中科院细胞与分子免疫学课程课件Chapter11

SectionIVEffectorMechanismsofImmuneResponsesChapter11CytokinesNomenclature:1.Basedontheircellularsources:Monocyte--Monokine;Lymphocyte--Lymphokine;2.Becausemanycytokinesaremadebyleukocytesandactonotherleukocytes,theyarealsocalledinterleukines.3.Inthisbook,weusetermcytokine,whichdoesnotimplyrestrictedcellularsourcesorbiologicactivities.Nomenclature:GeneralPropertiesofCytokines:1.Cytokinesecretionisabrief,self-limitedevent.1)Cytokinesarenotusuallystoredasperformedmolecules.2)Whencellwasactivated,thesynthesisofcytokinesisinitiated.2Cytokinescanactinthreedifferentmanners•Autocrine–Cytokinebindstoreceptoroncellthatsecretedit.2.ParacrineCytokinebindstoreceptorsonnearbycells3.EndocrineCytokinebindscellsindistantpartsofthebody3CytokineActions•Pleiotropy–Actonmorethanonecelltype•Redundancy–Morethanonecytokinecandothesamething(IL-2,IL-4,IL-5)•Synergy–Twoormorecytokinescooperatetoproduceaneffectthatisdifferentorgreaterthanthecombinedeffectofthetwocytokineswhenfunctioningseparately(IFN-gandTNF)•Antagonism–Twoormorecytokinesworkagainsteachother(IL-10andIFN-g)4.CytokinesmakefunctionsinbindingtoreceptorKd:10-10---10-125.Externalsignalsregulatetheexpressionofcytokinereceptor.6.Cytokinescanchangethegeneexpressionintargetcells.FunctionalClassificationofCytokine1.Mediatorsandregulatorsofinnateimmunity:Secretedbymononuclearphagocytes,thesemembersofcytokinescanstimulatetheearlyinflammations.2.Mediatorsandregulatorsofadaptiveimmunity.SecretedbyTlymphocytes,someofthemregulatetheproliferationanddifferentiationoflymphocytes.Recruit,activate,regulatespecializedeffectorcells.3.Stimulatorsofhematopoiesis.Areproducedbyboneborrowstromalcells,stimulatethegrowthanddifferentiationofimmatureleukocytes.Table11-1.ComparativeFeaturesoftheCytokinesofInnateandAdaptiveImmunityFeaturesInnateimmunityAdaptiveimmunityExamplesTNF-α,IL-1,IL-12,IFN-γ*IL-2,IL-4,IL-5,IFN-γ*MajorcellsourceMacrophages,NKcellsTlymphocytesPrincipalphysiologicfunctionsMediatorsofinnateimmunityandinflammation(localandsystemic)Adaptiveimmunity:regulationoflymphocytegrowthanddifferentiation;activationofeffectorcells(macrophages,eosinophils,mastcells)StimuliLPS(endotoxin),bacterialpeptidoglycans,viralRNA,Tcell-derivedcytokines(IFN-γ)ProteinantigensAmountsproducedLocalorsystemiceffectsMaybehigh;detectableinserumBothGenerallylow;usuallyundetectableinserumUsuallylocalonlyRolesindiseaseSystemicdiseases(e.g.,septicshock)Localtissueinjury(e.g.,granulomatousinflammation)InhibitorsofsynthesisCorticosteroidsCyclosporine,FK-506CytokineReceptorsCytokineReceptor:consistofoneormoretransmembraneproteins,theclassificationofcytokinereceptorsisbasedonstructural.Cytokinereceptorsaredividedintofivefamilies:1)ClassIcytokinereceptorfamily(hemopoietinreceptors)–Bindsmostofthecytokinesintheimmuneandhematopoietinsystems2)ClassIIcytokinereceptorfamily3)Immunoglobulinsuperfamilyreceptors4)TNFreceptorfamily5)ChemokinereceptorfamilyFivefamiliesofCytokineReceptorStructure1.Type1cytokinereceptors1)TwoConservedpairsofcysteineresidues2)MembraneproximalWSXWSsequence3)Uniqueligandbindingandothersforsignal-transducingchains.Amongtype1cytokinereceptor,threesubtypefamilyexit:2.TypeIIcytokinereceptors1)Withconservedcysteins2)WithoutWSXWSmotif3.Igsuperfamilyfamily.4.TNFrecptorsWithconservedcysteine-richextracellulardomains.5.Seven-transmembranea–helicalreceptors1)Alsocalledserpentinereceptors2)Mediaterapidandtransientresponsestoafamilyofcytokines.CytokinesinImmunityCytokinesthatmediateandregulateinnateimmunityCytokineSizePrincipalcellsourcePrincipalcelltargetsandbiologiceffectsTumornecrosisfactor(TNF)17kD;51-kDhomotrimerMacrophages,TcellsEndothelialcells:activation(inflammation,coagulation)Neutrophils:activationHypothalamus:feverLiver:synthesisofacute-phaseproteinsMuscle,fat:catabolism(cachexia)（恶病质）Manycelltypes:apoptosisInterleukin-1(IL-1)17kDmatureform;33-kDprecursorsMacrophages,endothelialcells,someepithelialcellsEndothelialcells:activation(inflammation,coagulation)Hypothalamus:feverLiver:synthesisofacute-phaseproteinsChemokines(seeTable11-4)8-12kDMacrophages,endothelialcells,Tcells,fibroblasts,plateletsLeukocytes:chemotaxis,activation;migrationintotissuesInterleukin-12(IL-12)Heterodimerof35-kD+40-kDsubunitsMacrophages,dendriticcellsTcells:TH1differentiationNKcellsandTcells:IFN-γsynthesis,increasedcytolyticactivityTypeIIFNs(IFN-α,IFN-β)IFN-α:15-21kDIFN-β:20-25kDIFN-α:macrophagesIFN-β:fibroblastsAllcells:antiviralstate,increasedclassIMHCexpressionNKcells:activationInterleukin-10(IL-10)Homodimerof34-40kD;18-kDsubunitsMacrophages,Tcells(mainlyTH2)Macrophages,dendriticcells:inhibitionofIL-12productionandexpressionofcostimulatorsandclassIIMHCmoleculesInterleukin-6(IL-6)19-26kDMacrophages,endothelialcells,TcellsLiver:synthesisofacute-phaseproteinsBcells:proliferationofantibody-producingcellsInterleukin-15(IL-15)13kDMacrophages,othersNKcells:proliferationTcells:proliferation(memoryCD8+cells)Interleukin-18(IL-18)17kDMacrophagesNKcellsandTcells:IFN-γsynthesis一．TumorNecrosisFactor(TNF):1.Definition:TNF-a,asubstanc