title: Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts.
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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Erika
authors.identifier: 0000-0001-8733-7623
authors.initials: E
authors.lastname: Della Mina
authors.affiliation: Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy.|Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Borghesi
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Salim
authors.initials: S
authors.lastname: Bougarn
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Sabri
authors.initials: S
authors.lastname: Boughorbel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Israel
authors.affiliation: Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.|Medical Genetics, University Hospital of Siena, 53100 Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy.|Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Mazzucchelli
authors.affiliation: Laboratory of Transplant Immunology/Cell Factory, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Basso
authors.affiliation: General Paediatrics Operative Unit, Vittorio Emanuele University Hospital, University of Catania, 95100 Catania, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Pavone
authors.affiliation: General Paediatrics Operative Unit, Vittorio Emanuele University Hospital, University of Catania, 95100 Catania, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Falsaperla
authors.affiliation: Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.affiliation: Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Cerbo
authors.affiliation: Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy.|Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Stronati
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, 75015 Paris, France.|Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, 75015 Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Nico
authors.initials: N
authors.lastname: Marr
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; casanova@rockefeller.edu anne.puel@inserm.fr.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.|Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, 75015 Paris, France.|Howard Hughes Medical Institute, New York, NY 10065.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; casanova@rockefeller.edu anne.puel@inserm.fr.|Imagine Institute, Paris Descartes University, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
mesh_terms: D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency* / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: IRAK-1; IRAK-4; Toll-like receptor; interleukin-1 receptor; primary immunodeficiency