固有免疫和适应免疫

固有免疫和适应免疫第1页/共38页HowdoestheImmuneSystem(IS)affectyourlife?InfectiousDiseases:Almostanydeficiencyinimmunity--youdieAutoimmunediseases:Graves'/hyperthyroidism,TypeIdiabetes,perniciousanemia,rheumatoidarthritis,thyroiditis,andvitiligoTheincidenceof24autoimmunediseasesis1/31Americans.Womenareat2.7xgreaterrisk

ClinImmunolImmunopathol1997Sep;84(3):223-43Cancer:EvidenceinthepastyearindicatesthattheimmunesystemdoesindeedfunctionintumorsurveillanceHypersensitivityDiseases:Allergy-Incidencerisefrom6%-20%inthepasttwodecadesAsthma-Incidencerisefrom3%-8%ofthetotalpopulationinthepasttwodecades-Thehygienehypothesis-HeartDisease-Thebloodvascularsystemisanintegralpartoftheimmunesystem.Itinstructsleukocytestomigratefromthebloodtoasiteofinfection.Newevidencesupportsthatideathatcoronaryheartdiseaseresultsfromchronicarterialinflammation第2页/共38页Bigbugshavelittlebugs

Upontheirbackstobite‘em

Littlebugshavelittlerbugs

Andsoonadinfinitum-OgdenNash,IthinkColonizationoflargeorganismsbysmallerorganismsorvirusesisthe“inversefoodchain”LargecomplexorganismspresentasourceofenergyandahabitatforsmallerorganismsandvirusesviacolonizationColonizationanddefenseagainstcolonizationisafundamentalprincipleinbiologyTheimmunesystemisprincipallyandmostimportantlyevolvedtosculptcolonizationtobenefitthehostImmuneEvolution第3页/共38页DanceoftheEonsVirtuallyeveryorganismfacespressurefromviralormicrobialcolonizationandsohasevolvedstrategiestocontrolcolonizationLikewise,everyparasiticorganismorpieceofselfishDNAhasevolvedastrategytomitigatetheeffectsofimmunityThiseternalwaltzofparasitesandtheirhostssurelybeganwiththeoriginoflifeCorollariesJustaspredatorspeciesimprovethefitnessoftheirprey,colonialagentsselectforfitnessintheirhostsJustasahostcannotbetoopermissiveforaparasiticagent,theparasiticagentcannotbetooeffectiveinkillingahostThemoreeffectivetheimmunesystem,themorecomplicatedandevolvedtheparasitePerhapsweshouldviewthehost-parasiteinteractionasaconstantlyescalatingwaroranuneasy(metastable)truce第4页/共38页Oneviewof

animalphylogeny第5页/共38页BiologicalInvention

ofAcquiredImmunity第6页/共38页Innatevs.AdaptiveImmunityFigure1.5Memory第7页/共38页InnateImmunityAllanimalshavean“innate”immunesystemInnateimmunityismanifestinmanycellsofthebody.Thebasisistherecognitionofmolecularpatterns,thatoccurinmicrobesbutnotanimals(e.g.,unmethylatedDNAsequences,dsRNA,cellwallcomponents,etc)Thisisthebedrockofimmunityinallorganisms--evenbacteriahavedefensemechanismsagainstbacterialviruses第8页/共38页InnateImmunity,con’tAnapparentlimitationisthatparasiticagentshaveagenerationtimeordersofmagnitudelessthanthatoftheirhostsAsecondlimitationisthatthereisonlylimitedamplificationoftheresponseAthirdlimitationisthatthereisnomemory第9页/共38页AdaptiveImmunityRecognizesanybiochemicaldeterminantProvidesamechanismforimmunerecognitionthatcanevolveasrapidlyastheparasite(clonalselection)ThereisrapidamplificationofaresponseThereismemory第10页/共38页Toagivenorganism,otherspeciescanrepresentasourceofenergyandnutrition:FoodChain-Largeanimalseatsmalleranimals(simplified)InverseFoodChain:Colonization-Smallanimals(ormicrobesandviruses)colonizelargeranimalsthat,inturn,provideanenvironmentforreplicationAlllivingorganismshaveaformofimmunitytodefendagainstcolonization:frombacteriatobluewhalestogiantsequoia,thereareamyriadofmechanismsthathaveevolvedtopreventcolonization第11页/共38页Innatevs.AcquiredImmunityTheinnateimmunesystemofaspeciesdetectsmolecularpatternsfoundinother(parasitic)organisms,butnotinthespeciesitself.Detectionsetsuparesponsethatcankilltheparasite.Thelimitationoftheinnateimmunesystemisthatparasiticmicrobeshaveamuchshortergenerationtimethanhigheranimals,andthereforevariantscanarisetocircumventtherecognitionorresponse.Theacquiredimmunesystemlearnsthemolecular“self”andanythingelseispotentiallyatargetforresponse.Theabilitytorespondtonewmoleculardeterminantsisonatime-scalesimilartothegenerationtimeofmicrobes.第12页/共38页Components PrincipleFunctionsBarriersEpitheliallayers PrevententryDefensinsandCryptidins MicrobialkillingCirculatingandTissueEffectorCellsNeutrophils EarlyphagocytosisandkillingofmicrobesMastCells ReleaseofinflammatorygranulesMacrophages Efficientphagocytosisandkillingofmicrobes:cytokinesEosinophils Nastytoxiccellsdesignedtokillhelminths(worms)NKcells Lysisofinfectedcells,activationofmacrophagesCirculatingProteinsComplement(C’) Killingofmicrobes,opsonizationofmicrobes,actvnleukocytesMannose-bindingprotein OpsonizationofmicrobesandactivationofC’C-reactiveprotein OpsonizationofmicrobesandactivationofC’Lysozyme BacterialcellwalllysisCytokines

TNF,IL-1,6,18 InflammationIFNa,b ResistencetoviralinfectionIFNg MacrophageactivationIL-12 IFNgproductionbyNKcellsIL-15 ProliferationofNKcells,memoryTcellsIL-10,TGFb ControlofInflammationAdaptedfrom:Abbas(Saunders)ComponentsofInnateImmunity第13页/共38页Defensins(epithelium)Figure8.6第14页/共38页Figure1.4第15页/共38页Figure8.9第16页/共38页Figure8.1第17页/共38页SalmonellainfectionwithandwithoutadaptiveimmunityMicedeficientforinnateimmunity(macrophage)WTTlymphocytedeficient第18页/共38页Whatisthebasisforinnateimmunity,andhowdoesisrelatetovertebrates?Drosophilamelanogastermutantswerefoundthatweresusceptibletofungalandbacterialinfections.

ImmunityinDrosophila(Innate)Tollmutantlacksdefenseagainstfungalinfections18WheelerlacksdefenseagainstbacteriaThisledtothediscoveryofafamilyofreceptorsknownastheToll-relatedreceptors(TLR)presentinvertebrates第19页/共38页InnateImmunityPatternRecognitionMolecularPatternofMicrobeSourcePatternRecognitionReceptorPrincipleInnateImmuneResponsedsRNAReplicatingvirusesds-RNAactivatedkinase&TLR3IFNa,bLPSGram-negativebacteriaLBP/CD14/TLR4MacrophageactivationN-formylmethionylpeptidesBacterialproteinsNFMreceptorsNeutrophilandmacrophageact.Mannose-richglycansMicrobialglycoproteinsMFmannoserecptrPlasmamannoselectinPhagocytosisOpsonization,C’activationPhosphorylcholineandrelatedMicrobialmembranesPlasmac-reactiveproteinOpsonization,C’activationCpG(PuPuCpGPyPy)Bacteria?TLR9/DNAPKMacrophageactivationOther:teichoicacid,第20页/共38页GenestoCells

6

(9),

733-742KiyoshiTakedaandShizuoAkira(2001)Activationofthetranscriptionfactor:NFkB第21页/共38页Tollfamilyofreceptors第22页/共38页Toll-likereceptors[TLR1-10]Recognitionaloneorincombinationsof:LPS(gram-negativecellwallcomponent)Lipopeptidesandpeptidoglycan(grampositivecellwallcomponentsYeastparticlesTIRDomainActivationofNFkBtranscriptionfactorandthusinductionofcytokinesandothergenesthatareanti-microbial第23页/共38页Interfacebetweentheinnateandadaptiveimmunesystems第24页/共38页UnifiedImmunityConceptInnateImmunitymolecularpatternrecognitioninflammation(alarmanddanger)mobilizationofmanyimmunecomponentsincludingpresentationofforeignagentstothelymphoidsystemAdaptiveImmunityclonalrecognitionofforeignagentsbyTandBcellsfollowedbyselectiveexpansion(productionofantibodies,cytokines,andchemokines)+mechanismsexclusivetoadaptiveimmunity第25页/共38页ProgressionofImmunityAtleasttwocelltypesresidewithinorbeneaththeepitheliumandinduceinflammationinresponsetotraumaormicrobialproducts:MacrophagesandMastCellsFigure8.5第26页/共38页Alveolarmacrophages(lung)Histiocytes(connectivetissue)Kupffercells(liver)Mesangialcells(kidney)Microglialcells(brain)TissuemacrophageFigure1.6ij第27页/共38页ReceptorsonMacrophages:LPSreceptor-CD14Toll-likereceptorsFcreceptorsMannosereceptorComplementreceptorsIFNgreceptorChemokinereceptorsFigure1.13第28页/共38页Functionindisease,notentirelyunderstoodContainshighaffinityreceptorsforIgE,andpreformedgranulesthatcontaininflammatorymediatorsincluding:histamine;heparin;TNFa;chondroitinsulfate;neutralproteases;andother.Mastcellscanalsosecrete:cytokinestoinduceinflammation;chemokinestoinduceinfiltrationbymonocytes,andneutrophils,leukotriencestoinducemusclecontractionandincreasevascularpermeabilityMastcellsarecapableofinducinganinflammatorycascadeFigure1.6gh第29页/共38页MastcellsarealsofoundinthetissuesMastcellscanreleasehistamineswhichinduceinflammationRedness,swelling(erythema,edema)NeutrophilsandmonocytesarerecruitedFigure1.14TNF第30页/共38页HighaffinityFceRIreceptor.Effectiveagainstworminfections.Granulescontainmediators-smoothmusclecontractionandwormtoxicityExpresssomeofthesamereceptorsfoundonmacrophagesFigure1.6ef第31页/共38页LPSreceptor: CD14 toll-likereceptor-4CR3,4: Complement(C’)receptors(