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

• Published in: Clinical immunology (Orlando, Fla.) Vol. 256; p. 109777
• Main Authors: Kapp, Friedrich G., Kretschmer, Stefanie, Beckmann, Cora C.A., Wäsch, Lena, Molitor, Anne, Carapito, Raphaël, Schubert, Mario, Lucas, Nadja, Conrad, Solène, Poignant, Sylvaine, Isidor, Bertrand, Rohlfs, Meino, Kisaarslan, Ayşenur Paç, Schanze, Denny, Zenker, Martin, Schmitt-Graeff, Annette, Strahm, Brigitte, Peters, Anke, Yoshimi, Ayami, Driever, Wolfgang, Zillinger, Thomas, Günther, Claudia, Maharana, Shovamayee, Guan, Kaomei, Klein, Christoph, Ehl, Stephan, Niemeyer, Charlotte M., Unal, Ekrem, Bahram, Seiamak, Hauck, Fabian, Lee-Kirsch, Min Ae, Speckmann, Carsten
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-11-2023; Elsevier
• Subjects: Autoinflammation; CDC42; Immunology; JAK inhibition; Life Sciences; NOCARH; Ruxolitinib; Type I interferonopathy; CDC42; Ruxolitinib; Autoinflammation; Type I interferonopathy; JAK inhibition; NOCARH; dpf; NGS; hpf; genetics, etiology
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2023.109777

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.
•C-terminal mutations in CDC42 lead to a previously unrecognized type I interferonopathy in NOCARH syndrome.•Autoinflammation is caused by innate immune activation due to sensing of cytosolic nucleic acids released from mitochondria.•JAK1/2 inhibition with ruxolitinib can control autoinflammatory symptoms in patients with NOCARH syndrome.