title: Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity.
abstract: 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.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuchimoto
authors.forename: Janet
authors.initials: J
authors.lastname: Chou
authors.forename: Haifa
authors.initials: H
authors.lastname: Jabara
authors.forename: Erin
authors.initials: E
authors.lastname: Janssen
authors.forename: Salomé
authors.initials: S
authors.lastname: Glauzy
authors.forename: Brennan G
authors.initials: BG
authors.lastname: Olson
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.forename: Toshiro K
authors.initials: TK
authors.lastname: Ohsumi
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz
authors.forename: Markianos
authors.initials: M
authors.lastname: Kyriacos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kane
authors.forename: Kumiko
authors.initials: K
authors.lastname: Torisu
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.forename: Eman
authors.initials: E
authors.lastname: Al-Idrissi
authors.forename: Hasan
authors.initials: H
authors.lastname: Aldhekri
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mizui
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: John P
authors.initials: JP
authors.lastname: Manis
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Susan S
authors.initials: SS
authors.lastname: Wallace
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004706:Endodeoxyribonucleases / Q000172:deficiency* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009699:N-Glycosyl Hydrolases / Q000172:deficiency* / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; C428703:LRBA protein, human; C498954:Lrba protein, mouse; D004706:Endodeoxyribonucleases; C540052:NEIL3 protein, mouse; D009699:N-Glycosyl Hydrolases; C468764:NEIL3 protein, human; D011070:Poly I-C