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- Title
A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.
- Authors
Alsina, Laia; Israelsson, Elisabeth; Altman, Matthew C; Dang, Kristen K; Ghandil, Pegah; Israel, Laura; von Bernuth, Horst; Baldwin, Nicole; Qin, Huanying; Jin, Zongbo; Banchereau, Romain; Anguiano, Esperanza; Ionan, Alexei; Abel, Laurent; Puel, Anne; Picard, Capucine; Pascual, Virginia; Casanova, Jean Laurent; Chaussabel, Damien
- Abstract
Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.
- Subjects
GENETIC transcription; GENETIC mutation; MYELOID differentiation factor 88; ADAPTOR proteins; INTERLEUKIN-1 receptors; PROTEIN kinases
- Publication
Nature Immunology, 2014, Vol 15, Issue 12, p1134
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni.3028