Enhanced Selection of High Affinity DNA-Reactive B Cells Following Cyclophosphamide Treatment in Mice 英文参考文献.docVIP

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Enhanced Selection of High Affinity DNA-Reactive B Cells Following Cyclophosphamide Treatment in Mice 英文参考文献.doc

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Enhanced Selection of High Affinity DNA-Reactive B Cells Following Cyclophosphamide Treatment in Mice 英文参考文献

EnhancedSelectionofHighAffinityDNA-ReactiveBCells FollowingCyclophosphamideTreatmentinMice DaisukeKawabata.,JeganathanVenkatesh.,MeeraRamanujam,AnneDavidson,ChristineM.Grimaldi, BettyDiamond* CenterforAutoimmuneandMusculoskeletalDisease,TheFeinsteinInstituteforMedicalResearch,Manhasset,NewYork,UnitedStatesofAmerica Abstract Amajorgoalforthetreatmentofpatientswithsystemiclupuserythematosuswithcytotoxictherapiesistheinductionof long-term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstitutingBcellrepertoire.SincethereisrecentevidencesuggestingthatBcelllymphopeniamightattenuatenegative selection of autoreactive B cells, we elected to investigate the effects of cyclophosphamide on the selection of the re- emergingBcellrepertoireinwildtypemiceandtransgenicmicethatexpresstheHchainofananti-DNAantibody.The reconstitutingBcellrepertoireinwildtypemicecontainedanincreasedfrequencyofDNA-reactiveBcells;inheavychain transgenicmice,thereconstitutingrepertoirewascharacterizedbyanincreasedfrequencyofmature,highaffinityDNA- reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase inserum levelsofBAFF. Treatmentoftransgene-expressing mice withaBAFF blockingagent orwithDNase to reduce exposure to autoantigen limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. ThesestudiessuggestthatduringBcellreconstitution,notonlyisnegativeselectionofhighaffinityDNA-reactiveBcells impairedbyincreasedBAFF,butalsothatBcellsescapingnegativeselectionarepositivelyselectedbyautoantigen.There aresignificantimplicationsfortherapy. Citation:KawabataD,VenkateshJ,RamanujamM,DavidsonA,GrimaldiCM,etal.(2010)EnhancedSelectionofHighAffinityDNA-ReactiveBCellsFollowing CyclophosphamideTreatmentinMice.PLoSONE5(1):e8418.doi:10.1371/journal.pone.0008418 Editor:WasifN.Khan,UniversityofMiami,UnitedStatesofAmerica ReceivedOctober9,2009;AcceptedNove