固有免疫和適應(yīng)免疫

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

Upontheirbackstobite‘em

Littlebugshavelittlerbugs

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

animalphylogeny第5頁(yè)/共38頁(yè)BiologicalInvention

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

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

6

(9),

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