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

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

  • Clin Immunol. 2023 Sep 21;109777. doi: 10.1016/j.clim.2023.109777.
Friedrich G Kapp 1,  Stefanie Kretschmer 2,  Cora C A Beckmann 3,  Lena Wäsch 3,  Anne Molitor 4,  Raphaël Carapito 4,  Mario Schubert 5,  Nadja Lucas 2,  Solène Conrad 6,  Sylvaine Poignant 7,  Bertrand Isidor 6,  Meino Rohlfs 8,  Ayşenur Paç Kisaarslan 9,  Denny Schanze 10,  Martin Zenker 10,  Annette Schmitt-Graeff 11,  Brigitte Strahm 3,  Anke Peters 3,  Ayami Yoshimi 3,  Wolfgang Driever 12,  Thomas Zillinger 13,  Claudia Günther 14,  Shovamayee Maharana 15,  Kaomei Guan 5,  Christoph Klein 8,  Stephan Ehl 16,  Charlotte M Niemeyer 3,  Ekrem Unal 17,  Seiamak Bahram 4,  Fabian Hauck 8,  Min Ae Lee-Kirsch 2,  Carsten Speckmann 18
Affiliations

Affiliations

  • 1 Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany. Electronic address: [email protected].
  • 2 Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 3 Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
  • 4 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.
  • 5 Institute of Pharmacology and Toxicology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 6 Service de Génétique Médicale, CHU Nantes, Nantes, France.
  • 7 Service de pédiatrie, CHU de Nantes, Nantes, France.
  • 8 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 9 Erciyes University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Rheumatology, 38039 Melikgazi, Kayseri, Türkiye.
  • 10 Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany.
  • 11 University of Freiburg, Freiburg, Germany.
  • 12 Developmental Biology, Faculty of Biology, Institute of Biology 1, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • 13 Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany.
  • 14 Department of Dermatology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 15 Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India.
  • 16 Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
  • 17 Erciyes University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology-Oncology, 38039 Melikgazi, Kayseri, Turkey.
  • 18 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.
PMID: 37741518 DOI: 10.1016/j.clim.2023.109777
Abstract

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.

Keywords

Autoinflammation; CDC42; JAK inhibition; NOCARH; Ruxolitinib; Type I interferonopathy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12874
    99.82%, GTPase Cdc42 Inhibitor