Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity
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
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
View: Text | PDF
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

×

Figure 6

Defective peripheral B cell tolerance checkpoint in the NEIL3-deficient subject and in an LRBA-deficient patient.

Options: View larger image (or click on image) Download as PowerPoint
Defective peripheral B cell tolerance checkpoint in the NEIL3-deficient ...
(A) Reactivity of recombinant antibodies expressed by single new emigrant/transitional B cell clones from a representative healthy age-matched control, the NEIL3-deficient subject, and an LRBA-deficient patient against dsDNA, insulin, and LPS tested by ELISA. Dotted lines show the results from a positive control designated ED38. Horizontal lines show the OD405 cutoff for positive reactivity. The frequencies of polyreactive B cells are summarized in the pie charts, with the number of antibody-secreting B cell clones tested shown in the center. Clones are considered polyreactive when they recognize all 3 antigens. (B) Percentage of polyreactive new emigrant/transitional B cell clones from the NEIL3-deficient subject (NEIL3-def.), the LRBA-deficient patient, patient 3, and 12 controls. (C) Reactivity of recombinant antibodies expressed by single mature naive B cell clones from a control, the NEIL3-deficient subject, and the LRBA-deficient patient against lysates of HEp-2 cells tested by ELISA. Dotted lines show the results from the positive control ED38. Horizontal lines show the OD405 cutoff for positive reactivity. 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 cell clones tested shown in the center. (D) Percentage of HEp-2–reactive mature naive B cell clones from the NEIL3-deficient subject, the LRBA-deficient patient, patient 3, and 12 controls. The percentage of reactive clones from patient 3 represented in Figure 2 was added to B and D for comparison with the subject with NEIL3 deficiency and the patient with LRBA deficiency. Each symbol represents 1 individual. The horizontal bar represents the mean of the controls. (E) Intracellular CTLA-4 staining in Tregs from 2 controls and the NEIL3-deficient subject. The numbers in the plots represent mean fluorescence intensity (MFI).