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1、Innate Immunity,monocyte,macrophage,bacteria,The most ancient defense Recognition by the innate immune system sets the stage for an effective adaptive immune response. Physical & chemical barriers and cellular line,机体在种系发生和进化过程中逐渐形成的一种天然免疫防御功能，构成机体抵御病原生物入侵的第一道防线.,The evolution of immune system,Parts
2、 of mammalian TLR signalling are conserved in C. elegans,Time course of primary infection in healthy individuals, and people who lack immune or adaptive immunity,In the absence of innate immunity, there is also no adaptive immunity,Infection is cleared from the body by combined actions of innate and
3、 adaptive immunity,一、固有免疫系统的组成,屏障细胞分子,皮肤黏膜屏障：物理、化学、微生物 血-脑屏障、血-胸腺屏障 血-胎屏障、气-血屏障,单核-巨噬细胞、中性粒细胞、树突状细胞、T 细胞、NK细胞、NKT细胞、B1细胞、肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞等。,抗菌肽、溶菌酶、急性期蛋白、补体、细胞因子和黏附分子、,The Epithelial Layer: The initial barrier to infection,Physical barrier of the epithelial layer (toughness of barrier varies by lo
4、cation due to other functions: air exchange, nutrient uptake, etc.) Mucus/cilia to remove particles (lung, intestines) Acid pH of the stomach Anti-microbial peptides secreted by some epithelial cells (small intestines, small airways of lungs) Commensal bacteria (compete with pathogenic bacteria) 6.
5、Secretory IgA (adaptive immunity) 7. Intraepithelial lymphocytes (adaptive immunity),Epithelium is protected by a flora of nonpathogenic microorganisms (commensal species),Commensal species are nonpathogenic microorganisms that protect epithelium by competing with pathogens for nutrients and attachm
6、ent sites (commensal = “they eat at the same table”) There are about 500 microbial species living in healthy human gut After antibiotic treatment, the nonpathogenic flora is killed, which can result in re-infection with other pathogens (Acidophilus therapy after antibiotic treatment facilitates re-c
7、olonization by commensal species),Respiratory tract and head outer ear, eye, mouth, oropharynx, nasopharynxSterile sites: sinuses, middle ear, brain, lower respiratory tract (trachea, bronchiole, lung) Gastrointestinal tractesophagus, stomach, small intestine, large intestine Genitourinary systemant
8、erior urethra, vaginaSterile sites: bladder, cervix, uterus Skin,Sites of human body that the normal flora microbes colonize,Normal flora may aid the host in several ways,Aid in digestion of food Protect the host from colonization with pathogenic microbes. Help the development of mucosa immunity,Thi
9、s may cause inflammation and bleeding,Normal Flora competing with Invading Pathogens. Antibiotic treatments disrupt the natural ecology of the colon,Physical, chemical and microbiological barriers of our body,1、固有免疫屏障,体内特殊生理屏障,血-胎屏障,血脑 屏障,血脑屏障血-脑屏障由软脑膜、脉络丛的脑毛细血管壁和包在壁外的星状胶质细胞形成的胶质膜共同组成。 血-胎屏障胎盘屏障由母体子
10、宫内膜的基蜕膜和胎儿绒毛膜共同组成，能够有效防止母体内的病原体及其毒性代谢产物进入胎儿体内。 其它屏障人体的胸腺、睾丸、附睾以及胃粘膜等部位存在屏障结构。,2、固有免疫细胞,Phagocyte NK ILLs（固有样淋巴细胞）DC MC Basophil Eosinophil, T细胞NKT细胞B1细胞,Monocyte-macrophage Neutrophil,Recognition of an infection once it gets past the epithelial barrier,(1) 吞噬细胞 phagocyte单核吞噬细胞（系统） 中性粒细胞 Mononuclear
11、phagocyte system neutrophils,单核细胞 巨噬细胞monocyte macrophage,Monocyte - blood Alveolar Mfslung Histiocytes connective tissue Kupffer cells liver Mesangial cells kidney Microglial cells brain,单核巨噬细胞,腹腔巨噬细胞粘附于玻璃表面黏附性,高尔基体发达，线粒体丰富,分化过程中体积增大、细胞器增多、伪足更多、吞噬能力增强、产生更多水解酶、分泌大量可溶性因子。,单核细胞是白细胞中体积较大，蹄状核,吞噬杀伤病原体,3个
12、阶段：识别recognition、吞噬ingestion、消化digestion,Opsonins and Phagocytic receptors,OpsoninsComplement components (C3b)Collectins (mannose-binding lectin)AntibodiesPhagocytic receptorsReceptors for opsonins (complementreceptors, Fc receptors)Pattern recognition receptors(mannose receptor, etc.)Receptors for
13、apoptotic cells,Surface receptors of macrophages,Toll-like receptors Toll样受体,Mac-1,Fc受体,Staphylococcal Protein A Inhibits Phagocytosis by Blocking Fc,Figure 8-21,What is happening in phagolysosomes?,Oxidative attack via ROS & RNS: generated by NADPH phagosome oxidase (phox) enzyme complex The oxygen
14、 consumed by phagocytes to support ROS production by the phox enzyme is provided by the respiratory burst, iNOS L-arginine + O2 + NADPH,Bacterium,Flavoprotein 黄素蛋白,NADPH H+,e- + O2,O2-,H+,H2O2,cytochrome细胞色素558,“Respiratory burst(呼吸爆发)过程中产生大量过氧化氢(hydrogen peroxide )及其它活性离子，是吞噬细胞消化被吞噬微生物或其它异物的主要武器。参与
15、该过程的辅酶 II (NADPH) 氧化酶体由黄素蛋白和细胞色素 b558组成。,The production of H2O2,Reactive Oxygen Intermediates,NO pathway, yield NOL-Aginine + 1/2O2 Citruline + NO Yield Nitric peroxide (过氧化氮) free redical.NO + O2 - ONOO-,inducible nitric oxide synthetase (iNOS),介导炎症：分泌炎症介质，参与炎症,Figure 1-14,Macrophages engulf bacteria and produce inflammatory cytokines,Activated macrophages secrete numerous pro-inflammatory cytokines and chemokines,抗肿瘤作用,膜融合，胞内溶酶体作用,蛋白水解酶、溶细胞素、TNF-,ADCC,Polarization of Tumor-associated macrophages (TAM),M2-polarized TAM play a pivotal role in tumor growth and progression.,
