IRAK-4 Mutation (Q293X): Rapid Detection and Characterization of Defective Post-Transcriptional TLR/IL-1R Responses in Human Myeloid and Non-Myeloid Cells

J Immunol. 2006 Dec 1;177(11):8202-11. doi: 10.4049/jimmunol.177.11.8202.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cytokines
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Toll-Like Receptors
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Extracellular Signal-Regulated MAP Kinases