C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib.

Autor: Kapp FG; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany. Electronic address: friedrich.kapp@uniklinik-freiburg.de., Kretschmer S; Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Beckmann CCA; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Wäsch L; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Molitor A; Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France., Carapito R; Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France., Schubert M; Institute of Pharmacology and Toxicology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Lucas N; Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Conrad S; Service de Génétique Médicale, CHU Nantes, Nantes, France., Poignant S; Service de pédiatrie, CHU de Nantes, Nantes, France., Isidor B; Service de Génétique Médicale, CHU Nantes, Nantes, France., Rohlfs M; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Kisaarslan AP; Erciyes University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Rheumatology, 38039 Melikgazi, Kayseri, Türkiye., Schanze D; Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany., Zenker M; Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany., Schmitt-Graeff A; University of Freiburg, Freiburg, Germany., Strahm B; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Peters A; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Yoshimi A; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Driever W; Developmental Biology, Faculty of Biology, Institute of Biology 1, Albert-Ludwigs-University of Freiburg, Freiburg, Germany., Zillinger T; Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany., Günther C; Department of Dermatology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Maharana S; Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India., Guan K; Institute of Pharmacology and Toxicology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Klein C; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Ehl S; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany., Niemeyer CM; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Unal E; Erciyes University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology-Oncology, 38039 Melikgazi, Kayseri, Turkey., Bahram S; Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France., Hauck F; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Lee-Kirsch MA; Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Speckmann C; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
Jazyk: angličtina
Zdroj: Clinical immunology (Orlando, Fla.) [Clin Immunol] 2023 Nov; Vol. 256, pp. 109777. Date of Electronic Publication: 2023 Sep 22.
DOI: 10.1016/j.clim.2023.109777
Abstrakt: C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH.
Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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