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

• 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.

Keyword

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

Publication and Content Type

ref (subject category)

art (subject category)