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Innate Immunity Dr Allison Imrie [email protected] MICR2209

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Page 1: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

InnateImmunity

[email protected]

MICR2209

Page 2: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Synopsis:InthislecturewewillreviewthedifferentmechanismswhichconsBtutetheinnateimmuneresponse,andexaminethemajorcellsinvolved

Outcomes:Youshouldbeabletodescribethemajorcomponentsofinnateimmunity,thecellsthatareinvolved,andtheanBgenrecogniBonpathways

Page 3: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors
Page 4: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Threephasesofimmuneresponse

Innatephase:immediateimmuneresponsesEarlyinducedinnateresponses:aswithinnatephase,reliesonrecogniBonofpathogenbygermline-encodedreceptorsoftheinnateimmunesystemAdap7veimmunityoccurslatebecausetheTcellsandBcellsspecificfortheinvadingpathogenmustfirstundergoclonalexpansionbeforetheydifferenBateintoclonalcellswhichmigratetositeofinfecBon

Page 5: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Manybarrierspreventpathogensfromcrossingepitheliaandcolonizing7ssues

Surfaceepitheliaprovidemechanical,chemical,andmicrobiologicalbarrierstoinfecBon

Page 6: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Mucosalepithelia

• Internalepitheliaareknownasmucosalepitheliabecausetheysecreteaviscousfluidcalledmucous(whichcontainsglycoproteinscalledmucins)MucoushasmanyprotecBvefuncBons:

• Microorganismscoatedinmucousmaybepreventedfromadheringtoepithelium,orexpelledinoutwardflowofmucousdrivenbybeaBngofcilia

Page 7: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

A=erentering7ssues,manypathogensarerecognized,ingested,andkilledbyphagocytes

Infec7onandan7genrecogni7ontriggersaninflammatoryresponse

• MacrophagesencounteringbacteriaorothertypesofmicroorganismsinBssuearetriggeredtoreleasecytokinesthatincreasethepermeabilityofbloodvessels,allowingfluidandproteinstopassintoBssues

• Alsosecretechemokines,whichdirectthemigraBonofneutrophilstothesiteofinfecBon

• Neutrophilsandmacrophagesaretheprincipalinflammatorycells

Page 8: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Tissuemacrophagesarederivedfrombloodmonocytes

Page 9: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

NeutrophilsmakeupthefirstwaveofcellstocrossthebloodvesselwalltoenteraninflamedBssue

Page 10: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

PhagocytosisMacrophagesexpressreceptorsthatenablethemtotakeupmicrobesbyphagocytosisPhagosomesfusewithlysosomes,forminganacidifiedphagolysosomeinwhichtheingestedmaterialisbrokendownbylysosomalhydrolases

OpsonizaBonbyanBbodyorcomplementenhancesphagocytosis

Page 11: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Receptorbindingresultsinsynthesisofimmunemediatorsviaac7va7onoftranscrip7onfactors

TLRsacBvatetranscripBonfactorstoinduceexpressionofmoleculeswhichmediateimmuneresponsesOnesuchtranscripBonfactorisnuclearfactorkappabeta(NFκB)NFκBactsprimarilytoinduceexpressionofpre-inflammatorycytokinesandchemotacBcfactors

Page 12: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

ComplementSystem• PathogenswhichbreachhostepithelialbarriersandiniBalanimicrobialdefensesthenencounterComplement• Threedifferentpathways:Classical,LecBn,andAlternaBve• EachgeneratesaC3convertase,whichcleavestheplasmaproteinC3toform2subunits,C3aandC3b• C3bisanopsinizingmolecule–coatsmicrobestoenhancephagocytosis• SequenBalcleavageofcomplementproteinsbyproteasesproducesinflammatorymediators(eg.C3a)whichforexamplerecruitphagocytes• EndpointofcomplementcascadeisformaBonofmembraneaEackcomplexwhichlysesbacteria

Page 13: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Complementfunc7ons

Page 14: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Toll-likereceptorsrecognizearrayofmicrobes

EachoftheTLRswhosespecificityisknownrecognizesoneormoremolecularpa]erns,generallybydirectinteracBonwithmoleculesonpathogensurface(PAMPs)

FliesdeficientinTollreceptoraresuscepBbletofungalinfecBon

Page 15: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

AcBvaBonofTLRsandNLRstriggerschangesingeneexpressioninmacrophagesanddendriBccellsthatdirectlyaffecttheimmuneresponse

Page 16: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

TLRareexpressedoninternalandexternalcellsurfaces

• SomeTLRsarelocatedoncellsurfaceofdendriBccells,macrophages,andothercells,wheretheycandetectextracellularPAMPs

• TLRsactasdimers–heterodimersareindicatedhere,restarehomodimers

• TLRslocatedintracellularlyinendosomewallscanrecognizegenomicmaterial–DNAandRNA

• ThediacylandtriacyllipopepBdesrecognizedbytheheterodimersTLR-2:TLR2andTLR-1:TLR2,respecBvely,arederivedfromlipoteichoicacidofGram+vebacterialcellwallsandthelipoproteinsofGram–vebacterialcellsurfaces

Page 17: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

TLRsac7vatethetranscrip7onfactorsNFκΒ,AP-1,andIRFtoinducetheexpressionofinflammatorycytokinesandtype1interferons

Page 18: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

TheNODreceptorsactasintracellularsensorsofbacterialinfec7on

• SomeintracellularreceptorscandetectPAMPsinthecytoplasm• TheseproteinscontainanuceloBde-bindingoligomerizaBondomain(NOD)

• NODproteinsrecognizefragmentsofbacterialcellwallpepBdoglycans• ExpressedincellsrouBnelyexposedtobacteriaeg.epithelialcells;alsoinmacrophagesanddendriBccellsthatingestbacteriawhichhaveenteredbody• NODgeneloss-of-funcBonmutaBonsareassociatedwithCrohn’sdiseaseinhumans

Page 19: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

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

Page 20: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

TNF-αisanimportantcytokinethattriggerslocalcontainmentofinfecBonbutinducesshockwhenreleasedsystemicallyTNF-αisproducedbymacrophagesacBvatedbypathogeninBssues

Page 21: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

Naturalkillercells

• ArisefromlymphoidprogenitorbutarenotTcells–donotexpressTcellreceptor,thereforearenotMHC-restricted• Killviral-infectedcellsusingsamemoleculesasCD8+Tcells• Recognizetargets(virus-infectedcells)usingdifferentmechanisms:lackofMHContargetcellsurfacetriggerskilling

Page 22: Innate Immunity - UWA€¦ · Innate phase: immediate immune responses Early induced innate responses: as with innate phase, relies on recogniBon of pathogen by germline-encoded receptors

InnatevsAdap7veimmunity


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