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Nat Immunol. 2014 Dec;15(12):1134-42. doi: 10.1038/ni.3028. Epub 2014 Oct 26.

A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.

Author information

1
1] Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA. [2] Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona Universitat de Barcelona, Barcelona, Spain.
2
Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
3
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France.
4
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] Department of Pediatric Pneumology and Immunology, Charité Hospital-Humboldt University, Berlin, Germany.
5
Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
6
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA.
7
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA. [4] Study Center of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris, France. [5] Howard Hughes Medical Institute, New York, USA.
8
1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA. [4] Howard Hughes Medical Institute, New York, USA. [5] Pediatric Hematology-Immunology Unit, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
9
1] Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA. [2] Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA. [3] Sidra Medical and Research Center, Doha, Qatar.

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.

Comment in

PMID:
25344726
PMCID:
PMC4281021
DOI:
10.1038/ni.3028
[Indexed for MEDLINE]
Free PMC Article

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