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

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36 Citations (Scopus)


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-1β, and TNF-α signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-κB 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)8202-8211
Number of pages10
JournalJournal of Immunology
Issue number11
Publication statusPublished - 1 Dec 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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