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: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 177 Issue 11 Pg. 8202-11 (Dec 01 2006) ISSN: 0022-1767 [Print] United States
• PMID: 17114497 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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