医学免疫学英文版课件：Innate immunity

InnateimmunityIMMUNOLOGYObjectives

ofthisclassistounderstand:InnateimmuneresponseInnateimmunesystemThebarrierCellsintheinnateimmunesystemReceptorsintheinnateimmunesystemTherelationshipbetweentheinnateandadaptiveimmunesystemsObjectives

ofthisclassistounderstand:InnateimmuneresponseInnateimmunesystemThebarrierCellsintheinnateimmunesystemReceptorsintheinnateimmunesystemTherelationshipbetweentheinnateandadaptiveimmunesystemsImmuneResponse

Innateimmuneresponse

naturalimmuneresponse

non-specificimmuneresponse

Adaptiveimmune

response

acquiredimmuneresponse

specificimmuneresponseInnateimmunityItreferstoanyinbornimmunitythatisalreadypresentthefirsttimeapathogenisencountered.Innateimmunityistheinitialresponsetomicrobesthatprevents,controls,oreliminatesinfectionofthehostbymanymicrobes.TheprincipalmechanismsofinnateandadaptiveimmunityInnateImmunity

FirstLineofDefenseCharacteristics:rapiddoesnotgenerateimmunologicmemorydependentupongermlineencodedreceptorsrecognizingstructurescommontomanypathogensCharacteristicsofInnateandAdaptiveImmunityAntigenindependentpatternrecognitionNotimelagNotantigenspecificNomemoryAntigendependentTCR/BCRAlagperiodAntigenspecificMemoryInnateImmunityAdaptiveImmunityFunctionsInnateimmunityistheinitialresponsetomicrobesthatprevents,controls,oreliminatesinfectionofthehostbymanymicrobes.Innateimmunemechanismsrecognizetheproductsofdamagedanddeadhostcellsandservetoeliminatethesecellsandtoinitiatetheprocessoftissuerepair.Innateimmunitytomicrobesstimulatesadaptiveimmuneresponsesandcaninfluencethenatureoftheadaptiveresponsestomakethemoptimallyeffectiveagainstdifferenttypesofmicrobes.9Objectives

ofthisclassistounderstand:InnateimmuneresponseInnateimmunesystemThebarrierCellsintheinnateimmunesystemReceptorsintheinnateimmunesystemTherelationshipbetweentheinnateandadaptiveimmunesystemsInnateImmuneSystem1.Physical,chemical，microbialbarriersphysicalbarriersincludeskinandmucusmembranes(epithelial)chemicalbarriersincludestomachacidity,secretedanti-microbialpeptides,defensins(防御素),cathelicidins(抗菌肽)Normalbacterialflora2.Cellsmacrophages,neutrophils,DC,NK,B1,T,NKT…3.solubleproteinsComplementandmediatorsofinflammation4.Cytokines1112BarrierSkin-mucosalbarrierPhysicalbarrierChemicalbarrierBiologicalbarrierTheinsidebarriersBloodbrainbarrierBloodplacentalbarrierEpithelialdefensemechanisms1415表皮EpidermisofskinGutepithelium17板层小体：防水脂质层防御素和抗菌肽Whathappenswhenthephysicalandchemicalbarriersarebreached?18Objectives

ofthisclassistounderstand:InnateimmuneresponseInnateimmunesystemThebarrierCellsintheinnateimmunesystemReceptorsintheinnateimmunesystemTherelationshipbetweentheinnateandadaptiveimmunesystemsCellsininnateandadaptiveimmunesystemsGlennDranoffNatureReviewsCancer4,11-22(January2004)phagocytesInnate-likelymphocytes（ILLs）Unique,minorsubsetsofTandBlymphocytesthatundergoreceptorgenerearrangementstogeneratereceptordiversity(unlikeNKcells)Thesesubsetsexpresslimitedreceptordiversity,utilizingonlyasmallnumberofreceptorgenesegments-Tendtofoundinspecificlocationsinthebody,usuallysitesthatencounterexogenousantigensorpathogens21NKTcellDistributionbonemarrow,liver,thymus,spleen,peripheralblood,lymphnodeNKT＜1%inbloodTcells；

most

NKTinliver(mouse30%，human4%）NKTcellFunction:anti-infection,anti-tumor1.cytokine:IL-4,IFN-,IL-12

2.cytotoxityperforinandFasL/Fas3.MCP-1(单核细胞趋化蛋白),MIP-1(人巨噬细胞炎性蛋白)Surfacemarker：TCR、CD4-CD8-、CD8+distribution：skin、mucosaofintestine、lungandgenitalsrestriction：non-classicalMHCⅠmoleculerestrictionclassification：epidermisTcellsystemicTcellγδT细胞TcellFunction:Anti-infectionAnti-tumorImmuneregulationImmunetoleranceB1cellCD5+,mIgM+B1cellmainlylocatedinabdomencavity,thoraxandintestinesB1cellrecognizeLPSandcapsularpolysaccharideIgMantibodyNoclassswitchandimmunememoryThemajorleukocytesofinnateimmunityAntigenpresentation:aneventtoconnectinnateandadaptiveimmunityDCsaretheonlycelltypethatcanprimenaïveTcells.Th1Th2TregTh17InnateimmuneresponseInnateimmunesystemregulatesadaptiveimmunesystem.PAMP:pathogenassociatedmolecularpatternPRR:patternrecognitionreceptorPRRPAMPCytokinesadaptiveimmuneresponseDCDCsandMacrophagesengulfbacteriaandproduceinflammatorycytokinesTwotypesofphagocytes

(1)Neutrophilgranulocytesphagocytosis,intracellularkilling,inflammationandtissuedamagecharacteristicnucleus,cytoplasmgranulesandCD67membranemarker.(2)Monocytesandmacrophagesphagocytosis,intracellularandextra-cellularkilling,tissuerepair,antigenpresentationforspecificimmuneresponsecharacteristicnucleusandCD14membranemarker.monocyte/macrophagemacrophageFunction:Phagocytosisandcytotoxicactivityoxygen-dependent:ROS,NOoxygen-independent(2)inflammation:MCP-1,MIP-1α/β,IL-8,IL-1(3)Antigenprocessingandpresentation(4)Immuneregulationmonocyte/macrophagecDCmyeloidDC,conventionalDCpDC(plasmacytoidDC)highlevelofTLR7,9typeIinterferon(IFNα/β)Dendriticcells,DCNKcellsNKcellsweredefinedinitiallybytheirabilitytolysecertaintumorcelllinesandviralinfectedcellswithoutpriorimmunization,andsomediateaformofinnate(ornatural)immunitythatistermed“naturalkilling”.Surfacemarkers1.CD562.CD16(FcγRⅢ)ADCC3.FcRHumanNKcellsaregenerallyTCR-,mIg-,CD16+,CD56+.MouseNK:TCR-,mIg-,NK1.1+,Ly49+41ActivationofNKcellsistheneteffectofinhibitoryandactivatingsignalsNKreceptors42Thereceptorsassociatedwithactivationorinhibition1.ThereceptorsrecognizingMHCⅠmolecules(1)Killerimmunoglobulin-likereceptor,KIRKIR2DLITIMinhibitoryreceptorKIR3DLITIMinhibitoryreceptorKIR2DSbindingwithDAP-12(ITAM)activatingreceptorKIR3DSbindingwithDAP-12(ITAM)activatingreceptorIntracellularsignalingpathwayscoordinateinhibitoryandactivatingsignals(2)Killerlectin-likereceptor,KLR

CD94NKG2AITIMinhibitoryreceptorCD94NKG2CbindingwithDAP-12(ITAM)activatingreceptorWhilebothKIRsandKLRssensethepresence(absence)ofMHCclassImolecules,activatingaswellasinhibitoryreceptorsarefoundinbothfamiliesofreceptors.TheKIRsaresubdividedaccordingtothenumberofimmunoglobulin-likedomains(2or3domains)andthelengthoftheircytoplasmictail:Shorttail=activatingreceptorsLongtail=inhibitoryreceptorsTheKLRareheterodimersofCD94associatedwithaNKG2molecule.SixdistinctNKG2isoformsexistinhumans.NKG2C/CD94=activatingreceptorNKG2A/CD94=inhibitoryreceptorNKG2B/CD94=inhibitoryreceptorNKG2Dhomodimer=activatingreceptor.NKreceptors:‘Defenseisthebestoffense”46(3)ThesignificanceofKIRandKLRNKcellsarepreventedfromkillinghostcellsbecausetheyrecognizethehostclassⅠMHCmolecules.Thus,theyonlyattackcellswhoseclassⅠMHCmoleculesarelostoraltered,asoccursfrequentlyinmalignancyorviralinfection.2.Thereceptorsrecognizingnon-MHCⅠmolecules

(1)NKG2DbindingwithDAP-10(ITAM)activatingreceptorligand:MⅠCA/B(onsometumorcells)(2)naturalcytotoxicityreceptor,NCRNKp46,NKp30bindingwithCD3(

)NKp44expressedonactivatedNKcellsbindingwithDAP-12(ITAM)activatingreceptor49FunctionsofNKcells1.Anti-infection

provideanearlyinnatebarriertoinfectionbyeliminatinginfectedhostcells2.Anti-tumor

killtumorcellsdirectly:perforin,granzymes,ADCC3.ImmunoregulationActivatedNKcellsproducecytokinessuchasIFN-,TNF-,G-CSF.ThesecytokinescanactivateTcells.Functions51ReleaseofcytotoxicgranulesatthesiteofcontactwithinfectedcellsFirstcontactbetweenaCTLorNKcellwithinfectedcellsisvianon-specificbindingofadhesionmolecules(LFA-1(blue)onTandNKcellswithICAM-1orICAM-2(brown)ontargetcells).Thismakesachannelbetweenthetargetandthecytotoxiccell.Specificantigen/MHCclassIrecognitionbyTCRonCTL,orengagementoftheNK’snaturalcytotoxicreceptors(NCR)(green)bynon-MHCligands(orange)onthesurfaceofthetargetcell.Thisresultsinapolarizationofthecell:theactincytoskeleton(greenstainingintheimmunofluorescencemicroscopy)atthesiteofcontactisreorganizedastoaligningthemicrotubule-organizingcenter(MTOC),aswellasthesecretoryapparatus,includingtheGolgi(GA).TheGA-derivedlyticgranules(stainedinredinthephotomicrograph)arespecificallydirectedontothetargetcell.Thecontentofthegranulesisdirectlyreleasedontothetargetcell.TargetcellNKcellWhyareNKcellsprominenttumorkillers?-Theregressionoftransplantedtumorsinanormalmousemodel(blueline)islargelyduetotheactionofCTLsrecognizingtumorantigenspresentedonMHCclassI(rightpanel).AlbeitthepresenceofNKcells,thisregressionisabsentinnudemice(redline)inwhichCTLsdonotdevelop.TumorvariantsthatexpresslowlevelsofMHCclassIbecomesusceptibletoNKcells,especiallyinnudemice(havehigherlevelsofNKcellsthanwildtypemice).ThustumorsthataresensitivetoNKkillinggrowlesswellinnudethannormalmice(centralpanel).-TransfectionofMHCclassIgenesresultinginhighexpressionofthisproteinrestoresNKcellresistancebutsusceptibilitytoCTLinnormalmice(leftpanel;blueline).Similartomanypathogens,tumorcellscanescapetheadaptiveimmunesystem,bydownregulatingtheexpressionofMHCclassI.ThismakesthemmoresusceptibletoNKcells.Objectives

ofthisclassistounderstand:InnateimmuneresponseInnateimmunesystemThebarrierCellsintheinnateimmunesystemReceptorsintheinnateimmunesystemTherelationshipbetweentheinnateandadaptiveimmunesystemsInnateImmuneReceptorsInnateimmunereceptorsarenotclonallydistributedBindingofreceptorsresultsinrapidresponseInnateimmunereceptorsmediatethreefunctions:-phagocyticreceptorstostimulatepathogenuptake-chemotacticreceptorsthatguidephagocytestositeofinfection-stimulateproductionofeffectormoleculesandcytokinesthatinduceinnateresponsesandalsoinfluencedownstreamadaptiveimmuneresponses55MostmicroorganismsexpressrepeatingpatternsofmolecularstructurestermedPathogenAssociatedMolecularPatterns(PAMPs)EndogenousmoleculesthatareproducedbyorreleasedfromdamagedanddyingcellsarecalledDamage-AssociatedMolecularPatterns(DAMPs)InnateimmunesystemhasevolvedmechanismscapableofrecognizingtheserepeatingpatternstermedPatternRecognitionReceptors(PRRs)PathogenRecognition5657TheDangerModel:ARenewed

SenseofSelfPollyMatzingerPAMPsDAMPs60StructureofbacteriapilinforadhesionflagellumformotionshapeandrigidityDNA61EngagementofinnateimmunityRecognitionoforganismsbasedonconservedpatternsLipopolysaccharide(gm-)Peptidoglycan(mostbacteria)Flagella(manybacteria)UnmethylatedCpGinDNASingle-strandedRNA(viral)6263Sharedfeaturesofbacteria:cellwallspeptidoglycanteichoicacidproteinslipopolysaccharideproteinspeptidoglycanIMOM胞壁酸Peptidoglycan

肽聚糖peptidoglycanteichoicacidproteins64N-乙酰氨基葡糖和N-乙酰胞壁酸交替的杂多糖65Lipopolysaccharide脂多糖peptidoglycanlipidA类脂质A脂多糖层磷脂层脂蛋白层/周质层肽聚糖层66Flagellin鞭毛钩状体丝状体BacterialDNABacteriaFrequentCGsequencesCytosinenotmethylatedMammalsRareCGsequencesCytosineinCGismethylated67Virusesanddouble-strandedRNASomeviruseshavedsRNAgenomes(rare)Manymoreviruseshavesingle-strandedRNAgenomesbutproducedsRNAduringreplicationandmRNAsynthesis68ExamplesofPatternRecognitionReceptors(PRRs): -Mannose-BindingLectin(MBL) -MacrophageMannoseReceptor -ScavengerReceptors -Toll-likeReceptors(TLRs) -RIG-IlikeReceptors(RLRs) -Nod-likeReceptors(NLRs)PathogenRecognition6970Toll-likereceptorssinglestrandedRNATLR8咪唑喹啉Toll-LikeReceptors(TLRs)CellularLocalization:Lysosomallocalization(i.e.subcellular)ofTLR-3andTLR7,8,9TLR-3and7,8,9recognizeviral/bacterialnucleicacidslysosomalexpressionisolatespathogennucleicacidrecognitionawayfrompotentialcross-reactionwithhostmammaliannucleicacidmotifsTNFaIFNab7172RLRs：RetinoicAcid-InducibleGene-I-likeReceptorsRIG-I,RetinoicAcid-InducibleGene-1MDA5,MelanomaDifferentiation-AssociatedGene5CARD-containing;melanomagrowth-suppressivepropertiesLGP2,LaboratoryofGeneticsandPhysiology2DExH/D-boxmotifandacarboxy-terminalhelicasedomainRD73RIG-ILikeReceptors(RLRs)747576Nod-likereceptors(NLRs)Nucleotide-bindingandoligomerizationdomain(NOD)-likereceptorsCytoplasmicproteinsAtleast22membersRecognizemicrobialcomponentsWorksynergisticallywithTLRMDP：胞壁酰二肽iE-DAP：γ谷氨酰基二氨基庚二酸

NOD-ILikeReceptors(NLRs)NLRsarecytoplasmicbacterialsensors14NLRPsactivateIL-1β

InflammasomeIPAF/NLRC4NLRP3NLRP178inflammasomesTheNLRPsubfamilyofNLRsrespondtocytoplasmic