IRAK-4 mutation (Q293X): rapid detection, and characterisation of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells1

• Published in: The Journal of immunology (1950) 2006-12, Vol.177 (11), p.8202-8211
• Main Authors: Davidson, Donald J., Currie, Andrew J., Bowdish, Dawn M. E., Brown, Kelly L., Rosenberger, Carrie M., Ma, Rebecca C., Bylund, Johan, Campsall, Paul A., Puel, Anne, Picard, Capucine, Casanova, Jean-Laurent, Turvey, Stuart E., Hancock, Robert E. W., Devon, Rebecca S., Speert, David P.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

Innate immunodeficiency has recently been reported resulting from the Q293X IRAK-4 mutation, with consequent defective TLR/IL-1R signalling. Here we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell-type specificity and ligand specificity in defective IRAK-4-deficient cellular responses, indicating differential roles for this protein in human peripheral blood mononuclear cells and primary dermal fibroblasts, and in LPS, IL-1β and TNF-α signalling. We demonstrate transcriptional and post-transcriptional defects, despite NF-κB signalling and intact MyD88-independent signalling, and propose that dysfunctional Complex 1 (IRAK1/TRAF6/TAK1) signalling, as a consequence of IRAK-4-deficiency, generates specific defects in mitogen-activated protein kinase 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 signalling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory pro-inflammatory signalling to normal human innate immune responses and immunodeficiencies.