Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint
Tineke Cantaert, … , Anne Durandy, Eric Meffre
Tineke Cantaert, … , Anne Durandy, Eric Meffre
Published October 4, 2016
Citation Information: J Clin Invest. 2016;126(11):4289-4302. https://doi.org/10.1172/JCI84645.
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Research Article Autoimmunity

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

Tineke Cantaert, Jean-Nicolas Schickel, Jason M. Bannock, Yen-Shing Ng, Christopher Massad, Fabien R. Delmotte, Natsuko Yamakawa, Salome Glauzy, Nicolas Chamberlain, Tuure Kinnunen, Laurence Menard, Aubert Lavoie, Jolan E. Walter, Luigi D. Notarangelo, Julie Bruneau, Waleed Al-Herz, Sara Sebnem Kilic, Hans D. Ochs, Charlotte Cunningham-Rundles, Mirjam van der Burg, Taco W. Kuijpers, Sven Kracker, Hideo Kaneko, Yujin Sekinaka, Shigeaki Nonoyama, Anne Durandy, Eric Meffre

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Figure 1

Defective peripheral tolerance checkpoint in patients with AICDA gene mutations.

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Defective peripheral tolerance checkpoint in patients with AICDA gene mu...
(A) Increased frequency of VH/4-34 gene usage in AID-deficient (AID-def) patients (n = 8), asymptomatic healthy heterozygotes (AID+/–) (n = 5), and AD-AID patients (n = 4) compared with that of HDs (n = 11) or UNG-deficient (UNG-def) patients (n = 3). Bars indicate the mean ± SD; dashed line indicates the mean value for the HDs. (B) Antibodies from mature naive B cells were tested by ELISA for anti–HEp-2 cell reactivity. Dotted lines show ED38-positive control, and solid lines show binding for each cloned recombinant antibody. Horizontal lines define the cutoff OD405 for positive reactivity. For each individual, the frequency of autoreactive (black area) and nonautoreactive (white area) clones is summarized in pie charts, with the total number of clones tested indicated in the centers. Summaries of the frequencies of HEp-2–reactive (C), polyreactive (D), and antinuclear (E) mature naive B cells in HDs (n = 11) and AID-deficient (n = 6), AID+/– (n = 5), AD-AID (n = 4), and UNG-deficient (n = 3) patients. Bars indicate the mean, and dashed lines indicate the mean value for HDs as a comparison. (F) Diverse staining patterns of antibodies expressed by mature naive B cells obtained by IFA on HEp-2 cells. Original magnification, ×40. P values were determined by ANOVA with Dunnett’s correction for multiple comparisons.