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IRAK-4 mutation (Q2...
IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells
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Davidson, D. J. (author)
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Currie, A. J. (author)
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Bowdish, D. M. (author)
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Brown, K. L. (author)
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Rosenberger, C. M. (author)
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Ma, R. C. (author)
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- Bylund, Johan, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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Campsall, P. A. (author)
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Puel, A. (author)
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Picard, C. (author)
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Casanova, J. L. (author)
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Turvey, S. E. (author)
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Hancock, R. E. (author)
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Devon, R. S. (author)
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Speert, D. P. (author)
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(creator_code:org_t)
- 2006
- 2006
- English.
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In: J Immunol. ; 177:11, s. 8202-11
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https://gup.ub.gu.se...
Abstract
Subject headings
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- 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.
Keyword
- Amino Acid Sequence
- Blotting
- Western
- Cytokines/biosynthesis
- Extracellular Signal-Regulated MAP Kinases/immunology
- Fibroblasts/*immunology
- Gene Expression
- Humans
- Immune System Diseases/*genetics
- Interleukin-1 Receptor-Associated Kinases/*genetics
- Male
- Molecular Sequence Data
- Mutation
- Myeloid Cells/*immunology
- Myeloid Differentiation Factor 88/immunology
- NF-kappa B/immunology
- Pedigree
- RNA
- Messenger/analysis
- Receptors
- Interleukin-1/*immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Toll-Like Receptors/*immunology
- Transcription
- Genetic
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Davidson, D. J.
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Currie, A. J.
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Bowdish, D. M.
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Brown, K. L.
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Rosenberger, C. ...
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Ma, R. C.
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show more...
-
Bylund, Johan, 1 ...
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Campsall, P. A.
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Puel, A.
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Picard, C.
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Casanova, J. L.
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Turvey, S. E.
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Hancock, R. E.
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Devon, R. S.
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Speert, D. P.
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show less...
- Articles in the publication
- J Immunol
- By the university
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University of Gothenburg