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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0026882,
umls-concept:C0086418,
umls-concept:C0439677,
umls-concept:C0439831,
umls-concept:C0871261,
umls-concept:C1149184,
umls-concept:C1511790,
umls-concept:C1704632,
umls-concept:C1706817,
umls-concept:C1880022,
umls-concept:C2911692
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pubmed:issue |
11
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pubmed:dateCreated |
2006-11-20
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/IRAK4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1 Receptor-Associated...,
http://linkedlifedata.com/resource/pubmed/chemical/MYD88 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Myeloid Differentiation Factor 88,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptors
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-1767
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pubmed:author |
pubmed-author:BowdishDawn M EDM,
pubmed-author:BrownKelly LKL,
pubmed-author:BylundJohanJ,
pubmed-author:CampsallPaul APA,
pubmed-author:CasanovaJean-LaurentJL,
pubmed-author:CurrieAndrew JAJ,
pubmed-author:DavidsonDonald JDJ,
pubmed-author:DevonRebecca SRS,
pubmed-author:HancockRobert E WRE,
pubmed-author:MaRebecca CRC,
pubmed-author:PicardCapucineC,
pubmed-author:PuelAnneA,
pubmed-author:RosenbergerCarrie MCM,
pubmed-author:SpeertDavid PDP,
pubmed-author:TurveyStuart ESE
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
177
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8202-11
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pubmed:dateRevised |
2010-10-4
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pubmed:meshHeading |
pubmed-meshheading:17114497-Amino Acid Sequence,
pubmed-meshheading:17114497-Blotting, Western,
pubmed-meshheading:17114497-Cytokines,
pubmed-meshheading:17114497-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:17114497-Fibroblasts,
pubmed-meshheading:17114497-Gene Expression,
pubmed-meshheading:17114497-Humans,
pubmed-meshheading:17114497-Immune System Diseases,
pubmed-meshheading:17114497-Interleukin-1 Receptor-Associated Kinases,
pubmed-meshheading:17114497-Male,
pubmed-meshheading:17114497-Molecular Sequence Data,
pubmed-meshheading:17114497-Mutation,
pubmed-meshheading:17114497-Myeloid Cells,
pubmed-meshheading:17114497-Myeloid Differentiation Factor 88,
pubmed-meshheading:17114497-NF-kappa B,
pubmed-meshheading:17114497-Pedigree,
pubmed-meshheading:17114497-RNA, Messenger,
pubmed-meshheading:17114497-Receptors, Interleukin-1,
pubmed-meshheading:17114497-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:17114497-Toll-Like Receptors,
pubmed-meshheading:17114497-Transcription, Genetic
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pubmed:year |
2006
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pubmed:articleTitle |
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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pubmed:affiliation |
Child and Family Research Institute and Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. Donald.Davidson@ed.ac.uk
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pubmed:publicationType |
Journal Article,
Case Reports,
Research Support, Non-U.S. Gov't
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