固有免疫和適應(yīng)免疫

固有免疫和適應(yīng)免疫第1頁/共38頁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頁/共38頁Bigbugshavelittlebugs

Upontheirbackstobite‘em

Littlebugshavelittlerbugs

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

animalphylogeny第5頁/共38頁BiologicalInvention

ofAcquiredImmunity第6頁/共38頁Innatevs.AdaptiveImmunityFigure1.5Memory第7頁/共38頁InnateImmunityAllanimalshavean“innate”immunesystemInnateimmunityismanifestinmanycellsofthebody.Thebasisistherecognitionofmolecularpatterns,thatoccurinmicrobesbutnotanimals(e.g.,unmethylatedDNAsequences,dsRNA,cellwallcomponents,etc)Thisisthebedrockofimmunityinallorganisms--evenbacteriahavedefensemechanismsagainstbacterialviruses第8頁/共38頁InnateImmunity,con’tAnapparentlimitationisthatparasiticagentshaveagenerationtimeordersofmagnitudelessthanthatoftheirhostsAsecondlimitationisthatthereisonlylimitedamplificationoftheresponseAthirdlimitationisthatthereisnomemory第9頁/共38頁AdaptiveImmunityRecognizesanybiochemicaldeterminantProvidesamechanismforimmunerecognitionthatcanevolveasrapidlyastheparasite(clonalselection)ThereisrapidamplificationofaresponseThereismemory第10頁/共38頁Toagivenorganism,otherspeciescanrepresentasourceofenergyandnutrition:FoodChain-Largeanimalseatsmalleranimals(simplified)InverseFoodChain:Colonization-Smallanimals(ormicrobesandviruses)colonizelargeranimalsthat,inturn,provideanenvironmentforreplicationAlllivingorganismshaveaformofimmunitytodefendagainstcolonization:frombacteriatobluewhalestogiantsequoia,thereareamyriadofmechanismsthathaveevolvedtopreventcolonization第11頁/共38頁Innatevs.AcquiredImmunityTheinnateimmunesystemofaspeciesdetectsmolecularpatternsfoundinother(parasitic)organisms,butnotinthespeciesitself.Detectionsetsuparesponsethatcankilltheparasite.Thelimitationoftheinnateimmunesystemisthatparasiticmicrobeshaveamuchshortergenerationtimethanhigheranimals,andthereforevariantscanarisetocircumventtherecognitionorresponse.Theacquiredimmunesystemlearnsthemolecular“self”andanythingelseispotentiallyatargetforresponse.Theabilitytorespondtonewmoleculardeterminantsisonatime-scalesimilartothegenerationtimeofmicrobes.第12頁/共38頁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頁/共38頁Defensins(epithelium)Figure8.6第14頁/共38頁Figure1.4第15頁/共38頁Figure8.9第16頁/共38頁Figure8.1第17頁/共38頁SalmonellainfectionwithandwithoutadaptiveimmunityMicedeficientforinnateimmunity(macrophage)WTTlymphocytedeficient第18頁/共38頁Whatisthebasisforinnateimmunity,andhowdoesisrelatetovertebrates?Drosophilamelanogastermutantswerefoundthatweresusceptibletofungalandbacterialinfections.

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

6

(9),

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