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1、Cellular and Molecular Immunology,Xian-Hui He Department of Immunobiology Jinan University 2014-10,Chapter 3 The Induced Responses of Innate Immunity (诱导性固有免疫反应),Pattern recognition by cells of the innate immune system. (固有免疫系统的模式识别) Induced innate responses to infection. (针对感染的诱导性固有免疫反应),Part I Int
2、roduction,Pattern recognition by cells of the innate immune system. (固有免疫系统的模式识别),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,Pattern recognition by cells of the innate immune system.,3-1 After
3、entering tissues, many pathogens are recognized, 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) There are three major classes of phagocytic cells in the innate immune system: macrophages and monocytes, granulocytes, and dendritic cells.,-葡聚糖受体,甘露糖受体,清道夫受体,吞噬细胞抗微生物机制,酸化,毒性氧衍生物,抗菌肽,酶类,
4、竞争物,乳铁蛋白,单态氧,超氧阴离子,Pattern recognition by cells of the innate immune system.,3-2 G-protein-coupled receptors (GPCR) on phagocytes link microbe recognition with increased efficiency of intracellular killing. (吞噬细胞上的G蛋白偶联受体传递识别信号，增强胞内杀伤效应)-诱导性,Pus (脓),NADPH oxidase (NOX): 反应性氧 (ROS),Neutrophil respira
5、tory burst (呼吸爆发),超氧阴离子,Pattern recognition by cells of the innate immune system.,3-3 Pathogen recognition and tissue damage initiate an inflammatory response. (病原体识别和组织损伤诱发炎症反应) Inflammation has three essential roles in combating infection. (炎症在抗感染中有三个基本作用) deliver additional effector molecules and
6、 cells from the blood into sites of infection (吸引细胞进入感染部位) induce local blood clotting (诱导局部凝血) promote the repair of injured tissue (促进损伤组织修复),Inflammatory responses are operationally characterized by pain, redness, heat, and swelling at the site of an infection, reflecting four types of change in
7、the local blood vessels.,Inflammation (炎症),Pattern recognition by cells of the innate immune system.,3-4 Toll-like receptors (TLR) represent an ancient pathogen-recognition system. (Toll样受体是古老的病原体识别系统) Toll is required for antifungal responses in Drosophila melanogaster. (Toll是果蝇抗真菌反应所必需）,Immunology
8、 takes prize for Physiology/Medicine (2011), but award comes three days too late for one recipient,Jules A. Hoffmann,Bruce Beutler,Ralph M. Steinman,Jules A. Hoffmann,Bruce Beutler,Ralph M. Steinman,Ralph M. Steinman,Pattern recognition by cells of the innate immune system.,3-5 Mammalian Toll-like r
9、eceptors are activated by many different pathogen-associated molecular patterns (PAMPs). (多种不同的PAMPs可激活哺乳动物的TLR),目前已知的TLR分子：TLR 1-13,脂磷壁酸,TLRs cell distribution and their ligands,TLR-5 is expressed on the cell surface of macrophages, dendritic cells, and intestinal epithelial cells; it recognizes fl
10、agellin (鞭毛蛋白), the protein subunit of bacterial flagella. TLR-3 is expressed by macrophages, intestinal epithelial cells, dendritic cells, and natural killer cells (NK cells); it recognizes double-stranded RNA (dsRNA), which is a replicative intermediate of many types of viruses, not only those wit
11、h RNA genomes. TLR-7 and TLR-9 are found in plasmacytoid dendritic cells, NK cells, B cells, and eosinophils. TLR-7 and 8 is activated by single-stranded RNA (ssRNA). TLR-9 recognizes unmethylated CpG oligonucleotides (CpG寡核苷酸).,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、TL
12、R7/8、TLR9； 胞浆：NOD1/2；RIG-I/MDA-5,Direct recognition of pathogen-associated molecular patterns by TLR-1 and TLR-2.,Pattern recognition by cells of the innate immune system.,3-6 TLR-4 recognizes bacterial lipopolysaccharide (LPS) in association with the host accessory proteins MD-2 and CD14. (TLR-4与MD
13、-2和CD14共同识别细菌脂多糖LPS) TLR4主要表达于DC和巨噬细胞等免疫细胞 LPS先结合与血液中的LPS结合蛋白，然后转移到CD14，最后与TLR4/MD2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,Pattern recognition by cells of the innate immune system.,3-7 TLRs activate the transcription factors NF-B, AP-1, and interferon regulatory factor (IRF) to induc
14、e the expression of proinflammatory cytokines (IL-1, TNF-, IL-6) and type I interferons (IFN-/). (TLRs通过膜受体诱发信号转导，激活NF-B、AP-1、干扰素调节因子IRF，前2者诱导细胞因子表达，后者诱导I型干扰素表达),Expression of antiviral interferons in response to viral nucleic acids can be stimulated by two different pathways from different TLRs. 病毒
15、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,Pattern recognition by cells of the innate immune system.,3-8 The NOD-like receptors (NLR) act as intracellular sensors of bacterial infection. (NLR是胞内细菌感染的感受器) Nucleotide-binding Oligomerization Domain (NOD) The NOD subfamily
16、 has an amino-terminal caspase recruitment domain (CARD) NLRs are intracellular sensors for microbial products and activate NF-B to initiate the same inflammatory responses as the TLRs.,Pattern recognition by cells of the innate immune system.,3-8 The NOD-like receptors (NLR) act as intracellular se
17、nsors of bacterial infection. NOD1 recognizes -glutamyl diaminopimelic acid (iE-DAP), a breakdown product of Gram-negative bacterial cell walls. (-谷酰基-二氨基庚二酸) NOD2 recognizes muramyl dipeptide, which is present in the peptidoglycans of most bacteria. (胞壁酰二肽) In epithelial cells, TLRs are expressed w
18、eakly or not at all, and NOD1 is an important activator of the innate immune response in these cells. NOD2 seems to have a more specialized role, being strongly expressed in the Paneth cells of the gut, where it regulates the expression of potent antimicrobial peptides such as the - and -defensins.,
19、Crohns disease (克隆氏病) -inflammatory bowel disease (炎症性肠炎),Human loss-of-function mutations in NOD2 are associated with the inflammatory bowel condition known as Crohns disease. Some patients with this condition carry mutations in the LRR domain of NOD2 that impair its ability to sense muramyl dipept
20、ide (MDP) and activate NF-B. This is thought to diminish the production of defensins and other antimicrobial peptides, thereby weakening the natural barrier function of the intestinal epithelium and leading to the inflammation characteristic of this disease.,NLRP and inflammasome (炎症小体),Another larg
21、e subfamily of NLR proteins: Some NLR proteins containing pyrin domains (PYD); The best characterized is NALP3 (also called NLRP3), which is an important sensor of cellular damage or stress. Others contain caspase recruitment domain (CARD), directly recruiting caspase-1.,Inflammasome (炎症小体)激活的主要途径,经
22、典途径(canonical pathway): 如胞外ATP、Silica - NLRP3与AIM2炎症小体: 需ASC参与，募集Caspase-1 - NLRC3、NLRC4炎症小体: 不需ASC, 直接募集Caspase-1 非经典途径(non-canonical pathway): 胞内LPS - Pro-caspase-11 (human caspase-4)直接结合LPS，形成多聚 物，激活NLRP3下游的Caspase-1，释放IL-1和IL-18 - 激活Caspase-11诱导细胞发生Pyroptosis (焦亡)、IL-1、 HMGB1释放,NALP3 (NLRP3) and
23、 Gout (痛风),The disease gout has been known for many years to be caused by monosodium urate (尿酸钠) crystals deposited in the cartilaginous tissues of joints, causing inflammation. Urate crystals (尿酸钠晶体) activate the NALP3 inflammasome, and that this induces the inflammatory cytokines that cause the sy
24、mptoms of gout.,Pattern recognition by cells of the innate immune system.,3-9 The RIG-I-Iike helicases (解旋酶) detect cytoplasmic viral RNAs and stimulate interferon production. (RIG-I监测胞浆病毒RNA，刺激I型干扰素产生) TLR-3, TLR-7, and TLR-9 can detect viral RNAs and DNAs, but they interact primarily with extracel
25、lular material entering the endocytic pathway rather than with nucleic acids present in the cytoplasm of a virus-infected cell as a result of viral replication. Cytoplasmic viral RNAs are sensed by proteins called the RIG-I-like helicases (RLHs), which have an RNA helicase-like domain that binds to
26、viral RNAs, and two amino-terminal CARD domains that interact with adaptor proteins and activate signaling when viral RNAs are bound.,RIG-I: retinoic acid-inducible gene I (视黄酸诱导性基因I),RIG-I is widely expressed across tissues and cell types and serves as an intracellular sensor for several kinds of i
27、nfections. RIG-I senses the unmodified 5-triphosphate end of ssRNA. (RIG-I识别ssRNA 5未修饰的三磷酸末端) MDA-5 (melanoma differentiation-associated 5) is similar in structure to RIG-I, but it senses dsRNA. (MDA-5识别dsRNA 5未修饰的三磷酸末端) Sensing of viral RNAs by RIG-I and MDA-5 induces the production of type I inter
28、ferons. (RIG-I和MDA-5感知病毒RNA后诱导I型干扰素的产生),RIG-I and MDA-5 are cytoplasmic sensors of viral RNA,Pattern recognition by cells of the innate immune system.,3-10 Activation of TLRs and NLRs triggers changes in gene expression in macrophages and dendritic cells that have far-reaching effects on the immune
29、response. Cytokines : IL-12 Co-stimulatory molecules: B7.1 (CD80) and B7.2 (CD86),Pattern recognition by cells of the innate immune system.,3-11 TLR signaling shares many components with Toll signaling in Drosophila. 3-12 TLR and NOD genes have undergone extensive diversification in both invertebrat
30、es and some primitive chordates.,2. Induced innate responses to infection: macrophages and dendritic cells,Induced innate responses to infection,3-13 Macrophages and dendritic cells activated by pathogens secrete a range of cytokines that have a variety of local and distant effects. (巨噬细胞和DC被病原体激活后分
31、泌多种细胞因子，发挥局部和远程效应),Activated macrophage& secrete a range of cytokines,IL-8,内源性热源,Induced innate responses to infection,3-14 Chemokines released by macrophages and dendritic cells recruit effector cells to sites of infection. (巨噬细胞和DC释放的趋化因子募集效应细胞至感染部位),Induced innate responses to infection,3-15 Cell
32、-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response. (炎症反应过程中细胞黏附分子控制白细胞与内皮细胞间的相互作用),选择素,Induced innate responses to infection,3-15 Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammato
33、ry response.,整合素,名 称 分 布 配 体,Induced innate responses to infection,3-15 Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response.,免疫球蛋白超家族,名 称 分 布 配 体,Induced innate responses to infection,3-16 Neutrophils make up the first wave of cells t
34、hat cross the blood vessel wall to enter an inflamed tissue. (中性粒细胞是第一批穿过血管壁进入炎症组织的细胞),Induced innate responses to infection,3-16 Neutrophils make up the first wave of cells that cross the blood vessel wall to enter an inflamed tissue.,活化的内皮细胞还表达ICAM-1,炎症组织表达IL-8,Induced innate responses to infectio
35、n,3-17 TNF- is an important cytokine that triggers local containment of infection but induces shock when released systemically. TNF- acting on endothelial cells stimulates the expression of adhesion molecules and aids the extravasation of cells such as monocytes and neutrophils. Another important ac
36、tion of TNF- is to stimulate endothelial cells to express proteins that trigger blood clotting in the local small vessels, occluding them and cutting off blood flow.,Induced innate responses to infection,3-18 Cytokines released by macrophages and dendritic cells activate the acute-phase response. En
37、dogenous pyrogens (热原): TNF-, IL-1 and IL-6 Exogenous pyrogen: LPS,Endogenous pyrogens,COX2,PGE2,Hypothalamus,Exogenous pyrogens,Fever,Elevated temperature benefits the host,Liver,acute-phase proteins,Induced innate responses to infection,3-19 Interferons induced by viral infection make several cont
38、ributions to host defense.,Induced innate responses to infection,3-20 NK cells are activated by interferon and macrophage-derived cytokines to serve as an early defense against certain intracellular infections.,Induced innate responses to infection,3-21 NK cells possess receptors for self molecules
39、that prevent their activation by uninfected cells.,Induced innate responses to infection,3-21 NK cells possess receptors for self molecules that prevent their activation by uninfected cells.,The structural families of NK receptors encode both activating and inhibitory receptors.,活化受体,抑制受体,Induced in
40、nate responses to infection,3-22 NK cells bear receptors that activate their effector function in response to ligands expressed on infected cells or tumor cells. Natural cytotoxicity receptors (NCRs) NKG2D,Induced innate responses to infection,3-23 The NKG2D receptor activates a different signaling
41、pathway from that of the other activating NK receptors.,Induced innate responses to infection,3-24 Several lymphocyte subpopulations behave as innate-like lymphocytes (ILLs). - 分布于不同组织的固有型淋巴细胞具有不同的效应功能,腹腔,Induced innate responses to infection,3-24 Several lymphocyte subpopulations behave as innate-l
42、ike lymphocytes (ILLs). Innate lymphoid cells (ILCs): 固有淋巴样细胞 Group I: ILC1表达转录因子T-bet，相当于Th1 Group II: ILC2表达转录因子GATA3，相当于Th2 Group III: ILC3表达转录因子RORt，相当于Th17,Induced innate responses to infection,3-24 Several lymphocyte subpopulations behave as innate-like lymphocytes (ILLs). innate lymphoid cell
43、s (ILCs): 固有淋巴样细胞,第三章 内容小结,1. PRR的不同亚细胞分布及其识别的PAMPs： TLR3: double-stranded RNA (dsRNA), 感受内体中的病毒感染 TLR78: single-stranded RNA (ssRNA), 感受内体中的病毒感染 TLR9: unmethylated CpG oligonucleotides (未甲基化CpG寡核苷酸), 感受内体中的细菌感染 TLR4: LPS (Gram阴性菌)和脂磷壁酸(Gram阳性菌)，感受胞外细菌感染 TLR5: flagellin (鞭毛蛋白)，感受胞外细菌感染 NOD1: -glutam
44、yl diaminopimelic acid (iE-DAP) (-谷酰基-二氨基庚二酸), 革兰氏阴性菌细胞壁产物，感受胞浆中的细菌感染 NOD2: muramyl dipeptide (胞壁酰二肽)，感受胞浆中的细菌感染 2. 胞浆中的病毒感染的PRR RIG-I: unmodified 5-triphosphate end of ssRNA (5未修饰的三磷酸末端) MDA-5: unmodified 5-triphosphate end of dsRNA,第三章 内容小结,2. 诱导性固有免疫的效应机制： 巨噬细胞的吞噬和杀伤效应 NK细胞的杀伤效应 模式识别受体识别PAMPs后产生的反应：细胞因子、趋化因子、干扰素 炎症反应 炎症小体：IL-1 ILCs：,思考题,固有免疫系统如何通过不同的PRR识别不同亚细胞部位的病原体感染？ 诱导性固有免疫反应的主要效应机制有哪些？ 简述炎症小体的激活通路。,The end of chapter 3,