Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity
Michel J. Massaad, … , Susan S. Wallace, Raif S. Geha
Michel J. Massaad, … , Susan S. Wallace, Raif S. Geha
Published October 17, 2016
Citation Information: J Clin Invest. 2016;126(11):4219-4236. https://doi.org/10.1172/JCI85647.
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Research Article Autoimmunity Immunology

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

Michel J. Massaad, Jia Zhou, Daisuke Tsuchimoto, Janet Chou, Haifa Jabara, Erin Janssen, Salomé Glauzy, Brennan G. Olson, Henner Morbach, Toshiro K. Ohsumi, Klaus Schmitz, Markianos Kyriacos, Jennifer Kane, Kumiko Torisu, Yusaku Nakabeppu, Luigi D. Notarangelo, Eliane Chouery, Andre Megarbane, Peter B. Kang, Eman Al-Idrissi, Hasan Aldhekri, Eric Meffre, Masayuki Mizui, George C. Tsokos, John P. Manis, Waleed Al-Herz, Susan S. Wallace, Raif S. Geha

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Figure 2

Defective peripheral B cell tolerance checkpoint and impaired Treg function in patient 3.

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Defective peripheral B cell tolerance checkpoint and impaired Treg funct...
(A) Reactivity of recombinant antibodies expressed by single CD19+CD10+CD21+IgM+CD27– new emigrant/transitional B cells from a representative healthy age-matched control and patient 3 against dsDNA, insulin, and LPS. Clones were considered polyreactive when they recognized all 3 antigens. The frequencies of polyreactive B cells are summarized in the pie charts, with the number of antibody-secreting B cells tested shown in the center. (B) Percentage of polyreactive new emigrant/transitional B cell clones from patient 3 and 12 controls. (C) Reactivity of recombinant antibodies expressed by single CD19+CD10–CD21+IgM+CD27– mature naive B cell clones from a representative control and patient 3 against lysates of HEp-2 cells tested by ELISA. The frequencies of HEp-2– and non–HEp-2–reactive B cells are summarized in the pie charts, with the number of antibody-secreting B cells tested shown in the center. (D) Percentage of polyreactive new emigrant/transitional B cell clones from patient 3 and 12 controls. (E) Suppression by CD4+CD25+CD127lo Tregs from control (left panel) and patient 3 (right panel) of the proliferation of CellTrace Violet–labeled CD4+CD25+ Teff cells sorted from a third-party healthy subject stimulated with anti-CD3/CD28/CD2 beads at a 1:1 Treg/Teff ratio. (F) Quantification of the suppressive function of Tregs sorted from controls and patient 3 on Teff cells. Columns and bars in F represent mean ± SEM of 3 controls and patient 3. Dotted lines in A and C show the results from ED38. Horizontal lines show the OD405 cutoff for positive reactivity.