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-1, 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.
|Journal||The Journal of Immunology|
|Publication status||Published - 2006|
Davidson, D. J., Currie, A., Bowdish, D. M. E., Brown, K. L., Rosenberger, C. M., Ma, R. C., Bylund, J., Campsall, P. A., Puel, A., Picard, C., Casanova, J. L., Turvey, S. E., Hancock, R. E. W., Devon, R. S., & Speert, D. P. (2006). IRAK-4 Mutation (Q293X): Rapid Detection and Characterization of Defective Post-Transcriptional TLR/IL-1R Responses in Human Myeloid and Non-Myeloid Cells. The Journal of Immunology, 177(11), 8202-8211.