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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 Cells¹

Donald J. Davidson^*,2,3, Andrew J. Currie^*,2,4, Dawn M. E. Bowdish, Kelly L. Brown, Carrie M. Rosenberger^*, Rebecca C. Ma^*, Johan Bylund^*, Paul A. Campsall^*, Anne Puel, Capucine Picard, Jean-Laurent Casanova, Stuart E. Turvey^*, Robert E. W. Hancock, Rebecca S. Devon^* and David P. Speert^*

^* Child and Family Research Institute and Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; and Laboratoire de Génétique Humaine des Maladies Infectieuses, Institut National de la Santé et de la Recherche Médicale Unité 550, Faculté de Médecine Necker-Enfants Malades, Paris, France

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- signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ D.J.D. and R.S.D. are funded by Wellcome Trust Grants 060168 and 060161, D.J.D., A.J.C., and J.B. were supported by the Canadian Cystic Fibrosis Foundation, D.M.E.B. is supported by a Canadian Institutes for Health Research (CIHR) studentship, K.L.B. holds a fellowship from the CIHR-University of British Columbia Strategic Training Program for Translational Research in Infectious Diseases, C.M.R. holds studentships from CIHR and the Michael Smith Foundation for Health Research, R.E.W.H. holds a Canada Research Chair and was supported by a Pathogenomics of Innate Immunity grant provided by Genome British Columbia, and D.P.S. is supported by operating grants from CIHR and the Canadian Bacterial Diseases Network.

² D.J.D. and A.J.C. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Donald J. Davidson at the current address: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute W2.05, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland. E-mail address: Donald.Davidson{at}ed.ac.uk

⁴ Current address: Department of Medicine, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009.

⁵ Abbreviations used in this paper: IRAK, IL-1R-associated kinase; DD, death domain; hnRNA, heteronuclear RNA; IKK, I-B kinase; MDDC, monocyte-derived dendritic cell; MDM, monocyte-derived macrophage; MKK, MAPK kinase; poly(I:C), polyinosinic acid/polycytidylic acid; TAK, TGF--activated kinase; TRAF, TNFR-associated factor.

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