Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint
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
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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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 7

Decreased SHM frequencies in memory B cells from subjects with AICDA gene mutation(s).

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Decreased SHM frequencies in memory B cells from subjects with AICDA gen...
(A) Decreased SHM in IgM+ memory B cells from AD-AID patients. The number of mutations evaluated in VH sequences derived from single CD27+IgM+ B cells from HDs (n = 16), AID-deficient patients (n = 5), AID+/– subjects (n = 4), AD-AID patients (n = 4), and 1 UNG-deficient patient is shown. P values were determined by ANOVA with Dunnett’s correction for multiple comparisons. (B) Decreased SHM in IgG+ memory B cells from AID+/– subjects. The number of mutations in VH sequences from single CD27+IgG+ B cells from HDs (n = 15) and AID+/– healthy subjects (n = 7) is shown. Each sequence is depicted by a symbol, and bars represent the mean. P values were determined by an unpaired, 2-tailed Student’s t test. (C) Left: Control reactive cervical lymph node with lymphoid follicles composed of normal-sized GCs and a well-defined follicular mantle (FM). Middle: cervical lymph node biopsies from AID-deficient patient 1 showing lymphoid follicular hyperplasia with giant GCs and a characteristic reduced FM. Right: cervical lymph node biopsy from UNG-deficient patient 3 with lymphoid follicle hyperplasia with ill-defined GC separation from the normal-sized mantle zone. Original magnification, ×50.