title: Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans.
abstract: Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for class-switch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Greta
authors.initials: G
authors.lastname: Meyers
authors.forename: Yen-Shing
authors.initials: YS
authors.lastname: Ng
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bannock
authors.forename: Aubert
authors.initials: A
authors.lastname: Lavoie
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Sara S
authors.initials: SS
authors.lastname: Kilic
authors.forename: Guzide
authors.initials: G
authors.lastname: Aksu
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Conley
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000974:Antibodies, Antinuclear / Q000097:blood / Q000235:genetics; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics; D007589:Job Syndrome / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D054448:Precursor Cells, B-Lymphoid / Q000201:enzymology / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology; D055815:Young Adult; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000974:Antibodies, Antinuclear; D053264:B-Cell Activating Factor; D007075:Immunoglobulin M; C505719:TNFSF13B protein, human; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase