title: IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells.
abstract: Innate immunodeficiency has recently been reported as resulting from the Q293X IRAK-4 mutation with consequent defective TLR/IL-1R signaling. In this study we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell type specificity and ligand specificity in defective IL-1R-associated kinase (IRAK)-4-deficient cellular responses, indicating differential roles for this protein in human PBMCs and primary dermal fibroblasts and in LPS, IL-1beta, and TNF-alpha signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-kappaB signaling and intact MyD88-independent signaling and propose that dysfunctional complex 1 (IRAK1/TRAF6/TAK1) signaling, as a consequence of IRAK-4 deficiency, generates specific defects in MAPK activation that could underpin this patient's innate immunodeficiency. These studies demonstrate the importance of studying primary human cells bearing a clinically relevant mutation; they underscore the complexity of innate immune signaling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory proinflammatory signaling to normal human innate immune responses and immunodeficiencies.
authors.affiliation: Child and Family Research Institute and Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. Donald.Davidson@ed.ac.uk
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Currie
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Brown
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Rosenberger
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Ma
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Paul A
authors.initials: PA
authors.lastname: Campsall
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Devon
authors.forename: David P
authors.initials: DP
authors.lastname: Speert
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D022423:Myeloid Cells / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D010375:Pedigree; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases