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 8

Disruption of the peripheral B cell tolerance checkpoint by untamed GC reactions.

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Disruption of the peripheral B cell tolerance checkpoint by untamed GC r...
Decreased SHM processes result in a reduced efficiency at generating highly mutated specific antibodies, potentially leading to enhanced GC reactions, increased Tfh cell production, and cytokine secretion. These cytokines interfere with Treg suppressive function and potentially result in a defective peripheral B cell tolerance checkpoint. This impaired selection step allows the accumulation of large numbers of autoreactive B cells in the periphery that could be activated by Tfh cells and systemic cytokines that support not only autoantibody secretion but potentially the development of autoimmune manifestations.