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¹ Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France
² Necker Medical School, University Paris Rene Descartes, 75015 Paris, France
³ Department of Pediatrics, Technical University Dresden, 01309 Dresden, Germany
⁴ Department of Pediatrics, Dalhousie University, Halifax B3K 6R8, Nova Scotia, Canada
⁵ Department of Pediatrics, Duke University Medical Center, Durham, NC 27710
⁶ Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
⁷ Divison of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Ontario, Canada
⁸ Center for Pediatrics and Adolescent Medicine, University of Freiburg, 79106 Freiburg, Germany
⁹ Royal Children's Hospital, Parkville, Victoria 3052, Australia
¹⁰ Dynavax Technologies, Berkeley, CA 94710
¹¹ Division of Infectious Diseases and ¹² Division of Immunology, Children's Hospital Boston, Boston, MA 02115
¹³ Harvard Medical School, Boston, MA 02115
¹⁴ Department of Pediatrics, Division of Allergy and Immunology, University of South Florida and All Children's Hospital, St. Petersburg, FL 33701
¹⁵ 3M Center, St. Paul, MN 55144
¹⁶ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
¹⁷ Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Kingdom of Saudi Arabia
¹⁸ Centre for Infectious and Inflammatory Diseases, Child and Family Research Institute, Vancouver V5Z 4H4, British Columbia, Canada
¹⁹ Immunodeficiency Investigation Center, ²⁰ Laboratory of Histology, Embryology and Cytogenetics, Department of Molecular Cytogenetics and ²¹ Pediatric Hematology-Immunology Unit, Necker Hospital, 75015 Paris, France
²² Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195
²³ U838, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France
²⁴ Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale–Centre National de la Recherche Scientifique, Université Mediterranee, Campus de Luminy, 13288 Marseille, France
²⁵ Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Hungary
²⁶ Department of Pediatrics, Schneider Children's Medical Center of Israel, Petah Tiqva 49202, Israel
²⁷ Department of Immunology, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, England UK
²⁸ Department of Immunology, Hospital Universitario de Gran Canaria Dr. Negrín, 35020 Las Palmas de Gran Canaria, Spain
²⁹ Experimental Laboratory Medicine, University Hospital Leuven, 3000 Leuven, Belgium

CORRESPONDENCE Jean-Laurent Casanova: casanova{at}necker.fr

Human interleukin (IL) 1 receptor–associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3– and TLR4–interferon (IFN)-a/b pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4–dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4–dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.

C.-L. Ku and H. von Bernuth contributed equally to this work.

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