Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint

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 autoreac...

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Vydáno v:The Journal of clinical investigation Ročník 126; číslo 11; s. 4289 - 4302
Hlavní autoři: Cantaert, Tineke, Schickel, Jean-Nicolas, Bannock, Jason M., Ng, Yen-Shing, Massad, Christopher, Delmotte, Fabien R., Yamakawa, Natsuko, Glauzy, Salome, Chamberlain, Nicolas, Kinnunen, Tuure, Menard, Laurence, Lavoie, Aubert, Walter, Jolan E., Notarangelo, Luigi D., Bruneau, Julie, Al-Herz, Waleed, Kilic, Sara Sebnem, Ochs, Hans D., Cunningham-Rundles, Charlotte, van der Burg, Mirjam, Kuijpers, Taco W., Kracker, Sven, Kaneko, Hideo, Sekinaka, Yujin, Nonoyama, Shigeaki, Durandy, Anne, Meffre, Eric
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States American Society for Clinical Investigation 01.11.2016
Témata:
Analysis
Autoimmunity
B cells
B-Lymphocytes - immunology
B-Lymphocytes - pathology
Biomedical research
Cell Cycle Checkpoints - genetics
Cell Cycle Checkpoints - immunology
Cloning
Cytidine Deaminase - deficiency
Cytidine Deaminase - immunology
Cytokines
Defects
Experiments
Female
Gene mutations
Health aspects
Humans
Immune Tolerance
Immunoglobulins
Immunologic Memory
Interleukins
Lymphocyte receptors
Male
Mutation
Physiological aspects
R&D
Research & development
Somatic Hypermutation, Immunoglobulin - immunology
Studies
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - pathology
Massachusetts
ISSN:0021-9738, 1558-8238, 1558-8238
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Shrnutí: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.
Bibliografie:SourceType-Scholarly Journals-1
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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI84645