Cantaert, TinekeSchickel, Jean NicolasBannock, Jason M.Ng, Yen ShingMassad, ChristopherOe, TylerWu, ReneeLavoie, AubertWalter, Jolan E.Notarangelo, Luigi D.Herz, Waleed AlOchs, Hans D.Nonoyama, ShigeakiDurandy, AnneMeffre, Eric2022-06-092022-06-092015-11-17Cantaert, T. vd. (2015). "Activation-induced cytidine deaminase expression in human b cell precursors is essential for central b cell tolerance". Immunity, 43(5), 884-895.1074-7613https://doi.org/10.1016/j.immuni.2015.10.002https://www.sciencedirect.com/science/article/pii/S1074761315004021http://hdl.handle.net/11452/27007Activation-induced cytidine deaminase (AID), the enzyme- mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID(+) immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.eninfo:eu-repo/semantics/openAccessClass-switch recombinationSomatic hypermutationV(d)j recombinationAıid expressionDeficiencyMechanismsBcl6P53TranslocationsReceptorsImmunologyAdolescentAdultAgedAnimalsApoptosisCase-control studiesCentral toleranceChildChild, preschoolCytidine deaminaseDNA-binding proteinsFemaleGenes, immunoglobulinHumansLymphocyte activationMaleMiceMiddle agedNuclear proteinsPrecursor cells, B-lymphoidRecombination, geneticSomatic hypermutation, immunoglobulinYoung adultArticle0003668460000102-s2.0-8494742925788489543526546282ImmunologyAICDA (Activation-induced Cytidine Deaminase); Cytidine Deaminase; DNAActivation induced cytidine deaminaseRAG2 proteinShort hairpin RNACytidine deaminaseDNA binding proteinNuclear proteinRAG2 protein, humanAdultAnimal cellApoptosisArticleB lymphocyte toleranceBone marrowCell cloneCell functionCell maturationControlled studyEnzyme activityEnzyme inhibitionFemaleFetusGene dosageGenetic recombinationHumanHuman cellHuman tissueMiddle agedMouseNewbornNonhumanPre B lymphocytePriority journalProtein expressionAdolescentAgedAnimalCase control studyChildGeneticsImmunoglobulin geneImmunological toleranceImmunologyLymphocyte activationMalePre B lymphocytePreschool childSomatic hypermutationYoung adult