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.

Currie, A. J. (author)
Bowdish, D. M. (author)
Brown, K. L. (author)
Rosenberger, C. M. (author)
Ma, R. C. (author)
Bylund, Johan,1975Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research(Swepub:gu)xbyljo (author)
Campsall, P. A. (author)
Puel, A. (author)
Picard, C. (author)
Casanova, J. L. (author)
Turvey, S. E. (author)
Hancock, R. E. (author)
Devon, R. S. (author)
Speert, D. P. (author)
Göteborgs universitetInstitutionen för medicin, avdelningen för reumatologi och inflammationsforskning (creator_code:org_t)

By the author/editor: Davidson, D. J.; Currie, A. J.; Bowdish, D. M.; Brown, K. L.; Rosenberger, C. ...; Ma, R. C.; show more...; Bylund, Johan, 1 ...; Campsall, P. A.; Puel, A.; Picard, C.; Casanova, J. L.; Turvey, S. E.; Hancock, R. E.; Devon, R. S.; Speert, D. P.; show less...

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