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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

Davidson, D.J., Currie, A.J., 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. and 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. Journal of Immunology, 177 (11). pp. 8202-8211.

Link to Published Version: http://ukpmc.ac.uk/articles/PMC2948538//reload=0;j...
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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.

Publication Type: Journal Article
Publisher: The American Association of Immunologists, Inc.
Copyright: © 2006 by The American Association of Immunologists, Inc.
URI: http://researchrepository.murdoch.edu.au/id/eprint/9549
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