IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells

Donald J Davidson, Andrew J Currie, Dawn M E Bowdish, Kelly L Brown, Carrie M Rosenberger, Rebecca C Ma, Johan Bylund, Paul A Campsall, Anne Puel, Capucine Picard, Jean-Laurent Casanova, Stuart E Turvey, Robert E W Hancock, Rebecca S Devon, David P Speert

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8202-11
Number of pages10
JournalJournal of Immunology
Volume177
Issue number11
Publication statusPublished - 1 Dec 2006

Keywords

  • Amino Acid Sequence
  • Blotting, Western
  • Cytokines
  • Extracellular Signal-Regulated MAP Kinases
  • Fibroblasts
  • Gene Expression
  • Humans
  • Immune System Diseases
  • Interleukin-1 Receptor-Associated Kinases
  • Male
  • Molecular Sequence Data
  • Mutation
  • Myeloid Cells
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Pedigree
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptors
  • Transcription, Genetic

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