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-IdrissiHasan Aldhekri, Eric Meffre, Masayuki Mizui, George C. Tsokos, John P. Manis, Waleed Al-Herz, Susan S. Wallace, Raif S. Geha

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4219-4236
Number of pages18
JournalJournal of Clinical Investigation
Volume126
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

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Deoxyribonuclease (Pyrimidine Dimer)
Autoimmunity
DNA Repair
B-Lymphocytes
Enzymes
Autoantibodies
Apoptosis
Self Tolerance
Agammaglobulinemia
Peyer's Patches
Mutation
Germinal Center
Nephritis
Autoantigens
Missense Mutation
Serum
Drive
Siblings
Cell Death
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. / Massaad, Michel J.; Zhou, Jia; Tsuchimoto, Daisuke; Chou, Janet; Jabara, Haifa; Janssen, Erin; Glauzy, Salomé; Olson, Brennan G.; Morbach, Henner; Ohsumi, Toshiro K.; Schmitz, Klaus; Kyriacos, Markianos; Kane, Jennifer; Torisu, Kumiko; Nakabeppu, Yusaku; Notarangelo, Luigi D.; Chouery, Eliane; Megarbane, Andre; Kang, Peter B.; Al-Idrissi, Eman; Aldhekri, Hasan; Meffre, Eric; Mizui, Masayuki; Tsokos, George C.; Manis, John P.; Al-Herz, Waleed; Wallace, Susan S.; Geha, Raif S.

In: Journal of Clinical Investigation, Vol. 126, No. 11, 01.11.2016, p. 4219-4236.

Research output: Contribution to journalArticle

Massaad, MJ, Zhou, J, Tsuchimoto, D, Chou, J, Jabara, H, Janssen, E, Glauzy, S, Olson, BG, Morbach, H, Ohsumi, TK, Schmitz, K, Kyriacos, M, Kane, J, Torisu, K, Nakabeppu, Y, Notarangelo, LD, Chouery, E, Megarbane, A, Kang, PB, Al-Idrissi, E, Aldhekri, H, Meffre, E, Mizui, M, Tsokos, GC, Manis, JP, Al-Herz, W, Wallace, SS & Geha, RS 2016, 'Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity', Journal of Clinical Investigation, vol. 126, no. 11, pp. 4219-4236. https://doi.org/10.1172/JCI85647
Massaad, Michel J. ; Zhou, Jia ; Tsuchimoto, Daisuke ; Chou, Janet ; Jabara, Haifa ; Janssen, Erin ; Glauzy, Salomé ; Olson, Brennan G. ; Morbach, Henner ; Ohsumi, Toshiro K. ; Schmitz, Klaus ; Kyriacos, Markianos ; Kane, Jennifer ; Torisu, Kumiko ; Nakabeppu, Yusaku ; Notarangelo, Luigi D. ; Chouery, Eliane ; Megarbane, Andre ; Kang, Peter B. ; Al-Idrissi, Eman ; Aldhekri, Hasan ; Meffre, Eric ; Mizui, Masayuki ; Tsokos, George C. ; Manis, John P. ; Al-Herz, Waleed ; Wallace, Susan S. ; Geha, Raif S. / Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 11. pp. 4219-4236.
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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.",
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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.

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N2 - 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.

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