innate immunity - uwa€¦ · innate phase: immediate immune responses early induced innate...

InnateImmunity

DrAllisonImrieallison.imrie@uwa.edu.au

MICR2209

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