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

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

D.J. Davidson, A.J. Currie, D.M.E. Bowdish, K.L. Brown, C.M. Rosenberger, R.C. Ma, J. Bylund, P.A. Campsall, A. Puel, C. Picard, …
Journal of Immunology, Vol.177(11), pp.8202-8211
2006
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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-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.

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