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Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E514-E523. doi: 10.1073/pnas.1620139114. Epub 2017 Jan 9.

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.
2
Imagine Institute, Paris Descartes University, 75015 Paris, France.
3
Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy.
4
Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy.
5
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106.
6
Sidra Medical and Research Center, Doha, Qatar.
7
Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
8
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
9
Medical Genetics, University Hospital of Siena, 53100 Siena, Italy.
10
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
11
Laboratory of Transplant Immunology/Cell Factory, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy.
12
General Paediatrics Operative Unit, Vittorio Emanuele University Hospital, University of Catania, 95100 Catania, Italy.
13
Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
14
Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, 75015 Paris, France.
15
Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, 75015 Paris, France.
16
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; casanova@rockefeller.edu anne.puel@inserm.fr.
17
Howard Hughes Medical Institute, New York, NY 10065.

Abstract

Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.

KEYWORDS:

IRAK-1; IRAK-4; Toll-like receptor; interleukin-1 receptor; primary immunodeficiency

PMID:
28069966
PMCID:
PMC5278481
DOI:
10.1073/pnas.1620139114
[Indexed for MEDLINE]
Free PMC Article

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