Suchergebnisse

PubMed ID: 24186907 ; Background. Interleukin 12Rß1 (IL-12Rß1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rß1 deficiency.Results. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin.Conclusions. Patients who are deficient in IL-12Rß1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients. © The Author 2013. ; University of Chicago Tehran University of Medical Sciences and Health Services Institut National de la Santé et de la Recherche Médicale Rockefeller University Ege Üniversitesi University College London Istanbul Üniversitesi City, University of London, City Comer Children's Hospital, University of Chicago Medicine St. Giles Foundation Université Paris Descartes Ministerio de Economía y Competitividad: PI10/01718, PI06/ 1031 National Center for Advancing Translational Sciences: 8UL1TR000043 Institut National de la Santé et de la Recherche Médicale Fundación Canaria de Investigación y Salud, FUNCIS Ministerio de Ciencia y Tecnología, MICYT: 182817, 69992 European Social Fund, ESF Agence Nationale de la Recherche: GENCMCD 11-BSV3-005-01 Universidad de Las Palmas de Gran Canaria Rockefeller University ANR-10-LABX-62-IBEID National Center for Research Resources European Research Council European Regional Development Fund INREDCAN 05/06 ; 1Pediatric Hematology-Immunology Unit, National Bone Marrow Transplantation Center, Tunis, 2Faculty of Medicine, University of Tunis El Manar, 3Laboratory of Cytoimmunology, Pasteur Institut of Tunis, and 4Department of Cardiology, Ariana Hospital, Tunis, Tunisia; 5Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, 6Immunology Division, Hacettepe University Children's Hospital, 7Department of Pediatric Infectious Diseases, Dr Sami Ulus Maternity and Children's Health and Diseases Training and Research Center, and 8Department of Pediatric Immunology, Dr Sami Ulus Children's Health and Diseases Training and Research Center, Ankara, 9Department of Pediatric Infectious Diseases and Clinical Immunology, Istanbul University and Istanbul Medical Faculty, 10Department of Pediatric Immunology, Ege University Faculty of Medicine, Izmir, and 11Department of Pediatric Immunology, Necmettin Erbakan University Meram Medical Faculty, Konya, Turkey; 12Department of Immunology, Gran Canaria Dr Negrín University Hospital, 13Department of Pediatrics and 14Department of Internal Medicine, Complejo Hospitalario Universitario Insular Materno Infantil, and 15Department of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria, Spain; 16Unit of Biochemistry and 17Laboratory of Microbiology, National Institute of Medical Sciences and Nutrition Salvador Zubirán (INCMNSZ), and 18Department of Pediatric Pulmonology, Laboratory of Pulmonary Physiology, Hospital Infantil de México Federico Gómez, Mexico City; 19Department of Internal Medicine, University Hospital, Maastricht, Netherlands; 20Department of Clinical Biochemistry and Immunology, Addenbrookes Hospital, Cambridge, and 21Department of Medicine, University College London, United Kingdom; 22Pediatric Department, Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; 23Department of Pediatric Infectious Diseases, Comer Children's Hospital, University of Chicago Medicine, and 24Department of Pediatrics, University of Chicago Medical Center, Illinois; 25St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York; 26Department of Pediatrics, UFRJ–Federal University of Rio de Janeiro, Brazil; 27Group of Primary Immunodeficiencies, University of Antioquia, Medellin, Colombia; 28Department of Pediatrics, Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Iran; 29Department of Pediatrics, Hospital Puerto Montt, Chile; 30Department of ?linical Immunology, Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russia; 31Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, 32University Paris Descartes, Imagine Institute, 33Study Center for Primary Immunodeficiencies, Necker Hospital, AP-HP, and 34Pediatric Hematology-Immunology Unit, Necker-Enfants Malades Hospital, AP-HP, Paris, France -- Financial support. This work was supported by Fondo de Investiga-ciones Sanitarias, Ministerio de Economía y Competitividad (grants PI06/ 1031 and PI10/01718), the European Regional Development Fund–European Social Fund (FEDER-FSE), Fundación Canaria de Investigación y Salud (Canarian government; INREDCAN 05/06), Foundation Caja Rural de Cana-rias-Chil y Naranjo (research prize 2004), Universidad de Las Palmas de Gran Canaria (fellowship to E. H. R), INSERM, University Paris Descartes, Rockefeller University, National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (grant 8UL1TR000043), Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" (grant ANR-10-LABX-62-IBEID), the European Research Council, Agence Nationale de la Recherche (grant GENCMCD 11-BSV3-005-01), the St Giles Foundation, the Candidoser Association, and Consejo Nacio-nal de Ciencia y Tecnología de Mexico (grants 69992 and 182817). Potential conflicts of interest. All authors: No reported conflicts. --

Abstract The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo. ; The Laboratory of Human Genetics of Infectious Diseases is supported by the Agence Nationale de la Recherche, the Programme Hospitalier de Recherche Clinique, the European Union (grant LHSP-CT-2005-018736), the BNP Paribas Foundation, the March of Dimes, the Dana Foundation, and the Candi'Oser Association. L. de Beaucoudrey is supported by the Fondation pour la Recherche Medicale as part of the PhD program of Pierre et Marie Curie University. J.L. Casanova is an International Scholar of the Howard Hughes Medical Institute.