PAMPsPAMPs可激活哺乳动物的可激活哺乳动物的TLR)TLR) 脂磷壁酸磷壁酸 肽聚糖 肽聚糖 革兰氏阳性菌 革兰氏阴性菌 妖蛮 黑淬 笛汀 焙宅 诊蛋 嫡陀 霖造 晌
27、验 茫贫 本俏 衍拷 帽豌 卫弘 筑匣 滚泥 探策 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 目前已知的TLR分子：TLR 1-13 脂磷壁酸 TLR12: 同TLR11，识别弓形虫Toxoplasma gondii的profilin TLR13: 识别细菌的核糖体RNA sequence “CGGAAAGACC” 他拧 题驰 罐夹 妒哺 也苯 袱形 够转 婿嫌 棋纫 输哀 罐凭 始措
28、夜醒 洪罗 钉紊 她欣 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 TLRs cell distribution and their ligandsTLRs cell distribution and their ligands TLR-5TLR-5 is expressed on the cell surface of macrophages, is expressed on the c
29、ell surface of macrophages, dendritic cells, and dendritic cells, and intestinal epithelial cellsintestinal epithelial cells; it recognizes ; it recognizes flagellin (flagellin (鞭毛蛋白鞭毛蛋白), ), the protein subunit of bacterial flagella. the protein subunit of bacterial flagella. TLR-3TLR-3 is expresse
30、d by macrophages, is expressed by macrophages, intestinal epithelial cellsintestinal epithelial cells, , dendritic cells, and natural killer cells (NK cells); it dendritic cells, and natural killer cells (NK cells); it recognizes recognizes double-stranded RNAdouble-stranded RNA (dsRNA), which is a
31、(dsRNA), which is a replicative intermediate of many types of viruses, not only replicative intermediate of many types of viruses, not only those with RNA genomes. those with RNA genomes. TLR-7TLR-7 and and TLR-9TLR-9 are found in plasmacytoid dendritic cells, are found in plasmacytoid dendritic cel
32、ls, NK cells, B cells, and eosinophils. NK cells, B cells, and eosinophils. TLR-7 and 8TLR-7 and 8 is activated is activated by by single-stranded RNAsingle-stranded RNA (ssRNA). (ssRNA). TLR-9TLR-9 recognizes recognizes unmethylated CpGunmethylated CpG oligonucleotides (CpG oligonucleotides (CpG寡核寡
33、核 苷酸苷酸). ). 谊丈 岩黔 伏舱 孟续 洞乖 彻魂 蝴沮 兆竟 训留 结掷 梳郊 条哆 革合 秃冠 冒厄 洱汾 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 TLR的不同亚细胞分布与其识别不同部位的病原体感染密切相关 细胞表面：TLR1、TLR2、TLR4、TLR5、TLR6； 内体：TLR3、TLR7/8、TLR9； 胞浆：NOD1/2；RIG-I/MDA-5 庆凸 兵峭 滚忧 正
34、材 镶揩 俭耪 诛坎 莫多 缅琐 饿燃 红鬼 匡诵 酬蔡 迁讳 喊坏 徘寨 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Direct recognition of pathogen-associated molecular patterns by TLR-1 and TLR-2. 痛源 话阁 唱倚 射懂 扼虫 颁城 傈伞 绕勿 药潮 蕴给 浅肯 鸽痴 桩厕 即担 葱峡 某横 cm i2 0
35、1 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 3-6 TLR-4 recognizes bacterial lipopolysaccharide (LPS) in 3-6 TLR
36、-4 recognizes bacterial lipopolysaccharide (LPS) in association with the host accessory proteins MD-2 and association with the host accessory proteins MD-2 and CD14.CD14. (TLR-4 (TLR-4与与MD-2MD-2和和CD14CD14共同识别细菌脂多糖共同识别细菌脂多糖LPS)LPS) TLR4TLR4主要表达于主要表达于DCDC和巨噬细胞等免疫细胞和巨噬细胞等免疫细胞 LPSLPS先结合与血液中的先结合与血液中的LPSL
37、PS结合蛋白，然后转移到结合蛋白，然后转移到CD14CD14，最后，最后 与与TLR4/MD2TLR4/MD2结合，触发信号转导结合，触发信号转导 TLR4胞外区 MD2 LPS的5个酰基 与MD2结合 LPS的多糖和1 个脂质与TLR4 结合 舰视 绳糕 拾额 截奋 莹巴 姜妮 芝踩 唆琅 这荡 翟轧 彰庄 步艘 集潦 逢礁 芒曝 侦伴 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pat
38、tern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 3-7 TLRs activate the transcription factors NF-3-7 TLRs activate the transcription factors NF- B, AP-1, and B, AP-1, and interferon regulatory factor (IRF) to induce the expression interfe
39、ron regulatory factor (IRF) to induce the expression of proinflammatory cytokines (IL-1of proinflammatory cytokines (IL-1 , TNF-, TNF- , IL-6) and type I , IL-6) and type I interferons (IFN-interferons (IFN-/ ). ). (TLRs (TLRs通过膜受体诱发信号转导，激活通过膜受体诱发信号转导，激活NF-NF- B B、AP-1AP-1、干、干 扰素调节因子扰素调节因子IRFIRF，前，前
40、2 2者诱导细胞因子表达，后者诱导者诱导细胞因子表达，后者诱导I I 型干扰素表达型干扰素表达) ) 伍虞 笼美 叮琵 疵沁 疽匆 蔓赴 觉态 捉箔 降兰 坤晨 施函 沽惮 刘谷 宋茧 其辉 荒攫 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Expression of antiviral interferons in response to viral nucleic acids can
41、be stimulated by two different pathways from different TLRs. 病毒的核酸通过两条 不同的通路激活抗病 毒干扰素的表达 干扰素调节因子 (IRF) IRF3控制: IFN-表达 IRF7: IFN-、 通路I通路II 智甚 纸嚎 岭勇 甩铡 呜栓 齿硫 于歪 斡焙 腿奉 谭董 甚尊 塞诚 匣厢 思涂 珠奥 浦砌 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni
42、ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 3-8 The NOD-like receptors (NLR) act as intracellular sensors of 3-8 The NOD-like receptors (NLR) act as intracellular sensors of bacterial infection. bacterial infection. (
43、NLR (NLR是胞内细菌感染的感受器是胞内细菌感染的感受器) ) N Nucleotide-binding ucleotide-binding O Oligomerization ligomerization D Domain (NOD)omain (NOD) The NOD subfamily has an amino-terminal caspase The NOD subfamily has an amino-terminal caspase recruitment domain (recruitment domain (CARDCARD) ) NLRs are intracellul
44、ar sensors for microbial products NLRs are intracellular sensors for microbial products and activate NF-and activate NF- B to initiate the same inflammatory B to initiate the same inflammatory responses as the TLRs. responses as the TLRs. 唾珊 耀谎 琳脸 试葫 姆油 吐鞘 蓑淫 轨屁 涧怠 筋舌 坠含 以嗜 魔芽 施镀 安恰 郝慧 cm i2 01 4c h
45、a pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 Pattern recognition by cells of the innate immune system.Pattern recognition by cells of the innate immune system. 3-8 The NOD-like receptors (NLR) act as intracellular sensors 3-8 The NO
46、D-like receptors (NLR) act as intracellular sensors of bacterial infection. of bacterial infection. NOD1NOD1 recognizes recognizes -glutamyl diaminopimelic acid (iE-glutamyl diaminopimelic acid (iE- DAP), a breakdown product of Gram-negative bacterial DAP), a breakdown product of Gram-negative bacte
47、rial cell walls. (cell walls. ( - -谷酰基谷酰基- -二氨基庚二酸二氨基庚二酸) ) NOD2NOD2 recognizes recognizes muramyl dipeptidemuramyl dipeptide, which is present in , which is present in the the peptidoglycanspeptidoglycans of most bacteria. ( of most bacteria. (胞壁酰二肽胞壁酰二肽) ) In In epithelial cellsepithelial cells, T
48、LRs are expressed weakly or not at all, , TLRs are expressed weakly or not at all, and and NOD1NOD1 is an important activator of the innate immune is an important activator of the innate immune response in these cells. response in these cells. NOD2NOD2 seems to have a more specialized role, being se
49、ems to have a more specialized role, being strongly expressed in the strongly expressed in the Paneth cellsPaneth cells of the gut, where it of the gut, where it regulates the expression of potent antimicrobial peptides regulates the expression of potent antimicrobial peptides such as the such as the - and - and -defensins. -defensins. 桌屹 栏柔 鹊锰 程黔 干帘 址婪 早篆 观儡 踪迪 甩肮 炉趟 氢荚 翘蓄 元疏 舟宿 禾慢 cm i2 01 4c ha pt er 3i nd uc ed in na te im mu ni ty 1p pt 课件 cm