Endocytosis, Phagocytosis, and Innate Immune Responses: A Dissertation
Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate...
Transcript of Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate...
Synopsis:InthislecturewewillreviewthedifferentmechanismswhichconsBtutetheinnateimmuneresponse,andexaminethemajorcellsinvolved
Outcomes:Youshouldbeabletodescribethemajorcomponentsofinnateimmunity,thecellsthatareinvolved,andtheanBgenrecogniBonpathways
Threephasesofimmuneresponse
Innatephase:immediateimmuneresponsesEarlyinducedinnateresponses:aswithinnatephase,reliesonrecogniBonofpathogenbygermline-encodedreceptorsoftheinnateimmunesystemAdap7veimmunityoccurslatebecausetheTcellsandBcellsspecificfortheinvadingpathogenmustfirstundergoclonalexpansionbeforetheydifferenBateintoclonalcellswhichmigratetositeofinfecBon
Manybarrierspreventpathogensfromcrossingepitheliaandcolonizing7ssues
Surfaceepitheliaprovidemechanical,chemical,andmicrobiologicalbarrierstoinfecBon
Mucosalepithelia
• Internalepitheliaareknownasmucosalepitheliabecausetheysecreteaviscousfluidcalledmucous(whichcontainsglycoproteinscalledmucins)MucoushasmanyprotecBvefuncBons:
• Microorganismscoatedinmucousmaybepreventedfromadheringtoepithelium,orexpelledinoutwardflowofmucousdrivenbybeaBngofcilia
A=erentering7ssues,manypathogensarerecognized,ingested,andkilledbyphagocytes
Infec7onandan7genrecogni7ontriggersaninflammatoryresponse
• MacrophagesencounteringbacteriaorothertypesofmicroorganismsinBssuearetriggeredtoreleasecytokinesthatincreasethepermeabilityofbloodvessels,allowingfluidandproteinstopassintoBssues
• Alsosecretechemokines,whichdirectthemigraBonofneutrophilstothesiteofinfecBon
• Neutrophilsandmacrophagesaretheprincipalinflammatorycells
Tissuemacrophagesarederivedfrombloodmonocytes
NeutrophilsmakeupthefirstwaveofcellstocrossthebloodvesselwalltoenteraninflamedBssue
PhagocytosisMacrophagesexpressreceptorsthatenablethemtotakeupmicrobesbyphagocytosisPhagosomesfusewithlysosomes,forminganacidifiedphagolysosomeinwhichtheingestedmaterialisbrokendownbylysosomalhydrolases
OpsonizaBonbyanBbodyorcomplementenhancesphagocytosis
Receptorbindingresultsinsynthesisofimmunemediatorsviaac7va7onoftranscrip7onfactors
TLRsacBvatetranscripBonfactorstoinduceexpressionofmoleculeswhichmediateimmuneresponsesOnesuchtranscripBonfactorisnuclearfactorkappabeta(NFκB)NFκBactsprimarilytoinduceexpressionofpre-inflammatorycytokinesandchemotacBcfactors
ComplementSystem• PathogenswhichbreachhostepithelialbarriersandiniBalanimicrobialdefensesthenencounterComplement• Threedifferentpathways:Classical,LecBn,andAlternaBve• EachgeneratesaC3convertase,whichcleavestheplasmaproteinC3toform2subunits,C3aandC3b• C3bisanopsinizingmolecule–coatsmicrobestoenhancephagocytosis• SequenBalcleavageofcomplementproteinsbyproteasesproducesinflammatorymediators(eg.C3a)whichforexamplerecruitphagocytes• EndpointofcomplementcascadeisformaBonofmembraneaEackcomplexwhichlysesbacteria
Complementfunc7ons
Toll-likereceptorsrecognizearrayofmicrobes
EachoftheTLRswhosespecificityisknownrecognizesoneormoremolecularpa]erns,generallybydirectinteracBonwithmoleculesonpathogensurface(PAMPs)
FliesdeficientinTollreceptoraresuscepBbletofungalinfecBon
AcBvaBonofTLRsandNLRstriggerschangesingeneexpressioninmacrophagesanddendriBccellsthatdirectlyaffecttheimmuneresponse
TLRareexpressedoninternalandexternalcellsurfaces
• SomeTLRsarelocatedoncellsurfaceofdendriBccells,macrophages,andothercells,wheretheycandetectextracellularPAMPs
• TLRsactasdimers–heterodimersareindicatedhere,restarehomodimers
• TLRslocatedintracellularlyinendosomewallscanrecognizegenomicmaterial–DNAandRNA
• ThediacylandtriacyllipopepBdesrecognizedbytheheterodimersTLR-2:TLR2andTLR-1:TLR2,respecBvely,arederivedfromlipoteichoicacidofGram+vebacterialcellwallsandthelipoproteinsofGram–vebacterialcellsurfaces
TLRsac7vatethetranscrip7onfactorsNFκΒ,AP-1,andIRFtoinducetheexpressionofinflammatorycytokinesandtype1interferons
TheNODreceptorsactasintracellularsensorsofbacterialinfec7on
• SomeintracellularreceptorscandetectPAMPsinthecytoplasm• TheseproteinscontainanuceloBde-bindingoligomerizaBondomain(NOD)
• NODproteinsrecognizefragmentsofbacterialcellwallpepBdoglycans• ExpressedincellsrouBnelyexposedtobacteriaeg.epithelialcells;alsoinmacrophagesanddendriBccellsthatingestbacteriawhichhaveenteredbody• NODgeneloss-of-funcBonmutaBonsareassociatedwithCrohn’sdiseaseinhumans
TLRsac7vateinnateimmuneresponsetoviruses
• TLR-3,TLR-7andTLR-9locatedonendosomalmembranessensegenomicmaterialandhencecandetectviralandbacterialRNAandDNA
• viralssRNAinthecytoplasmcanbesensedbyRIG-1(reBnoicacidinduciblegene-1),widelyexpressedacrossmanyBssueandcelltypes• viraldsRNAinthecytoplasmmaybesensedbyMDA-5(melanomadifferenBaBon-associated5)• SensingbyRIG-1,MDA-5,andTLRsinducesproducBonofInterferon-αandInterferon-βviatheIRF(interferonregulatoryfactor)transcripBonfactors
InterferonsinhibitvirusreplicaBonandacBvatenaturalkiller(NK)cells
TNF-αisanimportantcytokinethattriggerslocalcontainmentofinfecBonbutinducesshockwhenreleasedsystemicallyTNF-αisproducedbymacrophagesacBvatedbypathogeninBssues
Naturalkillercells
• ArisefromlymphoidprogenitorbutarenotTcells–donotexpressTcellreceptor,thereforearenotMHC-restricted• Killviral-infectedcellsusingsamemoleculesasCD8+Tcells• Recognizetargets(virus-infectedcells)usingdifferentmechanisms:lackofMHContargetcellsurfacetriggerskilling
InnatevsAdap7veimmunity