2022-10-112022-10-112016-11Cantaert, T. vd. (2016). "Decreased somatic hypermutaton induces an impaired peripheral B cell tolerance checkpoint". Journal of Clinical Investigation, 126(11), 4289-4302.0021-97381558-8238https://doi.org/10.1172/JCI84645https://www.jci.org/articles/view/84645http://hdl.handle.net/11452/29051Çalışmada 27 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır.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.eninfo:eu-repo/semantics/openAccessResearch & experimental medicineInduced cytidine deaminaseClass-switch recombinationHyper-igm syndromeSystemic-lupus-erythematosusRegulatory T-cellsMemory BAntibody-responsesCD40 ligandActivationAidB-LymphocytesCell cycle checkpointsCytidine deaminaseFemaleHumansImmune toleranceImmunologic memoryMaleMutationSomatic hypermutation, immunoglobulinT-Lymphocytes, regulatoryArticle0003869929000202-s2.0-84994643712428943021261127701145Medicine, research & experimentalAICDA (Activation-induced Cytidine Deaminase); Cytidine Deaminase; DNAActivation induced cytidine deaminaseGamma interferonInterleukin 10Interleukin 17Interleukin 2Interleukin 6UracilAICDA (activation-induced cytidine deaminase)Cytidine deaminaseAntibody productionArticleAutosomal dominant inheritanceB lymphocyteCell proliferationControlled studyCytokine productionHumanHuman experimentImmunological toleranceMemory cellNormal humanPeripheral blood mononuclear cellPriority journalRegulatory T lymphocyteSomatic hypermutationB lymphocyteCell cycle checkpointDeficiencyFemaleGeneticsImmunological memoryImmunologyMaleMutationPathologySomatic hypermutation