固有免疫和適應(yīng)免疫

固有免疫和適應(yīng)免疫TheTriumphofDeath-PieterBruegheltheElderca.1562Whytheimmunesystem?Whatisitsfunction?Howwidelyisitpresentinnature?Whydoesitaffectsomanyaspectsoflife?Howcanwealteritforimprovedqualityoflife?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.NewevidencesupportsthatideathatcoronaryheartdiseaseresultsfromchronicarterialinflammationBigbugshavelittlebugs

Upontheirbackstobite‘em

Littlebugshavelittlerbugs

Andsoonadinfinitum-OgdenNash,IthinkColonizationoflargeorganismsbysmallerorganismsorvirusesisthe“inversefoodchain”LargecomplexorganismspresentasourceofenergyandahabitatforsmallerorganismsandvirusesviacolonizationColonizationanddefenseagainstcolonizationisafundamentalprincipleinbiologyTheimmunesystemisprincipallyandmostimportantlyevolvedtosculptcolonizationtobenefitthehostImmuneEvolutionDanceoftheEonsVirtuallyeveryorganismfacespressurefromviralormicrobialcolonizationandsohasevolvedstrategiestocontrolcolonizationLikewise,everyparasiticorganismorpieceofselfishDNAhasevolvedastrategytomitigatetheeffectsofimmunityThiseternalwaltzofparasitesandtheirhostssurelybeganwiththeoriginoflifeCorollariesJustaspredatorspeciesimprovethefitnessoftheirprey,colonialagentsselectforfitnessintheirhostsJustasahostcannotbetoopermissiveforaparasiticagent,theparasiticagentcannotbetooeffectiveinkillingahostThemoreeffectivetheimmunesystem,themorecomplicatedandevolvedtheparasitePerhapsweshouldviewthehost-parasiteinteractionasaconstantlyescalatingwaroranuneasy(metastable)truceOneviewof

animalphylogenyBiologicalInvention

ofAcquiredImmunityInnatevs.AdaptiveImmunityMemoryInnateImmunityAllanimalshavean“innate”immunesystemInnateimmunityismanifestinmanycellsofthebody.Thebasisistherecognitionofmolecularpatterns,thatoccurinmicrobesbutnotanimals(e.g.,unmethylatedDNAsequences,dsRNA,cellwallcomponents,etc)Thisisthebedrockofimmunityinallorganisms--evenbacteriahavedefensemechanismsagainstbacterialvirusesInnateImmunity,con’tAnapparentlimitationisthatparasiticagentshaveagenerationtimeordersofmagnitudelessthanthatoftheirhostsAsecondlimitationisthatthereisonlylimitedamplificationoftheresponseAthirdlimitationisthatthereisnomemoryAdaptiveImmunityRecognizesanybiochemicaldeterminantProvidesamechanismforimmunerecognitionthatcanevolveasrapidlyastheparasite(clonalselection)ThereisrapidamplificationofaresponseThereismemoryToagivenorganism,otherspeciescanrepresentasourceofenergyandnutrition:FoodChain-Largeanimalseatsmalleranimals(simplified)InverseFoodChain:Colonization-Smallanimals(ormicrobesandviruses)colonizelargeranimalsthat,inturn,provideanenvironmentforreplicationAlllivingorganismshaveaformofimmunitytodefendagainstcolonization:frombacteriatobluewhalestogiantsequoia,thereareamyriadofmechanismsthathaveevolvedtopreventcolonizationInnatevs.AcquiredImmunityTheinnateimmunesystemofaspeciesdetectsmolecularpatternsfoundinother(parasitic)organisms,butnotinthespeciesitself.Detectionsetsuparesponsethatcankilltheparasite.Thelimitationoftheinnateimmunesystemisthatparasiticmicrobeshaveamuchshortergenerationtimethanhigheranimals,andthereforevariantscanarisetocircumventtherecognitionorresponse.Theacquiredimmunesystemlearnsthemolecular“self”andanythingelseispotentiallyatargetforresponse.Theabilitytorespondtonewmoleculardeterminantsisonatime-scalesimilartothegenerationtimeofmicrobes.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)ComponentsofInnateImmunityDefensins(epithelium)SalmonellainfectionwithandwithoutadaptiveimmunityMicedeficientforinnateimmunity(macrophage)WTTlymphocytedeficientWhatisthebasisforinnateimmunity,andhowdoesisrelatetovertebrates?Drosophilamelanogastermutantswerefoundthatweresusceptibletofungalandbacterialinfections.

ImmunityinDrosophila(Innate)Tollmutantlacksdefenseagainstfungalinfections18WheelerlacksdefenseagainstbacteriaThisledtothediscoveryofafamilyofreceptorsknownastheToll-relatedreceptors(TLR)presentinvertebratesInnateImmunityPatternRecognitionMolecularPatternofMicrobeSourcePatternRecognitionReceptorPrincipleInnateImmuneResponsedsRNAReplicatingvirusesds-RNAactivatedkinase&TLR3IFNa,bLPSGram-negativebacteriaLBP/CD14/TLR4MacrophageactivationN-formylmethionylpeptidesBacterialproteinsNFMreceptorsNeutrophilandmacrophageact.Mannose-richglycansMicrobialglycoproteinsMFmannoserecptrPlasmamannoselectinPhagocytosisOpsonization,C’activationPhosphorylcholineandrelatedMicrobialmembranesPlasmac-reactiveproteinOpsonization,C’activationCpG(PuPuCpGPyPy)Bacteria?TLR9/DNAPKMacrophageactivationOther:teichoicacid,GenestoCells

6

(9),

733-742KiyoshiTakedaandShizuoAkira(2001)Activationofthetranscriptionfactor:NFkBTollfamilyofreceptorsToll-likereceptors[TLR1-10]Recognitionaloneorincombinationsof:LPS(gram-negativecellwallcomponent)Lipopeptidesandpeptidoglycan(grampositivecellwallcomponentsYeastparticlesTIRDomainActivationofNFkBtranscriptionfactorandthusinductionofcytokinesandothergenesthatareanti-microbialInterfacebetweentheinnateandadaptiveimmunesystemsUnifiedImmunityConceptInnateImmunitymolecularpatternrecognitioninflammation(alarmanddanger)mobilizationofmanyimmunecomponentsincludingpresentationofforeignagentstothelymphoidsystemAdaptiveImmunityclonalrecognitionofforeignagentsbyTandBcellsfollowedbyselectiveexpansion(productionofantibodies,cytokines,andchemokines)+mechanismsexclusivetoadaptiveimmunityProgressionofImmunityAtleasttwocelltypesresidewithinorbeneaththeepitheliumandinduceinflammationinresponsetotraumaormicrobialproducts:MacrophagesandMastCellsAlveolarmacrophages(lung)Histiocytes(connectivetissue)Kupffercells(liver)Mesangialcells(kidney)Microglialcells(brain)TissuemacrophageReceptorsonMacrophages:LPSreceptor-CD14Toll-likereceptorsFcreceptorsMannosereceptorComplementreceptorsIFNgreceptorChemokinereceptorsFunctionindisease,notentirelyunderstoodContainshighaffinityreceptorsforIgE,andpreformedgranulesthatcontaininflammatorymediatorsincluding:histamine;heparin;TNFa;chondroitinsulfate;neutralproteases;andother.Mastcellscanalsosecrete:cytokinestoinduceinflammation;chemokinestoinduceinfiltrationbymonocytes,andneutrophils,leukotriencestoinducemusclecontractionandincreasevascularpermeabilityMastcellsarecapableofinducinganinflammatorycascadeMastcellsarealsofoundinthetissuesMastcellscanreleasehistamineswhichinduceinflammationRedness,swelling(erythema,edema)NeutrophilsandmonocytesarerecruitedTNFHighaffinityFceRIreceptor.Effectiveagainstworminfections.Granulescontainmediators-smoothmusclecontractionandwormtoxicityExpresssomeofthesamereceptorsfoundonmacrophagesLPSreceptor: CD14 toll-likereceptor-4CR3,4: Complement(C’)receptors(C3b)Scavengerreceptor: sialicacid-b