title: Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance.
abstract: Activation-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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bannock
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Yen-Shing
authors.initials: YS
authors.lastname: Ng
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Massad
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Oe
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Wu
authors.affiliation: Division of Immunology/Allergy, Centre Hospitalier de l'Université de Québec, Québec City, G1V 4G2, Canada.
authors.forename: Aubert
authors.initials: A
authors.lastname: Lavoie
authors.affiliation: Pediatric Allergy & Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, 13110, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Uludag University Medical Faculty, Department of Pediatrics, Gorukle-Bursa, 16285, Turkey.
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.affiliation: Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.affiliation: Department of Pediatrics, National Defense Medical College, Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.affiliation: INSERM UMR 1163, Paris 75015, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address: eric.meffre@yale.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D061167:Central Tolerance / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003564:Cytidine Deaminase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005803:Genes, Immunoglobulin / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D011995:Recombination, Genetic / Q000235:genetics / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D003564:Cytidine Deaminase
keywords: AID-deficient patients; B cell development; B cell tolerance; activation-induced cytidine deaminase