免疫學(xué)課件-1-PPT幻燈片

PatternrecignitionandInnateprotection

?OverviewPatternrecognitionNegativeregulationofpatternrecognitionSignificanceofpatterrecognitionPRRandhumandiseases

DangeroussignalInnateImmunity:A(Very)BroadOverview

PatternrecignitionandInnateprotection

?OverviewPatternrecognitionNegativeregulationofpatternrecognitionSignificanceofpatterrecognitionPRRandhumandiseases

StrategyofHost?Microbesareheterogeneousandcanmutate

FOCUS----Onhighlyconserved structurespresentinlargegroupsofmicroorganisms.

PAMPS----Pathogen-associated

molecularpatternsPatternrecognition

機(jī)體接觸致病微生物后即迅速進(jìn)行識(shí)別并產(chǎn)生抵抗病原體入侵的反應(yīng)。發(fā)揮這一功能主要是巨噬細(xì)胞、樹突狀細(xì)胞和中性粒細(xì)胞。這些天然免疫細(xì)胞表達(dá)模式識(shí)別受體(pattern-recognitionreceptors/molecule,PRR/PRM),受體識(shí)別高度保守的病原體相關(guān)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)吞噬細(xì)胞對(duì)病原體的識(shí)別和吞噬Hostreceptorsthatsensethemoleculesofpathogens(NLR)(RLH)1.分泌型PRR甘露聚糖結(jié)合凝集素（MBL）*屬于肝臟合成的急性期反應(yīng)蛋白*識(shí)別并結(jié)合G-/G+菌、酵母菌、某些病毒和寄生蟲等表面的甘露糖*激活MBL補(bǔ)體途徑，發(fā)揮調(diào)理、致炎作用。AcutePhaseProteins2.Endocyticpattern-recognitionreceptors

甘露糖受體：特異性識(shí)別微生物細(xì)胞壁糖蛋白和糖脂末端的甘露糖和巖藻糖殘基，介導(dǎo)吞噬細(xì)胞吞噬。清道夫受體：識(shí)別并與細(xì)菌細(xì)胞壁某些組分(肽聚糖、磷壁酸）結(jié)合，有效地清除血循環(huán)中的細(xì)菌。內(nèi)吞型PRREndocyticpattern-recognitionreceptors

Endocyticpattern-recognitionreceptorsarefoundonthesurfaceofphagocytes

andpromotetheattachmentofmicroorganismstophagocytesandtheirsubsequentengulfmentanddestruction.Theyinclude:mannosereceptors

Mannosereceptorsbindtoterminalmannoseandfucosegroupsonmicrobialglycoproteinsandglycolipids.(HumanglycoproteinsandglycolipidstypicallyhaveterminalN-acetylglucosamineandsialicacidgroups.)scavengerreceptorsScavengerreceptorsbindtobacterialcellwallcomponentssuchasLPS,peptidoglyanandteichoicacids.Therearealsoscavengerreceptorsforcertaincomponentsofothertypesofmicroorganisms3.調(diào)理性受體

(FcR和CR)C3b、C4b、iC3b與吞噬細(xì)胞表面CR1、CR3和CR4結(jié)合，促進(jìn)吞噬。4.SignalingPRR針對(duì)細(xì)胞外病原體

-TLRs(Toll-likereceptors)針對(duì)細(xì)胞內(nèi)病原體

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

(TLRs)

ridge-abdominalpatternofflyfoetusTOLL蛋白最早在果蠅中發(fā)現(xiàn),是一種I型跨膜受體,可介導(dǎo)真菌和G+細(xì)菌對(duì)果蠅的感染免疫反應(yīng)。LRRdomain:leucinerichrepeatsdomainTIRdomain:TOLL/IL-1RToll-likereceptors(TLRs)

?Meansofdetectinginvasionbymicroorganisms?Recognize–Specificpatternofmicrobialcomponentsconservedamongpathogens–Patternsnotfoundinmammals到目前為止,在哺乳動(dòng)物細(xì)胞中已發(fā)現(xiàn)11種與TOLL蛋白同源的蛋白,命名為TOLL樣受體(TLR)。LRRTIRG+bacterialrialipoteichoicacidPGTLR-LigandAP-1,NF-kB,IRF-3,IRF-7KinasesZytokine,KostimulatorischeMolekülesiRNAQuantitativemRNAExpressionofTLRs1-10inHumanPBMCSubsets

TLR1主要在單核細(xì)胞、中性粒細(xì)胞、B細(xì)胞、自然殺傷細(xì)胞(NK細(xì)胞)上表達(dá);TLR2、TLR4和TLR5主要表達(dá)于除T、B、NK細(xì)胞以外的免疫細(xì)胞;TLR3主要表達(dá)于幼稚的樹突狀細(xì)胞(DC);TLR6-9廣泛表達(dá)于多種細(xì)胞;TLR10主要表達(dá)于淋巴樣組織中和脾臟細(xì)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識(shí)別,誘導(dǎo)促炎性細(xì)胞因子的釋放,促進(jìn)中性粒細(xì)胞的聚集。新型隱球菌的多糖莢膜成分葡糖醛氧化甘露聚糖GXM可與TLR2、TLR4、CD14結(jié)合,在單核細(xì)胞、巨噬細(xì)胞對(duì)GXM的內(nèi)化、吞噬中起重要作用。釀酒酵母胞壁成分酵母多糖則可激活TLR2、TLR6異源二聚體。4.SignalingPRR針對(duì)細(xì)胞外病原體

-TLRs(Toll-likereceptors)針對(duì)細(xì)胞內(nèi)病原體

-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