TY - JOUR AU - Massaad, Michel J. AU - Zhou, Jia AU - Tsuchimoto, Daisuke AU - Chou, Janet AU - Jabara, Haifa AU - Janssen, Erin AU - Glauzy, Salomé AU - Olson, Brennan G. AU - Morbach, Henner AU - Ohsumi, Toshiro K. AU - Schmitz, Klaus AU - Kyriacos, Markianos AU - Kane, Jennifer AU - Torisu, Kumiko AU - Nakabeppu, Yusaku AU - Notarangelo, Luigi D. AU - Chouery, Eliane AU - Megarbane, Andre AU - Kang, Peter B. AU - Al-Idrissi, Eman AU - Aldhekri, Hasan AU - Meffre, Eric AU - Mizui, Masayuki AU - Tsokos, George C. AU - Manis, John P. AU - Al-Herz, Waleed AU - Wallace, Susan S. AU - Geha, Raif S. T1 - Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity PY - 2016/11/01/ AB - Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3–/– mice. Although Neil3–/– mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3–/– mice, splenic T and B cells as well as germinal center B cells from Peyer’s patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI85647 VL - 126 IS - 11 UR - https://doi.org/10.1172/JCI85647 SP - 4219 EP - 4236 PB - The American Society for Clinical Investigation ER -