Meyers, GretaNg, Yen-ShingBannock, Jason M.Lavoie, AubertWalter, Jolan E.Notarangelo, Luigi D.Kilic, Sara S.Aksu, GuzideDebre, MarianneRieux-Laucat, FredericConley, Mary EllenCunningham-Rundles, CharlotteDurandy, AnneMeffre, Eric2019-10-272019-10-2720110027-8424https://doi.org/10.1073/pnas.1102600108https://hdl.handle.net/11454/46259Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for classs-witch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans.en10.1073/pnas.1102600108info:eu-repo/semantics/openAccessArticle108281155411559WOS:00029263520005321700883N/AQ1