title: PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity.
abstract: BACKGROUND
  PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.
  
  
  OBJECTIVE
  We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.
  
  
  METHODS
  Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.
  
  
  RESULTS
  We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.
  
  
  CONCLUSIONS
  Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; CNRS, UMR5308, Lyon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mathieu
authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France.
authors.forename: Estelle
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authors.lastname: Verronese
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Centre, Manchester, United Kingdom.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Pediatric Haematology and Oncology Department, Children Hospital-CHU NANCY Vandoeuvre les Nancy, Nancy, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Fouyssac
authors.affiliation: Institut d'Hématologie et d'Oncologie Pédiatrique (Hospices Civils de Lyon), Université Claude Bernard Lyon I, Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Sorbonne Paris Cité, Paris Descartes University, Imagine Institute, Paris Descartes University, Paris, France.
authors.forename: Capucine
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authors.lastname: Picard
authors.affiliation: INSERM UMR 1163, Laboratoire Dynamique du Génome et Système Immunitaire Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Chansel
authors.affiliation: Pediatric Allergy & Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
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authors.affiliation: Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
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authors.affiliation: Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Stanford University, Stanford, Calif.
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authors.affiliation: Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Stanford University, Stanford, Calif.
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authors.affiliation: Pediatric Allergy & Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
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authors.affiliation: Division of Molecular Radiation Biology Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Tex.
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authors.initials: DJ
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authors.affiliation: Department of Pediatrics, Division of Allergy, Immunology & Rheumatology, University of Utah School of Medicine, Salt Lake City, Utah.
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authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France.
authors.forename: Ana
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authors.lastname: Delgado
authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France.
authors.forename: Chantal
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authors.lastname: Rigal
authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France.
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authors.affiliation: INSERM UMR 1163, Laboratoire Dynamique du Génome et Système Immunitaire Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
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authors.affiliation: Pathology Department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
authors.forename: Brigitte
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authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; CNRS, UMR5308, Lyon, France; Immunobiology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Viel
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; CNRS, UMR5308, Lyon, France; Immunobiology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.
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authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France.
authors.forename: Christophe
authors.initials: C
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authors.forename: E Helen
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authors.affiliation: Biotechnology Department, Hospices Civils de Lyon, Lyon, France.
authors.forename: Isabelle
authors.initials: I
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authors.affiliation: Cell Immunology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
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authors.affiliation: Virology Unit, Hopital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
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authors.affiliation: Immunoscope Group, Immunology Department, Institut Pasteur, Paris, France.
authors.forename: Annick
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authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Centre, Manchester, United Kingdom.
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authors.affiliation: Immunobiology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Fabien
authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Ménétrier-Caux
authors.affiliation: INSERM UMR 1163, Laboratoire Dynamique du Génome et Système Immunitaire Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: De Villartay
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; CNRS, UMR5308, Lyon, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; CNRS, UMR5308, Lyon, France; Pediatric Rheumatology, Nephrology and Dermatology Department and EPICIME Hospices Civils de Lyon and Université Claude-Bernard Lyon 1, Lyon, France. Electronic address: alexandre.belot@chu-lyon.fr.
authors.forename: Alexandre
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authors.lastname: Belot
mesh_terms: D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059766:DNA End-Joining Repair / Q000276:immunology; D051747:DNA-Activated Protein Kinase / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006099:Granuloma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D060152:V(D)J Recombination / Q000276:immunology; D055815:Young Adult; D000096927:AIRE Protein
chemical_list: D001323:Autoantibodies; D051747:DNA-Activated Protein Kinase; D009687:Nuclear Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C497263:PRKDC protein, human
keywords: Autoimmune regulator; DNA-dependent protein kinase catalytic subunit; PRKDC; VDJ recombination; autoimmunity; recombination-activating gene; severe combined immunodeficiency; tolerance
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