《调节性B细胞》PPT课件.ppt

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1、Bregs-RegulatoryBcellsIntroductionIntroduction 1CluestoBregsexistenceCluestoBregsexistence2DevelopmentanddifferentiationDevelopmentanddifferentiation34ContentsPhenotypicalIdentificationPhenotypicalIdentification6BregsindiseasesBregsindiseasesFunctionofBregsFunctionofBregs 5IntroductionTraditionally,

2、BcellshavebeenthoughttocontributetodiseasethroughproductionofantibodiesInthepasttwodecades,investigatorshaveattributedadditionalfunctionstoBcells,includingantigenpresentation,theproductionofmultiplecytokinesRecently,theabilityofBcellstonegativelyregulatecellularimmuneresponsesandinflammationhasbeend

3、escribedandtheconceptofregulatoryBcellshasemerged.CluestoBregsexistence199620021974BcellssuppressDTHsuppressorBcellscouldregulatetheimmuneresponseIL-10-producingBcellsregulateautoimmunityCD19+CD1dhiBcellsproducingIL-10controlTh2-drivencolitistheterm“regulatoryBcells”,whichdefinesB-cellsubsetswithreg

4、ulatoryproperties,wasfirstintroduced BcelldeficientmicedevelopchronicEAEBcellscouldrestraintheseverityofautoimmunedisease1980antigen-activatedBcellscouldinducetoleranceinrecipientnaivemiceSupportasuppressiveframeworkforBcellsandintroducealinkwithT-celltoleranceDevelopmentandDifferentiationBcellBcell

5、B2B2B1B1在骨髓发育，分布外周淋巴器官，在骨髓发育，分布外周淋巴器官，在骨髓发育，分布外周淋巴器官，在骨髓发育，分布外周淋巴器官，参与特异性免疫参与特异性免疫参与特异性免疫参与特异性免疫定位于大网膜、胸腔及肠黏膜固有层，定位于大网膜、胸腔及肠黏膜固有层，定位于大网膜、胸腔及肠黏膜固有层，定位于大网膜、胸腔及肠黏膜固有层，参与非特异性免疫参与非特异性免疫参与非特异性免疫参与非特异性免疫DevelopmentandDifferentiationFOBcellT2MZPBcellMZBcellLeBien TW,Tedder TF.B lymphocytes:how they develop

6、and function.Blood.2008LeBien TW,Tedder TF.B lymphocytes:how they develop and function.Blood.2008DevelopmentandDifferentiationDevelopmentandDifferentiationMauri C,Ehrenstein MR.The short history of regulatory B cells.Trends Immunol.2008 Mauri C,Ehrenstein MR.The short history of regulatory B cells.T

7、rends Immunol.2008 DevelopmentandDifferentiationMauri C,Ehrenstein MR.The short history of regulatory B cells.Trends Immunol.2008 Mauri C,Ehrenstein MR.The short history of regulatory B cells.Trends Immunol.2008 DevelopmentandDifferentiationMizoguchi A,Bhan AK.A case for regulatory B cells.J Immunol

8、.2006PhenotypicalIdentificationHe Y.The roles of regulatory B cells in cancer.J Immunol Res.2014.He Y.The roles of regulatory B cells in cancer.J Immunol Res.2014.PhenotypicalIdentification Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.Mauri C.Immune regulatory function of B cells.A

9、nnu Rev Immunol.20122012PhenotypicalIdentification Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.20122012PhenotypicalIdentificationBodhankar S.IL-10-producing B-cells limit CNS inflammation and infarct volume in Bodhanka

10、r S.IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke.Metab Brain Dis.2013experimental stroke.Metab Brain Dis.2013PhenotypicalIdentificationThereisnouniquemarker,orsetofmarkers,thatexclusivelyidentifiestheBregsThereisnomasterregulatortranscriptionfactoridentifi

11、edinBregdevelopmentIL-10secretionisstillavitalstandardintheidentificationofBregsFunctionofBregsMizoguchi A,Bhan AK.A case for regulatory B cells.J Immunol.2006FunctionofBregs Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.Mauri C.Immune regulatory function of B cells.Annu Rev Immunol

12、.20122012FunctionofBregs Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.20122012 Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.Mauri C.Immune regulatory function of B cells.Annu Rev Immunol.20122012Functi

13、onofBregsBregsinautoimmunityExperimentalautoimmuneencephalomyelitis(EAE)InflammatoryBowelDisease(IBD)RheumatoidArthritis(RA)BregsinautoimmunityEAEB-cell-deficientmice(m mMT)failedtocontrolEAE,andunlikethewild-typemice,didnotundergospontaneousremission IntheabsenceofIL-10productionbyBcells,thepro-inf

14、lammatorytype1immuneresponsepersistedandmicedidnotrecover LackofdiseaseresolutionwasattributedtotheinabilityofTcellstoswitchtoaprotectiveTh2response BregsinautoimmunityIBDm mMTTCRa a-/-micemanifestanearlieronsetofdiseaseandanexacerbatedintestinalinflammationcomparedwiththeTCRa a-/-miceTheamelioratio

15、nofdiseasewasparalleledbyanincreaseintheclearanceofapoptoticcells,suggestinganautoantibody-mediatedprotectivemechanism AdministrationofpurifiedimmunoglobulinfromTCRa-/-micewithamixtureofmonoclonalautoantibodiesattenuatecolitisBregsinautoimmunityRAStimulationofarthritogenicBcellswithanagonisticanti-C

16、D40andcollagengeneratedasubsetofBcellsproducingIL-10ThissuppressiveeffectwasassociatedwithadownregulationofTh1cytokinesandwasdependentuponthereleaseofIL-10Transferofcollagenandanti-CD40-stimulatedBcellstosyngeneicimmunizedmicepreventedtheinductionofarthritisandamelioratedestablisheddiseaseBregsincan

17、cerBregssupportlungmetastasesviaTreggenerationOlkhanud PB.Tumor-evoked regulatory B cells promote breast cancer metastasis by Olkhanud PB.Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4converting resting CD4+T cells to T-regulatory cells.Cancer Res.2011 T c

18、ells to T-regulatory cells.Cancer Res.2011BregsincancerBregssupportlungmetastasesviaTreggenerationOlkhanud PB.Tumor-evoked regulatory B cells promote breast cancer metastasis by Olkhanud PB.Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4 T cells to T-regula

19、tory cells.Cancer Res.2011converting resting CD4 T cells to T-regulatory cells.Cancer Res.2011BregsincancerRegulatoryBcellproductionofIL-10inhibitslymphomadepletionduringCD20immunotherapyHorikawa M.Regulatory B cell production of IL-10 inhibits lymphoma depletion during Horikawa M.Regulatory B cell

20、production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice.J Clin Invest.2011CD20 immunotherapy in mice.J Clin Invest.2011BregsintransplantationGVHDRowe V.Host B cells produce IL-10 following TBI and attenuate acute GVHD after Rowe V.Host B cells produce IL-10 following TBI an

21、d attenuate acute GVHD after allogeneic bone marrow transplantation.Blood.2006allogeneic bone marrow transplantation.Blood.2006AcuteGVHDisinitiallyaugmentedinm mMTrecipientsrelativetowild-typerecipientsasaresultofanincreaseindonorT-cellproliferation,expansion,andinflammatorycytokineproductionRecipie

22、ntmiceinwhichBcellsareunabletoproduceIL-10developmoresevereacuteGVHDthanrecipientmiceinwhichBcellsarewildtypeTBIdepletemostBcellbutrapidlyinducessustainedinterleukin-10generationfromBcellsOutstandingquestionsandFuturuedirectionsweneedtobetteridentifysurfacemarkersthat,coupledwithtranscriptionalfacto

23、rs,wouldprovideauniquesignatureThequestionofwhetherallBcellsproducingIL-10,irrespectiveoftheirphenotype,arecapableofsuppressionorwhethermultipleBregsubsetsexistandiftheyareallequipollentisyettobedeterminedOutstandingquestionsandFuturuedirectionsWeneedtobetteridentifysurfacemarkersthat,coupledwithtra

24、nscriptionalfactors,wouldprovideauniquesignatureThequestionofwhetherallBcellsproducingIL-10,irrespectiveoftheirphenotype,arecapableofsuppressionorwhethermultipleBregsubsetsexistandiftheyareallequipollentisyettobedeterminedOutstandingquestionsandFuturuedirectionsTherearevirtuallynodatademonstratingwh

25、etherBregsmigratetothesiteofinflammationandwhethertheyinteractinsituwithproinflammatorycellsTowhatextenttheirsuppressiveeffectisantigenspecificisstilldebatableandlargelyunexplored.MostdatahavefocusedonthesuppressivefunctionthatBregshaveonTcells.StudyoftheinteractionofBregswithothercellsoftheimmunesystemmightunraveladditionalundiscoveredfunctions.