Hyper-responsive Toll-like receptor 7 and 9 activation in NADPH oxidase-deficient B lymphoblasts.
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 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 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.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Shawna
S
McLetchie
Department of Veterans Affairs, VA Northern California Healthcare System, Martinez, CA, USA.
Bryan D
BD
Volpp
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
Mary C
MC
Dinauer
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Janice S
JS
Blum
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D016207:Cytokines / Q000096:biosynthesis; D000066630:Ectopic Gene Expression; D015870:Gene Expression; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D021122:Protein Subunits; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases
B cell; Toll-like receptors; immunodeficiency diseases; inflammation; reactive oxygen species