Contributors: Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases; Centre International de Recherche en Infectiologie (CIRI); École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL); Centre Léon Bérard Lyon -Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Manchester Centre for Genomic Medicine Manchester, UK (MCGM); St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC); University of Manchester Manchester -University of Manchester Manchester -Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health Manchester, UK; University of Manchester Manchester; Service d'Oncologie Pédiatrique CHRU Nancy; Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy); Institut d'hématologie et d'oncologie pédiatrique CHU - HCL (IHOPe); Hospices Civils de Lyon (HCL); Imagine - Institut des maladies génétiques (IMAGINE - U1163); Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM); Center for Immunology and Inflammatory Diseases Boston, MA, USA; Harvard Medical School Boston (HMS); Department of Microbiology and Immunology Stanford; Stanford Medicine; Stanford University-Stanford University; University of Texas Southwestern Medical Center; School of Medicine University of Utah, Salt Lake City; University of Utah; Department of Pediatrics and Adolescent Medicine; Universität Ulm - Ulm University Ulm, Allemagne; Unité Pédiatrique Jeanne de Flandre; Hôpital Jeanne de Flandre Lille; Service de Pathologie CHRU Nancy; Epidémiologie, Pharmacologie, Investigation Clinique, Information médicale, Mère-Enfant (EPICIME); Département de Pathologie CHU Lyon-Sud - HCL; Centre Hospitalier Lyon Sud CHU - HCL (CHLS); Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL); Erasmus University Medical Center Rotterdam (Erasmus MC); University of Sheffield Sheffield; Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France; parent; Service de Virologie CHU Cochin; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Institut Pasteur Paris (IP)
نبذة مختصرة : International audience ; 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. CONCLUSION: 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.
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