title: Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint.
abstract: Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/- subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bannock
authors.forename: Yen-Shing
authors.initials: YS
authors.lastname: Ng
authors.forename: Christopher
authors.initials: C
authors.lastname: Massad
authors.forename: Fabien R
authors.initials: FR
authors.lastname: Delmotte
authors.forename: Natsuko
authors.initials: N
authors.lastname: Yamakawa
authors.forename: Salome
authors.initials: S
authors.lastname: Glauzy
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.forename: Tuure
authors.initials: T
authors.lastname: Kinnunen
authors.forename: Laurence
authors.initials: L
authors.lastname: Menard
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: Julie
authors.initials: J
authors.lastname: Bruneau
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.forename: Hideo
authors.initials: H
authors.lastname: Kaneko
authors.forename: Yujin
authors.initials: Y
authors.lastname: Sekinaka
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000276:immunology*; D003564:Cytidine Deaminase / Q000172:deficiency* / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D008297:Male; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase