调节性B细胞课件

Bregs-----RegulatoryBcells.Introduction

1CluestoBregsexistence2Developmentanddifferentiation34ContentsPhenotypicalIdentification6BregsindiseasesFunctionofBregs

5.IntroductionTraditionally,B

cellshavebeenthoughttocontributetodiseasethroughproductionofantibodiesInthepasttwodecades,investigatorshaveattributedadditionalfunctionstoBcells,includingantigenpresentation,theproductionofmultiplecytokinesRecently,theabilityofB

cellstonegativelyregulatecellularimmuneresponsesandinflammationhasbeendescribedandtheconceptofregulatoryB

cellshasemerged..CluestoBregsexistence199620021974BcellssuppressDTHsuppressorBcellscouldregulatetheimmuneresponseIL-10-producingBcellsregulateautoimmunityCD19+CD1dhiBcellsproducingIL-10controlTh2-drivencolitistheterm“regulatoryBcells”,whichdefinesB-cellsubsetswithregulatoryproperties,wasfirstintroduced

Bcell–deficientmicedevelopchronicEAEBcellscouldrestraintheseverityofautoimmunedisease1980antigen-activatedBcellscouldinducetoleranceinrecipientnaivemiceSupport

a‘suppressive

framework’forBcellsandintroducealinkwithT-celltolerance.DevelopmentandDifferentiationBcellB2B1在骨髓发育，分布外周淋巴器官，参与特异性免疫定位于大网膜、胸腔及肠黏膜固有层，参与非特异性免疫.DevelopmentandDifferentiationFOBcellT2–MZPBcellMZBcellLeBienTW,TedderTF.Blymphocytes:howtheydevelopandfunction.Blood.2008.DevelopmentandDifferentiation.Developmentand

DifferentiationMauriC,EhrensteinMR.The'short'historyofregulatoryBcells.TrendsImmunol.2008

.Developmentand

DifferentiationMauriC,EhrensteinMR.The'short'historyofregulatoryBcells.TrendsImmunol.2008

.Developmentand

DifferentiationMizoguchiA,BhanAK.AcaseforregulatoryBcells.JImmunol.2006.PhenotypicalIdentificationHeY.TherolesofregulatoryBcellsincancer.JImmunolRes.2014.

.PhenotypicalIdentificationMauriC.ImmuneregulatoryfunctionofBcells.AnnuRevImmunol.

2012.PhenotypicalIdentificationMauriC.ImmuneregulatoryfunctionofBcells.AnnuRevImmunol.

2012.PhenotypicalIdentificationBodhankarS.IL-10-producingB-cellslimitCNSinflammationandinfarctvolumeinexperimentalstroke.MetabBrainDis.2013.PhenotypicalIdentificationThereisnouniquemarker,orsetofmarkers,thatexclusivelyidentifiestheBregsThereisnomasterregulatortranscriptionfactoridentifiedinBregdevelopmentIL-10secretionisstillavitalstandardintheidentificationofBregs.FunctionofBregsMizoguchiA,BhanAK.AcaseforregulatoryBcells.JImmunol.2006.FunctionofBregsMauriC.ImmuneregulatoryfunctionofBcells.AnnuRevImmunol.

2012.FunctionofBregsMauriC.ImmuneregulatoryfunctionofBcells.AnnuRevImmunol.

2012.MauriC.ImmuneregulatoryfunctionofBcells.AnnuRevImmunol.

2012FunctionofBregs.BregsinautoimmunityExperimentalautoimmuneencephalomyelitis(EAE)InflammatoryBowelDisease(IBD)

RheumatoidArthritis(RA).Bregsinautoimmunity——EAEB-cell-deficientmice(mMT)

failedtocontrolEAE,andunlikethewild-typemice,didnotundergospontaneousremission

IntheabsenceofIL-10productionbyBcells,thepro-inflammatorytype1immuneresponsepersistedandmicedidnotrecover

LackofdiseaseresolutionwasattributedtotheinabilityofTcellstoswitchtoaprotectiveTh2response

.Bregsinautoimmunity——IBDmMTTCRa-/-micemanifestanearlieronsetofdiseaseand

anexacerbatedintestinalinflammationcomparedwiththe

TCRa-/-miceTheameliorationofdiseasewasparalleledbyanincreaseintheclearanceofapoptoticcells,suggestinganautoantibody-mediatedprotectivemechanism

Administrationofpurified

immunoglobulinfromTCRa-/-

micewithamixtureof

monoclonalautoantibodies

attenuatecolitis.Bregsinautoimmunity——RAStimulationofarthritogenicBcellswithanagonisticanti-CD40andcollagengeneratedasubsetofBcellsproducingIL-10ThissuppressiveeffectwasassociatedwithadownregulationofTh1cytokinesand

wasdependentupon

thereleaseofIL-10Transferofcollagenandanti-CD40-stimulatedBcellstosyngeneicimmunizedmicepreventedtheinductionofarthritisandamelioratedestablisheddisease.BregsincancerBregssupportlungmetastasesviaTreggenerationOlkhanudPB.Tumor-evokedregulatoryBcellspromotebreastcancermetastasisbyconvertingrestingCD4+TcellstoT-regulatorycells.CancerRes.2011.BregsincancerBregssupportlungmetastasesviaTreggenerationOlkhanudPB.Tumor-evokedregulatoryBcellspromotebreastcancermetastasisbyconvertingrestingCD4⁺TcellstoT-regulatorycells.CancerRes.2011.BregsincancerRegulatoryBcellproductionofIL-10

inhibitslymphomadepletionduringCD20immunotherapyHorikawaM.RegulatoryBcellproductionofIL-10inhibitslymphomadepletionduringCD20immunotherapyinmice.JClinInvest.2011.Bregsintransplantation——GVHDRoweV.HostBcellsproduceIL-10followingTBIandattenuateacuteGVHDafterallogeneicbonemarrowtransplantation.Blood.2006AcuteGVHDisinitiallyaugmentedin

mMTrecipientsrelativetowild-typerecipientsasaresultofanincreaseindonor

T-cellproliferation,expansion,andinflammatorycytokineproductionRecipientmiceinwhichBcellsareunabletoproduceIL-10develop

moresevereacute

GVHDthanrecipientmiceinwhichBcellsare

wildtypeTBIdepletemostBcellbutrapidlyinducessustainedinterleukin-10generationfromBcells.OutstandingquestionsandFuturuedirectionsweneedtobetteridentifysurfacemarkersthat,coupledwithtranscriptionalfactors,wouldprovideauniquesignatureThequestionofwhetherallBcellsproducingIL-10,irrespectiveoftheirphenotype,arecapableofsuppressionorwhethermultipleBregsubsetsexistandiftheyareallequipollentisyettobedetermined.OutstandingquestionsandFuturuedirectionsWeneedtobetteridentifysurfacemarkersthat,coupledwithtranscriptionalfactors,wouldprovideauniquesignatureThequestionofwhethera