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

Kapp, FG and Kretschmer, S and Beckmann, CCA and Wäsch, L and Molitor, A and Carapito, R and Schubert, M and Lucas, N and Conrad, S and Poignant, S and Isidor, B and Rohlfs, M and Kisaarslan, AP and Schanze, D and Zenker, M and Schmitt-Graeff, A and Strahm, B and Peters, A and Yoshimi, A and Driever, W and Zillinger, T and Günther, C and Maharana, S and Guan, K and Klein, C and Ehl, S and Niemeyer, CM and Unal, E and Bahram, S and Hauck, F and Lee-Kirsch, MA and Speckmann, C (2023) C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib. In: Clinical Immunology, 256 .

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Official URL: https://doi.org/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. © 2023 Elsevier Inc.

Item Type: Journal Article
Publication: Clinical Immunology
Publisher: Academic Press Inc.
Additional Information: The copyright for this article belongs to the Academic Press Inc.
Keywords: anakinra; canakinumab; corticosteroid; cyclosporine; emapalumab; immunoglobulin; interferon; Janus kinase 1; Janus kinase 2; nucleic acid; prednisone; protein Cdc42; ruxolitinib; tocilizumab; treosulfan, allogeneic hematopoietic stem cell transplantation; animal cell; animal experiment; animal tissue; Article; autoinflammatory disease; carboxy terminal sequence; case report; child; clinical article; controlled study; cytosol; embryo; enzyme inhibition; female; gene mutation; graft versus host reaction; human; human cell; immunopathogenesis; innate immunity; male; mitochondrion; neonatal onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis; nonhuman; palliative therapy; phenotype; preschool child; remission; treatment response; type I interferon signaling; zebra fish
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 01 Dec 2023 03:49
Last Modified: 01 Dec 2023 03:49
URI: https://eprints.iisc.ac.in/id/eprint/83384

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