免疫学课件-1-PPT幻灯片

PatternrecignitionandInnateprotection

•OverviewPatternrecognitionNegativeregulationofpatternrecognitionSignificanceofpatterrecognitionPRRandhumandiseases

DangeroussignalInnateImmunity:A(Very)BroadOverview

PatternrecignitionandInnateprotection

•OverviewPatternrecognitionNegativeregulationofpatternrecognitionSignificanceofpatterrecognitionPRRandhumandiseases

StrategyofHost?Microbesareheterogeneousandcanmutate

FOCUS----Onhighlyconserved structurespresentinlargegroupsofmicroorganisms.

PAMPS----Pathogen-associated

molecularpatternsPatternrecognition

机体接触致病微生物后即迅速进行识别并产生抵抗病原体入侵的反应。发挥这一功能主要是巨噬细胞、树突状细胞和中性粒细胞。这些天然免疫细胞表达模式识别受体(pattern-recognitionreceptors/molecule,PRR/PRM),受体识别高度保守的病原体相关分子模式(pathogen-associatedmolecularpatterns,PAMP)。PatternrecognitionDangeroussignal:-Exogenous:

PAMP(pathogenassociatedmolecularpattern)

-Endogenous:alarmins(Damageassociatedmolecularpattern,DAMP)PRR(patternrecognitionreceptor)Requirementsfortherecognitionoftargetsbytheinnateimmune

Molecularstructuresrecognizedbytheimmunesystemmustbesharedbylargegroupsofpathogens–molecularpatternsvs.particularstructures(antigens)•PAMPsmustbeconservedproductsofmicrobialmetabolismnotsubjecttoantigenicvariability•Therecognizedstructuresmustbeabsolutelydistinctfromselfantigens:discriminationofselfvs.non-selfCommonFeaturesofPAMPpathogen-associatedmolecularpatternsareproducedonlybymicrobialpathogens,andnotbytheirhosts.thestructuresrecognizedbytheinnateimmunesystemareusuallyessentialforthesurvivalorpathogenicityofmicroorganisms.pathogen-associatedmolecularpatternsareusuallyinvariantstructuressharedbyentireclassesofpathogens.PAMPsPAMPsthattriggerinnateimmuneresponsesinvariousvertebrateandnon-vertebrateorganismsincludelipopolysaccharides(LPS)fromGram-negativebacteria,bacterialflagellin,viralandbacterialnucleicacids,fungalcellwall-derivedglucans,chitins,mannansorproteinsandpeptidoglycans(PGN)fromGram-positivebacteria.StructureofaGram-PositiveCellWallStructureofaGram-NegativeCellWallpathogen-associatedmolecularpatterns(PAMP)Fungi: Cellwall

:mannan,glucansVirus: DoublestrandsRNA,Virion-CompositionParasite:modifiedsugar,parasitespecifiedprotein(GPIAnchorofcytoplasm)Bacterium:AlarminsTheyarerapidlyreleasedfollowingnon-programmedcelldeathbutarenotreleasedbyapoptoticcells.CellsoftheimmunesystemalsocanbeinducedtoproduceandreleasealarminswithoutdyinggenerallybyusingspecializedsecretionsystemsorbytheER-Golgisecretionpathway.Theyrecruitandactivatereceptor-expressingcellsoftheinnateimmunesystem,includingDCsandthusdirectlyorindirectlypromoteadaptiveimmunityresponse.Alarminsshouldrestorehomeostasisbypromotingthereconstructionofthetissuethatwasdestroyedeitherbecauseofthedirectinsultorthesecondaryeffectsofinflammation.PatternrecognitionDangeroussignal:-Exogenous:PAMP(pathogenassociatedmolecularpattern)-Endogenous:AlarminsPRR(patternrecognitionreceptor)Sensorsystems(PRR,PRM)•humoralcomponents:acutephaseproteins,complementendocyticPRRs:scavengerreceptors,lectinreceptorsopsonicphagocyticPRRs:FcRandCRSignalingPRR:-TLRs(Toll-likereceptors)-NLRs(NOD-likereceptors)-RLHs(RIG-likehelicases)吞噬细胞对病原体的识别和吞噬Hostreceptorsthatsensethemoleculesofpathogens(NLR)(RLH)1.分泌型PRR甘露聚糖结合凝集素（MBL）*属于肝脏合成的急性期反应蛋白*识别并结合G-/G+菌、酵母菌、某些病毒和寄生虫等表面的甘露糖*激活MBL补体途径，发挥调理、致炎作用。AcutePhaseProteins2.Endocyticpattern-recognitionreceptors

甘露糖受体：特异性识别微生物细胞壁糖蛋白和糖脂末端的甘露糖和岩藻糖残基，介导吞噬细胞吞噬。清道夫受体：识别并与细菌细胞壁某些组分(肽聚糖、磷壁酸）结合，有效地清除血循环中的细菌。内吞型PRREndocyticpattern-recognitionreceptors

Endocyticpattern-recognitionreceptorsarefoundonthesurfaceofphagocytes

andpromotetheattachmentofmicroorganismstophagocytesandtheirsubsequentengulfmentanddestruction.Theyinclude:mannosereceptors

Mannosereceptorsbindtoterminalmannoseandfucosegroupsonmicrobialglycoproteinsandglycolipids.(HumanglycoproteinsandglycolipidstypicallyhaveterminalN-acetylglucosamineandsialicacidgroups.)scavengerreceptorsScavengerreceptorsbindtobacterialcellwallcomponentssuchasLPS,peptidoglyanandteichoicacids.Therearealsoscavengerreceptorsforcertaincomponentsofothertypesofmicroorganisms3.调理性受体

(FcR和CR)C3b、C4b、iC3b与吞噬细胞表面CR1、CR3和CR4结合，促进吞噬。4.SignalingPRR针对细胞外病原体

-TLRs(Toll-likereceptors)针对细胞内病原体

-NLRs(NOD-likereceptors)-RLHs(RIG-likehelicases)Toll-likereceptors

(TLRs)

ridge-abdominalpatternofflyfoetusTOLL蛋白最早在果蝇中发现,是一种I型跨膜受体,可介导真菌和G+细菌对果蝇的感染免疫反应。LRRdomain:leucinerichrepeatsdomainTIRdomain:TOLL/IL-1RToll-likereceptors(TLRs)

•Meansofdetectinginvasionbymicroorganisms•Recognize–Specificpatternofmicrobialcomponentsconservedamongpathogens–Patternsnotfoundinmammals到目前为止,在哺乳动物细胞中已发现11种与TOLL蛋白同源的蛋白,命名为TOLL样受体(TLR)。LRRTIRG+bacterialrialipoteichoicacidPGTLR-LigandAP-1,NF-kB,IRF-3,IRF-7KinasesZytokine,KostimulatorischeMolekülesiRNAQuantitativemRNAExpressionofTLRs1-10inHumanPBMCSubsets

TLR1主要在单核细胞、中性粒细胞、B细胞、自然杀伤细胞(NK细胞)上表达;TLR2、TLR4和TLR5主要表达于除T、B、NK细胞以外的免疫细胞;TLR3主要表达于幼稚的树突状细胞(DC);TLR6-9广泛表达于多种细胞;TLR10主要表达于淋巴样组织中和脾脏细胞。CellularexpressionofTLRR&DsystemsReleaseofLPS(Endotoxin)fromtheGram-NegativeCellWallLPSPGNPeptidoglycan(PGN)isanessentialanduniquecomponentofthebacterialenvelopethatprovidesrigidityandstructuretothebacterialcell.AllbacteriacontainalayerofPGN,buttheamount,locationandspecificcompositionvary.PGNisperceivedinanimalsviavariouspatternrecognitionreceptors(PRRs),includingscavengerreceptors,nucleotide-bindingoligomerizationdomain-containingproteins(NODs),afamilyofpeptidoglycanrecognitionproteins(PGRPs),PGN-lyticenzymesandToll-likereceptorTLR2FlagellinFlagellinconsistsofaconserveddomainthatiswidespreadinbacterialspeciesandisdedicatedtofilamentpolymerization.MammalianhostsdetecttheconserveddomainonflagellinmonomersthroughToll-likereceptor(TLR)5,whichtriggersproinflammatoryandadaptiveimmuneresponsesCpG-DNADNAfrombacteriahasstimulatoryeffectsonmammalianimmunecells,whichdependonthepresenceofunmethylatedCpGdinucleotidesinthebacterialDNA.Incontrast,mammalianDNAhasalowfrequencyofCpGdinucleotides,andthesearemostlymethylated;therefore,mammalianDNAdoesnothaveimmuno-stimulatoryactivity.CpGDNAinducesastrongT-helper-1-likeinflammatoryresponse.CpGDNAisrecognizedbyToll-likereceptor9.Modifiednucleicacid

Double-strandedRNA(dsRNA)Double-strandedRNA(dsRNA)arisesinthecytoplasmduringviralreplication.Besidestheintracellularrecognition,releaseddsRNAfromdying,infectedcellscanfunctionasapathogen-associatedmolecularpattern(PAMP)fortheinnateimmunesystem.dsRNAisrecognizedbyTLR3.病原真菌

白色念珠菌表面的特征性糖磷脂甘露聚糖可被TLR2、TLR4识别,诱导促炎性细胞因子的释放,促进中性粒细胞的聚集。新型隐球菌的多糖荚膜成分葡糖醛氧化甘露聚糖GXM可与TLR2、TLR4、CD14结合,在单核细胞、巨噬细胞对GXM的内化、吞噬中起重要作用。酿酒酵母胞壁成分酵母多糖则可激活TLR2、TLR6异源二聚体。4.SignalingPRR针对细胞外病原体

-TLRs(Toll-likereceptors)针对细胞内病原体

-NLRs(NOD-likereceptors)-RLHs(RIG-likehelicases)Intracellularsensors

NOD-likereceptorsRIG-likehelicasesLRRNODs

NOD(nucleotide-bindingoligomerizationdomain)proteinsNOD1recognizespeptidoglycancontainingthemuramyldipeptideNAG-NAM-gamma-D-glutamyl-mesodiaminopimelicacid(mesodiaminopimelicacid,DAP),partofthepeptidoglycanmonomerincommongram-negativebacteriaandjustafewgram-positivebacteria.NOD2recognizespeptidoglycancontainingthemuramyldipeptideNAG-NAM-L-alanyl-isoglutamine(muramyldipeptide,MDP)foundinpracticallyallbacteria.Asmacrophagesphagocytoseeitherwholebacteriaorpeptidoglycanfragmentsreleasedduringbacterialgrowth,thepeptidoglycanisbrokendownintomuramyldipeptides.BindingofthemuramyldipetidestoNOD1orNOD2leadsto

theactivationofgenescodingforproinflammatorycytokinesinamannersimilartothecellsurfacetoll-likereceptors.EffectofPAMPrecognitionactivationofinnateeffectormechanisms

phagocytosis

antimicrobialpeptidesynthesis

inductionofNOinmacrophages

inductionofinflammatoryeffector

cytokinesandchemokines

inductionofco-stimulatorymolecules

onsurfaceofAPC(B7.1+B7.2)PatternrecignitionandInnateprotection

•OverviewPatternrecognition

NegativeregulationofpatternrecognitionSignificanceofpatterrecognitionPRRandhumandiseases

NegativeregulationofpatternrecognitionSolubleTLRs:sTLR2,sTLR4Intracellularnegativeregulators:MyD88sIRAKM,SOCS1,NOD2,PI3K,TOLLIPandA20Transmembraneproteinregulators:ST2,SIGIRRandTRAILRReductionofTLRexpression:-promotethedegradationofTLRs:TRIAD3A(TLR4andTLR9)-inhibitTLRexpression:IL-10,TGF-b-1(TLR4expression,↑MyD88degradation)RegulationofTLReffectbyapoptosis:TLRsfunctionasdeathreceptorsSolubleTLRsIntracellularTLRregulators↑TransmembraneTLRregulatorsST2L:interactswithMyD88andMAL.SIGIRR(singleimmunoglobulininterleukin-1-relatedreceptor)bindstoTLR4andIRAK.TRAILRsuppressesNF-κBactivation.Toll-likereceptorsinduceapoptoticandanti-apoptoticpathwaysPatternrecignitionandInnateprotection

•OverviewPatternrecognitionNegativeregulationofpatternrecognitionSignificanceofpatterrecognitionPRRandhumandiseases

Significanceofpatternrecognitioncleanuppathogensandmaintaintolerance.initiateinnateimmunityandinduceinflammationControladaptiveimmunity-triggeradaptiveimmunity-determinetypesofimmuneresponse-participateineffectorreponseofadaptiveimmunity

Distinctionofnon-selffromselfTherecognizedstructures(PAMP)mustbeabsolutelydistinctfromselfantigens:discriminationofselfvs.non-self.Alarminsareproducedandreleasedbyhostwhocanberecognizedandcleanedupbypatternrecognition.MaintaintoleranceinducePPARgexpressionInnateandadaptiveimmunityCytokines,ChemokinesandGrowthFactors

•ProductionmodulatedbyPRRengagement•Importantinrecruitmentofinnateeffectorcells•Maybeparacrineand/orend