Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity

J Clin Invest. 2016 Nov 1;126(11):4219-4236. doi: 10.1172/JCI85647. Epub 2016 Oct 17.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Autoantibodies / immunology
  • Autoimmune Diseases* / genetics
  • Autoimmune Diseases* / immunology
  • Autoimmune Diseases* / pathology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Endodeoxyribonucleases / deficiency*
  • Endodeoxyribonucleases / immunology
  • Female
  • Genetic Predisposition to Disease*
  • HeLa Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • N-Glycosyl Hydrolases / deficiency*
  • N-Glycosyl Hydrolases / immunology
  • Poly I-C / pharmacology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • Autoantibodies
  • LRBA protein, human
  • Lrba protein, mouse
  • Endodeoxyribonucleases
  • NEIL3 protein, mouse
  • N-Glycosyl Hydrolases
  • NEIL3 protein, human
  • Poly I-C