Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 11, Pages 4219-4236Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI85647
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Funding
- Lung GO Sequencing Project [HL-102923]
- WHI Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- Boston Children's Hospital Investigatorship Award
- Perkins Fund
- Dubai-Harvard Foundation for Medical research
- Kuwait Foundation for the Advancement of Sciences [2010-1302-05]
- NIH National Cancer Institute [P01098993]
- Japan Society for the Promotion of Science [22221004]
- National Institute of Allergy and Infectious Diseases (NIAID) [AI061093]
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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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