Cells and Tissues of the Immune Response...Cells and Tissues of the Immune Response Dr Allison Imrie...
Transcript of Cells and Tissues of the Immune Response...Cells and Tissues of the Immune Response Dr Allison Imrie...
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CellsandTissuesoftheImmuneResponse
DrAllisonImrie
MICR2209
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Synopsis:Inthislecturewewilldiscussthecellsand@ssuesoftheimmunesystemandtherolestheyplayininnateandadap@veimmuneresponses
Outcomes:Youshouldbeabletodescribethemajorcelltypesoftheimmunesystemandtheirlineage,andtheirbasicrolesininnateandadap@veimmunity
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Allthecellularcomponentsoftheimmunesystemderivefrompluripotenthematopoie5cstemcellsin
foetalliverandbonemarrow
• Pluripotentstemcellsgiverisetocellswithprogressivelymorelimitedpoten@al
• Firstdivision:myeloid/erythroidvslymphoidpoten@al
• Myeloidprogenitorgivesrisetoallnonlymphoidcells:monocytes(whichgiverisetodendri@ccellsandmacrophages)andgranulocytes(neutrophils,eosinophils,basophils)
• LymphocyteprogenitorgivesrisetoNKcells,Tcells,andBcells,andcertaindendri@ccells
Colony-s@mula@ngfactors(CSFs)andinterleukinsaffectdifferen@a@onandmatura@on
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Lymphocytes
• Lymphocytesaremostlysmallandinac@vecells
• Smallres@ngBandTlymphocyteshavenotyetencounteredan@gen;lookiden@cal
• S@mula@onbyan@geninducesthelymphocytetobecomeanac@velymphoblast• Lymphoblastsproliferateanddifferen@atetoeffectorTandBlymphocytes
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ClassesoflymphocytesAn5genrecogni5on Effectorfunc5on
Bcells
• Blymphocytesrecognizesolubleorcellsurfacean@gensanddifferen@ateintoan@body-producingcells,calledplasmacells• An@bodieseliminatean@gensby:
! Neutralizingtheabilityofmicrobestoinfecttargetcells! Labelingmicrobes(opsonizing)forphagocytosis! Ac@va@ngthecomplementpathway
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ClassesoflymphocytesAn5genrecogni5on Effectorfunc5on
HelperTcells(CD4+)
• HelperTlymphocytesrecognizean@genonthesurfaceofan@gen-presen@ngcells,andsecretecytokineswhichs@mulatedifferentmechanismsofimmunityandinflamma@on:
! Ac@va@onofmacrophages,toenhancephagocytosis! Ac@va@onofBcellstoproducean@bodies! Ac@va@onofCD8+killerTcells
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ClassesoflymphocytesAn5genrecogni5on Effectorfunc5on
CytotoxicTlymphocytes(CD8+)
• CytotoxicTlymphocytes(CTL)recognizean@genoninfectedcellsandkillthesecells.Thisisamajormechanismforcontrollingintracellularpathogens• Naturalkiller(NK)cellsrecognizeinfectedcells,usingdifferentmechanismsthanCTL,andkillthem
NaturalKillercells
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Macrophagesarephagocyteswhicheradicatemicrobesandalsoactasan5genpresen5ngcells
MHCClassIImoleculepresentspep@deoncellsurfaceforsurveillancebyCD4+Tcells
Macrophagesprocessingestedan@gentopep@des
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1oand2oLymphoidTissue
PrimarylymphoidorgansareorgansinwhichBandTcellsmature.Whilstmaturingtheylearnhowtodifferen@atebetweenhostcells(towhichtheydonotrespond)andforeignpathogens.Secondarylymphoidorgansareinvolvedinthepresenta@onofforeignan@genstoTandBcellstoac@vatetheadap@veimmunesystem.
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Lympha5cSystemThelympha@csystemisadrainageandfiltra@onsystemthatenablesinters@@alfluidandplasmaproteinstoflowbackintoblood.Itisalsoasystemforlymphocytecircula@onandan@[email protected]@lageandepidermis.Systemstartsaslymphcapillaries(closedend)[email protected]@onduetopressurefrommuscleac@onandonewayvalves.Lymphfromallpartsofbodyentersbloodstreamviasubclavianveinsandthoracicduct.Lymphisaclearliquidcontainingproteinsandlymphocytesandan@genpresen@ngcells(APC)
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BoneMarrow• BothTandBlymphocytesoriginateinbonemarrow.• Bcellsdevelopfromlymphoidstemcellsinfoetalliver
hematopoie@c@ssueat8-9weeks• Produc@onmovestobonemarrowwhereitcon@nuesthroughadult
life• BonemarrowissiteofBcelldevelopmentinmammals.• PrecursorTcellsmigratetothymusformatura@on• Followingan@genics@mula@oninlymphnodegerminalcentres,
matureBcellscandevelopintomemorycellsoran@genformingcells(AFC)
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Summary:Bcellsdevelopinbonemarrowandmigratetoperipherallymphoidorgans,wheretheycanbeac5vatedby
an5gen
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Thymus
• Mul@potentTcellprogenitorsformedinfoetalliverandbonemarrowenterthymusviahighendothelialvenules(HEV)andmigratetowardscortex
• Tcellprogenitorsundergoprolifera@onanddifferen@a@onincortex
• MatureTcellsleavethymusviaHEVandentercircula@on
Arrows:transloca@nglymphocytesArrowheads:highendothelialcellsofHEV
Arrowheads:highendothelialcellsofHEV;transloca@nglymphoytesareshown
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Themammalianthymusinvoluteswithage
• Inhumansatrophybeginsatpubertyandcon@nuesthroughoutlife
• Involu@onbeginswithinthecortex,whichmaydisappearcompletely
• Cor@calatrophyisverysensi@vetocor@costeroids;promotedbypregnancyandstress
• LikelythatTcellgenera@onwithinthymusdoescon@nueintoadultlife,atamuchlowerrate
Involu@onofthethymuswithreplacementbyadipose@ssue
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Summary:Tcellsdevelopinbonemarrowandmatureinthymus.Theymigratetoperipherallymphoidorgans,wheretheycanbeac5vatedbyan5gen�
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Onleavingbonemarrowandthymus,lymphocytesmigratetosecondarylymphoidorgansand@ssuesinspleen,lymphnodes,andmucosa-associatedlymphoid@ssue(MALT),wheretheyencounteran@genpresentedbyAPC
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Naïvelymphocytes(thosewhichhaveneverencounteredan@gen)encountertheirspecifican@gen,andareac@vated,intheperipherallymphoidorgans
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MucosalAssociatedLympha5cTissueSamplesan@genfromepithelialsurfaces
MALTshowninblue
Lymphoid@ssuesarefoundassingleoraggregatednodules
MALTincludesgut-associatedlymphoid@ssue(GALT)andbronchus-associatedlymphoid@ssue(BALT)
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Peyer’sPatchesarelymphoidnodulesfoundthroughoutsmallintes5ne(ileum)
PathogensinthegutaresampledinPPbyMcells
Primedlymphocytesmigratetomesentericlymphnodesthentoeffectorsites
Mcellstranscytosean@gentomucosallymphoid@ssueundertheepithelium
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Lymphocytesencounter,andareac5vatedby,an5gensbroughttolymphnodes(vialympha5cs)byan5genpresen5ngcells
Naïvelymphocytes(whichhavenotyetencounteredan5gen)entertheLNviathecircula5on
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Lymphnodes
TcellsandBcellsareseparatedintoseparateanatomicalcompartments:BcellsareconcentratedinfolliclesintheLNcortex.Ac@vated,prolifera@ngBcellsarelocatedinthegerminalcentres.
Tcellsarelocatedintheparacortex.Whenlymphocytesareac@vatedbymicrobial
pathogens,theymigratetowardseachotherandmeetattheedgeofthefollicles,whereThelpercellsinteractwithandhelpBcellstodifferen@ateintoan@body-producingcells.
Ac@vatedTcellsandBcellsleavetheLNthroughefferentlympha@cvessels,enterthecircula@on,andmigratetodistantsitesofinfec@on.
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LymphNodeandAPCLNcontain3APCtypes,eachdealingwithdifferentkindsofan@gen:• DCpickupan@genatperipheryand
migratetoTcellrichzonesinLN• MacrophagesarepresentthroughoutLN
andmonitorlymphentryandexit–theyphagocytosepathogensandpresenttoTcells
• Bcellsmonitorsolublean@genfrompathogensandpresentinGC
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Dendri@ccellsundergochangesinappearanceduringtheprocessofmatura@onandmigra@onfromperipheral@ssuestolymphoid@ssuesthroughthelympha@ccircula@on
Dendri@ccellssamplean@genfromthroughoutthebody,andmigratetolymphnodes(viathedraininglympha@cs)topresentan@gentoTcells
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Dendri5ccellscanprocessan5genfromawidearrayofpathogens
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Lymphadenopathy
Swollenlymphnodesinapa@entwithonchocerciasis
• Generalizedinfec@ous
lymphadenopathy,causedmostlybyviralinfec@on,resultsinnodalhyperplasiawithoutnecrosis,andresolvesspontaneouslyastheillnessresolves
• MicrobescanreachLNvialymphorblood.Localcytokinereleaseresultsinneutrophilrecruitmentandvascularengorgement.Thenodeeventuallyheals.MacrophagesinLNalsophaocytosean@gen
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Spleen• Thespleenhasnodirectcontactwithlympha@cs:filtersblood• Whitepulpcontainssheathoflymphocytes,mostlyTcells(theperiarteriolarlymphoidsheath,orPALS)aroundanarteriole.Lymphoidfollicles,andgerminalcentres,containBcells• An@genspresentinblood-bornepathogensarefilteredfromthebloodbymacrophagesandDCwithinthemarginalzone.TheseDCthenmovetoPALSandpresentan@gentoTcells• RedpulpissiteofRBCdisposal