Hyper-responsive Toll-like receptor 7 and 9 activation in NADPH oxidase-deficient B lymphoblasts

Shawna Mcletchie, Bryan D. Volpp, Mary C. Dinauer, Janice Blum

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Chronic granulomatous disease (CGD) is an inherited immunodeficiency linked with mutations in the multi-subunit leucocyte NADPH oxidase. Myeloid-derived phagocytic cells deficient in NADPH oxidase fail to produce sufficient levels of reactive oxygen species to clear engulfed pathogens. In this study we show that oxidase also influences B-cell functions, including responses to single-stranded RNA or unmethylated DNA by endosomal Toll-like receptors (TLRs) 7 and 9. In response to TLR7/9 ligands, B-cell lines derived from patients with CGD with mutations in either the NADPH oxidase p40phox or p47phox subunits produced only low levels of reactive oxygen species. Remarkably, cytokine secretion and p38 mitogen-activated protein kinase activation by these oxidase-deficient B cells was significantly increased upon TLR7/9 activation when compared with oxidase-sufficient B cells. Increased TLR responsiveness was also detected in B cells from oxidase-deficient mice. NADPH oxidase-deficient patient-derived B cells also expressed enhanced levels of TLR7 and TLR9 mRNA and protein compared with the same cells reconstituted to restore oxidase activity. These data demonstrate that the loss of oxidase function associated with CGD can significantly impact B-cell TLR signalling in response to nucleic acids with potential repercussions for auto-reactivity in patients.

Original languageEnglish (US)
Pages (from-to)595-606
Number of pages12
JournalImmunology
Volume146
Issue number4
DOIs
StatePublished - Dec 1 2015

Keywords

  • B cell
  • Immunodeficiency diseases
  • Inflammation
  • Reactive oxygen species
  • Toll-like receptors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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