博士生课程固有免疫模式识别ppt课件.ppt
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1、Innate Immunity,monocyte,macrophage,bacteria,The most ancient defense Physical & chemical barriers and cellular line Recognition by the innate immune system sets the stage for an effective adaptive immune response.,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.,复习,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
2、、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、,Physical, chemical and microbiological barriers of our body,1、固有免疫屏障,This may cause inflammation and bleeding,Normal Flora competing with Invading Pathogens. Antibiotic treatments
3、disrupt the natural ecology of the colon,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,Polarization of Tumor-associated macrophages (TAM),分泌,IL-1,IL-6,IL-12,TNF-,a,IL-8
4、,GM-CSF,细胞因子,酶,其它因子,杀伤,肿瘤细胞,抗原,呈递作用,前列腺素,白三烯,补体成分,纤维蛋白,结合蛋白,凝血因子,溶菌酶,酸性水解酶,赖氨酸酶,酯酶,胶原蛋白酶,弹性纤维蛋白酶,免疫调节作用,吞噬并杀伤,病原微生物,巨噬细胞的功能,Figure 8-19 part 2 of 2,Leukocyte recruitment to sites of infection: a multi-step navigation,1. Selectins 2. Chemokines 3. Integrins,IL-8,Interaction between Neutrophils and En
5、dothelium,Cellular Adhesion Molecules (CAMs): Mucin-like CAMs Selectins Integrins Ig-superfamily CAMs,Killer activatory receptor,Killer inhibitory receptor,KIR: KIR2DS,KIR3DS KLR: CD94/NKG2C NKG2D NKp46 NKp30 NKp44,NCR,KIR2DL,KIR3DL CD94/NKG2A,Bind class I HLA molecules,Function,Bind non-class I HLA
6、 molecules,Receptors associated with killer activation and killer inhibition on NK cells,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,过敏性疾病,抗原的处理与提呈,Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Natur
7、e. 2010 Mar 3.,Type-2 immunity: responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma. Type-2 cytokines: interleukin IL-4, IL-5 and IL-13. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL-25 and IL-33,
8、 and represent the predominant early source of IL-13 during helminth infection. In the combined absence of IL-25 and IL-33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL-13-defici
9、ent, nuocytes.,3、固有性免疫分子,指体表分泌液以及血浆和其它体液中能够识别或攻击病原体的可溶性分子。,抗菌肽 antimicrobial peptides 溶菌酶 lysozyme 急性期蛋白(acute phase proteins, APP) 脂多糖结合蛋白(LBP) 血清淀粉样蛋白(SAP) 甘露糖结合蛋白(MBP) C反应蛋白等(CRP) 补体 细胞因子和黏附分子,补体系统,细胞因子和免疫相关细胞表面分子,二、固有免疫识别,病原相关分子模式(Pathogen-associated molecular patterns, PAMPs) 损伤相关分子模式(damage-as
10、sociated molecular patterns,DAMPs) 模式识别受体(Pattern Recognition Receptors),病原相关分子模式(Pathogen-associated molecular patterns, PAMP) :是病原微生物(尤其是原核生物)表面存在一些人体所没有的,但可为许多相关微生物所共享、结构恒定、进化保守的分子结构。 PAMP的特征 1.通常为病原微生物所特有,乃天然免疫系统区分“自己”与“非己(微生物)”的分子基础。 脂多糖:多数革兰阴性菌细胞壁成分; 磷壁酸:多数革兰阳性菌胞壁成分; 肽聚糖:革兰阳性/阴性菌、真菌胞壁成分; 甘露糖:微
11、生物细胞壁上糖蛋白和糖脂成分 2.为微生物生存和致病性所必需 PAMP突变或缺失 微生物死亡或微生物对外界环境适应性 3.宿主泛特异性识别的分子基础 PAMP是由一群或一类特定的微生物所共有的恒定结构(如LPS)。 宿主由种系编码的有限数量PRR 可察觉任何微生物感染的存在,Pathogen- Associated Molecular Patterns (PAMP),Innate immune recognition of bacterial cell wall components,Gram-negative bacteria,Gram-positive bacteria,损伤相关分子模式
12、(damage-associated molecular patterns,DAMPs),机体自身细胞所释放的内源性分子,即内源性危险信号,来源于受损或坏死组织和某些激活的免疫细胞。主要有HMGB1、热体克蛋白等。,PAMP vs DAMP,Sterile inflammation,conserved microbial motifs VS non-microbial signals,模式识别受体( Pattern Recognition Receptors, PRRs) 固有免疫细胞表面、内体、溶酶体、细胞质中、可识别一种或多种PAMPs或DAMPs的识别分子。,PRR,甘露聚糖凝集素(MB
13、L) C反应蛋白(CRP) 血清淀粉样蛋白 (SAP) 脂多糖结合蛋白(LBP),可溶性:体液和血液,细胞吞噬型:细胞膜,甘露糖受体(MR) 清道夫受体(SR) 补体受体(CR) Fc受体(FcR) 甲酰甲硫氨酰肽受体(fMLPR),信号转导型,细胞膜 内体、溶酶体 细胞质,TLR1、2、4、5、6、10、11、12、13,TLR3、7、8、9,NLRs、RLRs、ALRs,EXTRACELLULAR/SECRETED PRRs,Mannose binding lectin/protein (MBP) C-reactive protein (CRP) Serum amyloid protein
14、 (SAP) LPS-binding protein (LBP),Acute phase proteins,Acute phase response (APR): the serum changes APR proteins: their concentrations rose or fell,(during the acute phase),Sites of injury or infection signals (proinflammatory cytokines: TNF- , IL-1, & IL-6 produced by phagocytes) stimulating Liver:
15、 synthesis of APR proteins Increase in the level of C-reactive protein & Mannose-binding lectin/MBL & Serum amyloid protein/SAP & fibrinogen),Involved in Clotting,Two Secreted PRRs: CRP, MBP,SAP made in acute phase liver response,Mannose binding lectin Lung surfactants A, D Ficolins “pattern recogni
16、tion receptors”; in this case pattern of terminal sugars on cell surfaces,Recognizing mannose-containing molecular patterns found on microbes but not on vertebrate cells directing complement attack,Mannose-binding lectin,Mannose binding protein (MBP) Part of C-type lectin superfamily Associates with
17、 and activates serine proteases: MASP-1 and MASP-2 After binding to pathogen surface this complex activates lectin pathway of complement system, C2 and C4,MB-LECTIN MASP = MBL-associated serine protease MBL mannose,MB-LECTIN,ANOTHER VERSION POINTS OUT TOTALITY OF CLEAVED C3 FUNCTIONS,Bind to phorpho
18、rylcholine (PC) on bacteria, other microorganisms, damaged host cell membranes PC found in teichoic acids, capsular carbohydrates, and lipopolysaccharides Requires Ca+ Function directly as opsonins (enhancer of phagocytosis) Function indirectly by binding to C1q of classical complement pathway and a
19、ctivate complement cascade,C-reactive protein (CRP) and serum amyloid protein (SAP),(belongs to a family of pentameric protein called pentraxins) binding to polysaccharide & phophorylcholine (= ligands) on the cell wall of bacteria & fungi in a calcium-dependent reaction activating complement system
20、 lysis, opsonization promoting phagocytosis & pathogen clearance,Lipid transfer molecule binds to monomeric LPS and to high-affinity LPS receptor named CD14 and, on macrophage, neutrophils, DCs LBP + bactericidal permeability increasing protein (BPI) binds LPS on bacteria and then to CD14, a high af
21、finity LPS receptor. See later TLR4,LPS-binding protein (LBP),Extracellular factor (LPS) carried by LBP to CD14 where it binds to TLR4 and then MD2 binds,Simplified Version,模式识别受体( Pattern Recognition Receptors, PRRs) 固有免疫细胞表面、内体、溶酶体、细胞质中、可识别一种或多种PAMPs或DAMPs的识别分子。,PRR,甘露聚糖凝集素(MBL) C反应蛋白(CRP) 血清淀粉样蛋白
22、 (SAP) 脂多糖结合蛋白(LBP),可溶性:体液和血液,细胞吞噬型:细胞膜,甘露糖受体(MR) 清道夫受体(SR) 补体受体(CR) Fc受体(FcR) 甲酰甲硫氨酰肽受体(fMLPR),信号转导型,细胞膜 内体、溶酶体 细胞质,TLR1、2、4、5、6、10、11、12、13,TLR3、7、8、9,NLRs、RLRs、ALRs,MANNOSE RECEPTOR The mannose receptor (MR) is a 175 kDa type I membrane molecule expressed in the mouse by most tissue macrophages a
23、nd lymphatic and hepatic endothelia.,Glycoprotein PRRs recognize LPS and lipoteichoic acid Intact G- and G+ bacteria Damaged host cells and tissues Apoptotic and senescent cells modified low-density lipoproteins Six classes,Scavenger receptors,甲酰甲硫氨酰肽受体(fMLPR),Staphylococcal Protein A Inhibits Phago
24、cytosis by Blocking Fc,果蝇的Toll受体胞浆的功能域与IL-1受体很相像(Toll/IL-1 receptor (TIR) domain),显然具有重要的免疫功能。 Toll突变后果蝇很容易受霉菌感染。Cell 86:973-83.,Toll-like receptor (TLR),Julie A. Hoffmann, Ph.D. Strasbourg, France,In 1996, Hoffmanns group Toll functions as a PRR in Drosophila,Toll-Like Receptors (TLRs) Total of 13
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