title: Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.
abstract: Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Weill Cornell Graduate School of Medical Sciences, New York, NY 10065.
authors: Alexandra Y
authors: AY
authors: Kreins
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Michael J
authors: MJ
authors: Ciancanelli
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Satoshi
authors: S
authors: Okada
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Xiao-Fei
authors: XF
authors: Kong
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Noé
authors: N
authors: Ramírez-Alejo
authors: Department of Pediatric Immunology, Uludağ University Faculty of Medicine, 16059 Görükle, Bursa, Turkey.
authors: Sara Sebnem
authors: SS
authors: Kilic
authors: Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.
authors: Jamila
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authors: Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan.
authors: Shigeaki
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authors: Nonoyama
authors: Pediatric Respiratory Diseases Research Center; and Department of Clinical Immunology and Infectious Diseases, Masih Daneshvari Hospital; National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 141556153 Tehran, Iran.
authors: Seyed Alireza
authors: SA
authors: Mahdaviani
authors: Clinical Immunology Unit, Department of Pediatrics, King Hassan II University, CHU Ibn Rochd, 20000 Casablanca, Morocco.
authors: Fatima
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authors: Ailal
authors: Clinical Immunology Unit, Department of Pediatrics, King Hassan II University, CHU Ibn Rochd, 20000 Casablanca, Morocco.
authors: Aziz
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authors: Bousfiha
authors: Pediatric Respiratory Diseases Research Center; and Department of Clinical Immunology and Infectious Diseases, Masih Daneshvari Hospital; National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 141556153 Tehran, Iran.
authors: Davood
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authors: Immunology Unit, Pediatric Hospital A. Fleming-OSEP, Mendoza 5500, Argentina.
authors: Elma
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authors: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors: Cindy S
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authors: Ma
authors: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors: Geetha
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authors: Immunology and Rheumatology Service, Garrahan Hospital, Buenos Aires 1408, Argentina.
authors: Andrea
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authors: Department of Laboratory Medicine, Clinical Center; and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD 20892.
authors: Hye
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authors: Sun Kuehn
authors: Department of Laboratory Medicine, Clinical Center; and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD 20892.
authors: Julie
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authors: Department of Laboratory Medicine, Clinical Center; and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD 20892.
authors: Jennifer
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authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Paul
authors: P
authors: Deveau
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Aurelie
authors: A
authors: Cobat
authors: Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco Faculty of Science-Kenitra, Ibn Tofaïl University, 14000 Kenitra, Morocco.
authors: Safa
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authors: Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco Faculty of Science-Kenitra, Ibn Tofaïl University, 14000 Kenitra, Morocco.
authors: Ayoub
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authors: Sabri
authors: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden Department of Clinical Research, Singapore General Hospital, Singapore 169856.
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authors: Pediatric Hematology/Immunology, Astrid Lindgrens Children's Hospital and Karolinska Institutet, 141 86 Stockholm, Sweden.
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authors: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors: Danielle T
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authors: Avery
authors: Asthma Research Chair and Prince Naif Center for Immunology Research, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia.
authors: Rabih
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authors: Halwani
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Audrey V
authors: AV
authors: Grant
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Bertrand
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authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Dusan
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authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Yuval
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authors: Itan
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Group of Primary Immunodeficiencies, Institute of Biology, University of Antioquia UdeA, 1226 Medellín, Colombia.
authors: Marcela
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authors: Moncada-Velez
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors: Ruben
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authors: Martinez-Barricarte
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Melanie
authors: M
authors: Migaud
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Caroline
authors: C
authors: Deswarte
authors: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, TX 75204 Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, TX 75204 Allergy and Clinical Immunology Department, Hospital Sant Joan de Deu, Barcelona University, 08950 Barcelona, Spain.
authors: Laia
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authors: Alsina
authors: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, D-80337 Munich, Germany.
authors: Daniel
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authors: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, D-80337 Munich, Germany.
authors: Christoph
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authors: Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany.
authors: Ingrid
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authors: Muller-Fleckenstein
authors: Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany.
authors: Bernhard
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authors: Valerie
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authors: Cormier-Daire
authors: Institute of Biochemistry, University of Kiel, D-24098 Kiel, Germany.
authors: Stefan
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authors: Rose-John
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Enfants Malades Hospital, 75015 Paris, France.
authors: Capucine
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authors: Picard
authors: Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden.
authors: Lennart
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authors: Hammarstrom
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Anne
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authors: Puel
authors: Asthma Research Chair and Prince Naif Center for Immunology Research, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia.
authors: Saleh
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authors: Al-Muhsen
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France.
authors: Laurent
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authors: Department of Laboratory Medicine, Clinical Center; and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD 20892 Department of Laboratory Medicine, Clinical Center; and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD 20892.
authors: Sergio D
authors: SD
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authors: Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Yoshiyuki
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authors: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors: Stuart G
authors: SG
authors: Tangye
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Enfants Malades Hospital, 75015 Paris, France.
authors: Jacinta
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authors: Bustamante
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France Pediatric Immunology and Hematology Unit, Necker Enfants Malades Hospital, 75015 Paris, France Howard Hughes Medical Institute, New York, NY 10065.
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France stbo603@rockefeller.edu.
authors: Stéphanie
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mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology; D053759:Interleukin-23 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007589:Job Syndrome / Q000150:complications / Q000209:etiology* / Q000235:genetics; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009154:Mutation; D009164:Mycobacterium Infections / Q000209:etiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D053634:TYK2 Kinase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014777:Virus Diseases / Q000209:etiology; D055815:Young Adult
chemical_list: D053759:Interleukin-23; D015850:Interleukin-6; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D053634:TYK2 Kinase; C070139:TYK2 protein, human