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CellsandMoleculesinInnateImmunityBaoxueGeInstitutPasteurofShanghaiYOURACTIVEIMMUNEDEFENSESINDUCTIONOFANIMMUNERESPONSEForeigninvaders-viruses,bacteria,allergens,toxinsandparasites-constantlybombardourbody.InnateImmunity-invariant(generalized)-early,limitedspecificity-thefirstlineofdefenseAdaptiveImmunity-variable(custom)-later,highlyspecific-‘‘remembers’’infectionInnateImmunity•Innateimmunitypredatesdevelopmentofadaptiveimmunity•Doesnotproduceprotectiveimmunity–Nomemoryresponse–Prerequisitefordevelopingadaptiveimmunity•Non-antigen-specificimmunity–Foundinplants,invertebratesandvertebratesInnateImmunity•Universalandevolutionarilyconservedmechanismofhostdefenseagainstinfection;firstlineofdefense;–Foundinallmulticellularorganisms(adaptiveonlyinvertebrates)–Usesreceptorsandeffectorsthatareancientintheirlineage–Providesprotectionagainstawidevarietyofpathogens•Distinguishesselffromnon-selfperfectly•DefectsininnateimmunityareveryrareandalmostalwayslethalInnateImmunity•Providessignalstoactivateandregulatethetypeofadaptiveimmuneresponsegenerated–Stimulationofco-stimulatorymolecules•B7family(CD80/86,PD-L,ICOSL)•TNFRfamily(OX40L)–Inductionofacytokine/chemokineresponse•Cytokines:IL-12,IL-23,IL-4•Chemokines:CXCR1,CXCR2,CCL20»avarietyanddependsonstimulusComponentsPrincipleFunctionsCirculatingandTissueEffectorCellsNeutrophilsEarlyphagocytosisandkillingofmicrobesMastCellsReleaseofinflammatorygranulesMacrophagesEfficientphagocytosisandkillingofmicrobes:cytokinesEosinophilsNastytoxiccellsdesignedtokillhelminths(worms)Naturalkiller(NK)cellsLysisofinfectedcells,activationofmacrophagesCirculatingProteinsComplement(C’)Killingofmicrobes,opsonizationofmicrobes,actvnleukocytesMannose-bindingproteinOpsonizationofmicrobesandactivationofC’C-reactiveproteinOpsonizationofmicrobesandactivationofC’LysozymeBacterialcellwalllysisCytokinesTNF,IL-1,6,18InflammationIFNa,bResistencetoviralinfectionIFNgMacrophageactivationIL-12IFNgproductionbyNKcellsIL-15ProliferationofNKcells,memoryTcellsIL-10,TGFbControlofInflammationComponentsofInnateImmunityMastcells•arefoundintissuesliketheskin,nearbloodvessels.•areactivatedafterantigenbindstoaspecifictypeofantibodycalledIgEthatisattachedtoreceptorsonthemastcell.•activatedmastcellsreleasesubstancesthatcontributetoinflammation,suchashistamine.•mastcellsareimportantinallergicresponsesbutarealsopartoftheinnateimmuneresponse,helpingtoprotectfrominfection.Macrophages(MQ)•Blood-Calledmonocytes(1-6%WBC)•Tissues-Calledmacrophages–matureformofmonocytes–normallyfoundintissuessuchasgastrointestinaltract,lung,liverandspleen•Functions:–Phagocytoseandkillsafterbactericidalmechanismsareactivated(Tcells)–Producecytokines/chemokines(initiatesinflammation)–Isanantigenpresentingcell(co-stim.Molecules)Neutrophils(PMN)•Presentinblood(55-60%ofWBC)•Phagocytic,likemacrophages•Releasetoxicchemicalsthatdestroyeverythinginthearea,includingtheneutrophilsthemselvesPhagocytosis(MQ&PMN)•Activeprocessinitiatedbybindingtopathogen•PathogenissurroundedandtheninternalizedPhagocytosis•Phagocytosis–Definition:uptakeoflargeparticles(0.5mm)–Actin-dependent,clathrin-independent–Highrate&efficiencyofinternalization•Professionalphagocyticcells–Macrophages–Neutrophils•Thesecellshavephagocyticreceptors•Externalreceptors–FcR,CR3,Mannosereceptor•Internalreceptors–TLRsMacrophageingestingyeastThishumanmacrophage,liketheneutrophil,isaprofessionalphagocyteoreatingcell(phago=eating,cyte=cell).Here,itenvelopscellsofayeast,Candidaalbicans.Afteringestion,thewhitecellmustkilltheorganismsbysomemeans,suchastheoxidativeburst.CELLSalive!KillingMechanisms•Phagosome-membraneboundedvesiclethatbecomesacidified•Lysozome-granulesthatcontainproductsthatdamageorkillpathogens–Enzymes•Lysozyme-dissolvescellwallsofsomebacteria•Acidhydrolases-digestsbacteria–Proteins•Lactoferrin-bindsFe++neededforbacterialgrowth–Peptides•Defensinsandcationicproteins-directantimicrobialsSignalingInteractionsduringPhagocytosisIdentificationofMicrobes•PRR–Recognizeconservedmolecularpatternsonmicrobescalledpathogen-associatedmolecularpatterns(PAMPs)–(PAMPs)whicharenotpresentonthehost•Notlimitedtopathogens–Identifyaclassofmicrobes•LPS,LTA,peptidoglycan,lipoarabinomannan,dsRNA,mannans,b-glycans–PAMPsareoftenessentialformicrobesurvival•ActionTime–Immediateactivationofeffectors–DelaysneedforadaptiveimmunityPatternRecognitionReceptors(PRRs)•ThreebroadclassesofPRRsbasedonexpressionprofile,localization,function–1)PRRsthatsignalaninfection•IncludetheTollReceptorFamily•Expressedexternalorinternally•Activationof“pro-inflammatory”signalingpathways–NFkBandMAPkinasesignalingpathways»Antimicrobialpeptides(Defensins)/lysozyme,»Inflammatorycytokines(TNFa,IL-8,IL-1)•Regulateactivationofadaptiveimmuneresponse»co-stimulatorymolecules–2)Phagocytic(endocytic)PRRs•Expressedonthesurfaceofphagocyticcells–(MQs,PMNs,DCs)•Mediateuptakeofmicrobeintophagocytes–3)SecretedPRRs•SecretedbyMQs,epithelialcells,liver•ActivateC’,opsonizemicrobialcells,functionasaccessoryproteinsforMAMPrecognitionPatternRecognitionReceptors(PRRs)TLR4TL