Davidson et al (2006) IRAK-4 mutation (Q293X): rapid detection, and characterisation of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells. J. Immunol. 177; 8202-8211

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

Davidson, D. J., Currie, A. J., Bowdish, D. M. E., Brown, K., Rosenberger, C., Ma, R., Campsall, P., Puel. A., Picard, C., Casanova J.-L., Turvey, S., Devon, R., Hancock, R. E. W, and Speert, D. P.
J. Immunol. (2006) 177; 8202-8211    PubMed     Free PMC Article
Davidson supported by funding from: Wellcome Trust/ CCFF

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. PMID: 17114497 PMCID: PMC2948538
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