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Hyper‐responsive Toll‐like receptor 7 and 9 activation in NADPH oxidase‐deficient B lymphoblasts
Author(s) -
McLetchie Shawna,
Volpp Bryan D.,
Dinauer Mary C.,
Blum Janice S.
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12530
Subject(s) - lymphoblast , nadph oxidase , toll , receptor , chemistry , toll like receptor , microbiology and biotechnology , immunology , biochemistry , biology , enzyme , innate immune system , genetics , cell culture
Summary 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 ( TLR s) 7 and 9. In response to TLR 7/9 ligands, B‐cell lines derived from patients with CGD with mutations in either the NADPH oxidase p40 phox or p47 phox 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 TLR 7/9 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 TLR 7 and TLR 9 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.