博士生课程固有免疫模式识别.ppt

InnateImmunity monocyte macrophage bacteria ThemostancientdefensePhysical chemicalbarriersandcellularlineRecognitionbytheinnateimmunesystemsetsthestageforaneffectiveadaptiveimmuneresponse 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 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 chemicalandmicrobiologicalbarriersofourbody 1 固有免疫屏障 Thismaycauseinflammationandbleeding NormalFloracompetingwithInvadingPathogens Antibiotictreatmentsdisruptthenaturalecologyofthecolon 2 固有免疫细胞 PhagocyteNKILLs 固有样淋巴细胞 DCMCBasophilEosinophil T细胞NKT细胞B1细胞 Monocyte macrophageNeutrophil Recognitionofaninfectiononceitgetspasttheepithelialbarrier PolarizationofTumor associatedmacrophages TAM 分泌 IL 1 IL 6 IL 12 TNF a IL 8 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 Figure8 19part2of2 Leukocyterecruitmenttositesofinfection amulti stepnavigation 1 Selectins2 Chemokines3 Integrins IL 8 InteractionbetweenNeutrophilsandEndothelium CellularAdhesionMolecules CAMs Mucin likeCAMsSelectinsIntegrinsIg superfamilyCAMs Killeractivatoryreceptor Killerinhibitoryreceptor KIR KIR2DS KIR3DSKLR CD94 NKG2CNKG2DNKp46NKp30NKp44 NCR KIR2DL KIR3DLCD94 NKG2A BindclassIHLAmolecules Function Bindnon classIHLAmolecules ReceptorsassociatedwithkilleractivationandkillerinhibitiononNKcells 2 固有免疫细胞 PhagocyteNKILLs 固有样淋巴细胞 DCMCBasophilEosinophil T细胞NKT细胞B1细胞 Monocyte macrophageNeutrophil 过敏性疾病 抗原的处理与提呈 Nuocytesrepresentanewinnateeffectorleukocytethatmediatestype 2immunity Nature 2010Mar3 Type 2immunity responsibleforprotectiveimmuneresponsestohelminthparasitesandtheunderlyingcauseofthepathogenesisofallergicasthma Type 2cytokines interleukinIL 4 IL 5andIL 13 Nuocytesexpandinvivoinresponsetothetype 2 inducingcytokinesIL 25andIL 33 andrepresentthepredominantearlysourceofIL 13duringhelminthinfection InthecombinedabsenceofIL 25andIL 33signalling nuocytesfailtoexpand resultinginaseveredefectinwormexpulsionthatisrescuedbytheadoptivetransferofinvitroculturedwild type butnotIL 13 deficient 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antimicrobialpeptides溶菌酶lysozyme急性期蛋白 acutephaseproteins 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 associatedmolecularpatterns PAMPs 损伤相关分子模式 damage associatedmolecularpatterns DAMPs 模式识别受体 PatternRecognitionReceptors 病原相关分子模式 Pathogen associatedmolecularpatterns 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 AssociatedMolecularPatterns PAMP Innateimmunerecognitionofbacterialcellwallcomponents Gram negativebacteria Gram positivebacteria 损伤相关分子模式 damage associatedmolecularpatterns 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 PAMPvsDAMP Sterileinflammation conservedmicrobialmotifsVSnon microbialsignals 模式识别受体 PatternRecognitionReceptors 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 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 SECRETEDPRRs Mannosebindinglectin protein MBP C reactiveprotein CRP Serumamyloidprotein SAP LPS bindingprotein LBP Acutephaseproteins Acutephaseresponse APR theserumchangesAPRproteins theirconcentrationsroseorfell duringtheacutephase Sitesofinjuryorinfection signals proinflammatorycytokines TNF IL 1 IL 6producedbyphagocytes stimulatingLiver synthesisofAPRproteins IncreaseinthelevelofC reactiveprotein Mannose bindinglectin MBL Serumamyloidprotein SAP fibrinogen InvolvedinClotting TwoSecretedPRRs CRP MBP SAPmadeinacutephaseliverresponse MannosebindinglectinLungsurfactantsA DFicolins patternrecognitionreceptors inthiscasepatternofterminalsugarsoncellsurfaces Recognizingmannose containingmolecularpatternsfoundonmicrobesbutnotonvertebratecells directingcomplementattack Mannose bindinglectin Mannosebindingprotein MBP PartofC typelectinsuperfamilyAssociateswithandactivatesserineproteases MASP 1andMASP 2Afterbindingtopathogensurfacethiscomplexactivateslectinpathwayofcomplementsystem C2andC4 MB LECTINMASP MBL associatedserineproteaseMBLmannose MB LECTIN ANOTHERVERSIONPOINTSOUTTOTALITYOFCLEAVEDC3FUNCTIONS Bindtophorphorylcholine PC onbacteria othermicroorganisms damagedhostcellmembranesPCfoundinteichoicacids capsularcarbohydrates andlipopolysaccharidesRequiresCa Functiondirectlyasopsonins enhancerofphagocytosis FunctionindirectlybybindingtoC1qofclassicalcomplementpathwayandactivatecomplementcascade C reactiveprotein CRP andserumamyloidprotein SAP belongstoafamilyofpentamericproteincalledpentraxins bindingtopolysaccharide phophorylcholine ligands onthecellwallofbacteria fungiinacalcium dependentreaction activatingcomplementsystem lysis opsonization promotingphagocytosis pathogenclearance LipidtransfermoleculebindstomonomericLPSandtohigh affinityLPSreceptornamedCD14and onmacrophage neutrophils DCsLBP bactericidalpermeabilityincreasingprotein BPI bindsLPSonbacteriaandthentoCD14 ahighaffinityLPSreceptor SeelaterTLR4 LPS bindingprotein LBP Extracellularfactor LPS carriedbyLBPtoCD14whereitbindstoTLR4andthenMD2binds SimplifiedVersion 模式识别受体 PatternRecognitionReceptors 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 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 MANNOSERECEPTORThemannosereceptor MR isa175kDatypeImembranemoleculeexpressedinthemousebymosttissuemacrophagesandlymphaticandhepaticendothelia GlycoproteinPRRsrecognizeLPSandlipoteichoicacidIntactG andG bacteriaDamagedhostcellsandtissuesApoptoticandsenescentcellsmodifiedlow densitylipoproteinsSixclasses Scavengerreceptors 甲酰甲硫氨酰肽受体 fMLPR StaphylococcalProteinAInhibitsPhagocytosisbyBlockingFc 果蝇的Toll受体胞浆的功能域与IL 1受体很相像 Toll IL 1receptor 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 Cell86 973 83 Toll likereceptor TLR JulieA Hoffmann Ph D Strasbourg France In1996 Hoffmann sgroupTollfunctionsasaPRRinDrosophila Toll LikeReceptors TLRs Totalof13TLRshavebeenidentifiedinmammalsHuman TLRs1 10 Mouse TLRs1 9 11 13 IngeneralTLRsrecognizeconstituentsofmicrobialcellwallsorpathogen specificnucleicacidsthatareessentialtotheintegrity functionorreplicationofmicrobes virusesthatcannotreadilybemodified Toll LikeReceptors TLRs TherearesixmajorcladesofTLRs eachrecognizingageneralclassofmolecularpatterns MoleculartreeofthevertebrateToll likereceptors TLRs TheevolutionofvertebrateToll likereceptors Toll LikeReceptors TLRs BasicArchitecture StructuralorganizationofhumanTLRs ENDOTOXIN StructuralcomponentoftheouterleafletoftheoutermembraneofGramnegativebacteria ContainstheO antigenicpolysaccharidedeterminant Presenceofpolysaccharideandlipidcomponents AlsotermedLipopolysaccharide LPS ThelipidcomponentorLipidA glycophospholipid isresponsibleforthebiologicalactivitiesofLPS toxicity fever LPS endotoxin Outermembrane Peptidoglycan Innermembrane O specificchainCoreRegionLipidA LPS thetoxiccenterofLPS TheBasicArchitectureofLPSStructureofLipidA LipidAisaglycophospholipidwithphosphorylatedD glucosamines LBPandCD14thefirstEndotoxinReceptors LPS BindingProtein LBP PlasmaproteinproducedintheLiver DeliversLPSfromtheserumtomacrophages EnhancesthesensitivityofmacrophagesforLPS CD14 GPI linkedmembraneprotein macrophages Alsoexistsinasolubleformrecruitedtoendothelialcells WorkswithLBPtobringLPStothecellsurface NolinkbetweenLBP CD14andintracellularsignaling However LPSdetectionbyimmunecellsresultsinanintracellularsignalingresponseandproductionofTNF DeliveryofLPStoTLR4bylipidtransferproteins BiologicalActivities LBP CD14Co receptor s MD 2 TLR4 TLRsignalingpathways ThegenerationofinflammatorycytokinesandchemokinesThegenerationofantimicrobialpeptides Initiation Signal inducedassemblyofpathwaycomponents involvementofanadaptormolecule Proteinkinase mediatedphosphorylation Initiationofanenzymecascade MAPkinasepathway inmanycelltypes NF Bpathway apowerfultranscriptionalfactor generatecytokines adhesionmolecules othereffectors affectthecellcycleorcellulardifferentiation ConservedpathwaysininnateimmunityinDrosophilaandmammals OtherBacterial Poisons Lipopeptides Peptidoglycan LipoteichoicAcid UnmethylatedDNAOligomers TLR4LigandsLipopolysaccharidestwogradesofpurity StandardLPS LPS EBandLPS EKarestandardpreparationsoflipopolysaccharide Theyareextractedbyaphenol watermixture LPS EBandLPS EKcontainotherbacterialcomponents suchaslipopeptides andthereforestimulatebothTLR4andTLR2 Ultra pureLPS UltrapureLPS EBareextractedbysuccessiveenzymatichydrolysisstepsandpurifiedbythephenol TEA DOCextraction TLR5LigandsFlagellin TLR6 TLR2Ligand MALP 2 TLR2Ligands Heat KilledBacteria Lipoglycans Lipopolysaccharide LipoteichoicAcids Peptidoglycans SyntheticLipoproteins Zymosan TLR3LigandsPoly I C asyntheticanalogofdouble strandedRNA dsRNA Poly A U TLR9Agonists StimulatoryODNs CpGODNs ControlODNs LabeledODNs E coliDNA E coliDNAef E colissDNA TLR7Ligands human mouseTLR7 CL264 Adenineanalog Gardiquimod imidazoquinolinecompound Gardiquimod Imiquimod imidazoquinolinecompound ImiquimodVacciGradeNEW Loxoribine guanosineanalogueTLR8Ligands humanTLR8 mouseTLR7 Single strandedRNAs E coliRNATLR7 8Ligands human mouseTLR7 humanTLR8 CL075 thiazoloquinolinecompound CL097 water solubleR848 imidazoquinolinecompound Poly dT thymidinehomopolymerphosphorothioateODN R848 Imidazoquinolinecompound MyD88 DependentandindependentSignaling TLR4cansignalusingbothpathways TRAM TRIF relatedadaptormoleculeTIRAP Toll interleukin1receptor TIR domain containingproteinTLR4signalinginducesthetranscriptionofbothproinflammatorycytokinesandIFN thatarerequiredforanti bacterialandanti viralimmuneresponses respectively CooperationofToll likereceptorsignalsininnateimmunedefense NegativeregulationofToll likereceptor4 TLR4 signaling ThenegativeregulatorsofTLRsignalingpathways NLRsarecytoplasmicbacterialsensorsthatactivateinflammasomes IL 1familymembers Commonsourcesofinterleukin 1 IL 1 familycytokines ICE IL 1 convertingenzyme caspase1 Pro IL 18 24kDaandmatureIL 18 18kDaPro IL 1beta 33kDaandmatureIL 1beta 17kDapro caspase 1 45 kDamaturecaspase 1 20KD10KD InflammasomesaremolecularplatformsactivateduponcellularinfectionorstressthattriggerthematurationofproinflammatorycytokinessuchasIL 1bandIL 18toengageinnateimmunedefenses THEINFLAMMASOMES Activatorsofthein ammasome TheHumanNLRFamilyMembers HumanandMouseNLRFamilyMembers DOMAINORGANIZATIONOFREPRESENTATIVENLRs TheNLRsfamilyiscomposedof 20members Theycontain aC terminalleucine richrepeatdomain LRRacentralnucleotide bindingdomain NACHTanN terminalprotein proteininteractiondomaincomposedofCARD caspaseactivationandrecruitmentdomain PyrindomainorBir baculovirusinhibitorofapoptosisrepeat domain SchroderandTschoppCell2010 NLRP1 NLRP3 IPAF andAIM2In ammasomes Whatisaninflammasomeandwhatdoesitdo ActivationmodelsandcompositionofNLRP3inflammasome SchroderandTschoppCell2010 PAMPs MDP LPS viral bacterialRNA aerolysin etc DAMPs ATP hyaluronan uricacid amyloid bpeptide ROS silica asbestos UVB etc ThechannelmodelofNLRP3inflammasomeactivation ProposedpathwaysforNLRP3activation AroleformitochondriainNLRP3inflammasomeactivation PathwaysforactivationoftheinflammasomebyPAMPsandDAMPs TheAIM2in ammasome Theroleoftheinflammasomesinhumandisease Theinfluenceofinflammasomeactivationonadaptiveimmunity RLRs等病毒识别受体HostResponsetoVirusInfection ViralNucleicAcidsdoublestranded ds RNAsinglestranded ss RNADNA hypomethylatedorCpGrich Some ViralProteins uncommone g glycoproteinsofHerpesvirusandRespiratorySyncytialVirus ViralPathogen AssociatedMolecularPatterns PAMP ProductionofType1 interferonsProductionofinflammatorymediators cytokinesandchemokinesMechanism InterferonResponseFactor3 7 IRF3 7 activationNF BactivationTranslocationfromcytoplasmtonucleus EngagementofViralPAMPReceptorson inCells cellsurfaceandendosomallocalizationcellcytoplasmlocalizationextracellularspacelocalization ViralPAMPReceptors anti viralsensors anti viralPRR ViralPAMPReceptors anti viralsensors TLR TollLikeReceptors cellsurface orendosomeEndosomalTLRTLR 9CpGDNA methylatedviralDNA TLR 7 8ssRNATLR 3dsRNA TLR9and7aremajortriggersofType1IFNproduction particularlybyplasmacytoidDC CellsurfaceTLRTLR 2andTLR 4 viralglycoproteins HCV RSV ThethirdmemberoftheRLRfamily LGP2 lacksanyCARDsandwasoriginallyidentifiedasanegativeregulatorofRLRsignaling Nevertheless LGP2anditsATPaseactivityweredispensablefortheresponsestosyntheticRNAligandsforMDA5andRIG I LGP2facilitatesviralRNArecognitionbyRIG IandMDA5throughitsATPasedomain