Abstract
Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Child
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Codon, Terminator
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Cytokines / metabolism
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Drosophila Proteins*
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Female
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Fibroblasts / immunology
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Humans
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Interleukin-1 Receptor-Associated Kinases
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Interleukins / immunology
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Interleukins / metabolism
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Lipopolysaccharides / immunology
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Male
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Monocytes / immunology
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Mutation
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Neutrophils / immunology
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Pedigree
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Phosphotransferases (Alcohol Group Acceptor) / deficiency*
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Phosphotransferases (Alcohol Group Acceptor) / genetics*
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Pneumococcal Infections / immunology*
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Pneumococcal Infections / metabolism
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Protein Structure, Tertiary
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / immunology
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Receptors, Cell Surface / metabolism
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Receptors, Interleukin / immunology
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Receptors, Interleukin-1 / chemistry
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Signal Transduction
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Staphylococcal Infections / immunology*
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Staphylococcal Infections / metabolism
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / immunology
Substances
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Codon, Terminator
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Cytokines
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Drosophila Proteins
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Interleukins
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Lipopolysaccharides
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Membrane Glycoproteins
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Receptors, Cell Surface
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Receptors, Interleukin
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Receptors, Interleukin-1
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Phosphotransferases (Alcohol Group Acceptor)
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Interleukin-1 Receptor-Associated Kinases