PUBLICATION
C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib
- Authors
- Kapp, F.G., Kretschmer, S., Beckmann, C.C.A., Wäsch, L., Molitor, A., Carapito, R., Schubert, M., Lucas, N., Conrad, S., Poignant, S., Isidor, B., Rohlfs, M., Kisaarslan, A.P., Schanze, D., Zenker, M., Schmitt-Graeff, A., Strahm, B., Peters, A., Yoshimi, A., Driever, W., Zillinger, T., Günther, C., Maharana, S., Guan, K., Klein, C., Ehl, S., Niemeyer, C.M., Unal, E., Bahram, S., Hauck, F., Lee-Kirsch, M.A., Speckmann, C.
- ID
- ZDB-PUB-240205-7
- Date
- 2023
- Source
- Clinical immunology (Orlando, Fla.) 256: 109777109777 (Journal)
- Registered Authors
- Driever, Wolfgang, Kapp, Friedrich
- Keywords
- Autoinflammation, CDC42, JAK inhibition, NOCARH, Ruxolitinib, Type I interferonopathy
- MeSH Terms
-
- Humans
- Infant, Newborn
- Inflammasomes/genetics
- Interferon Type I*
- Lymphohistiocytosis, Hemophagocytic*/etiology
- Nitriles
- Syndrome
- cdc42 GTP-Binding Protein
- PubMed
- 37741518 Full text @ Clin Immunol
Citation
Kapp, F.G., Kretschmer, S., Beckmann, C.C.A., Wäsch, L., Molitor, A., Carapito, R., Schubert, M., Lucas, N., Conrad, S., Poignant, S., Isidor, B., Rohlfs, M., Kisaarslan, A.P., Schanze, D., Zenker, M., Schmitt-Graeff, A., Strahm, B., Peters, A., Yoshimi, A., Driever, W., Zillinger, T., Günther, C., Maharana, S., Guan, K., Klein, C., Ehl, S., Niemeyer, C.M., Unal, E., Bahram, S., Hauck, F., Lee-Kirsch, M.A., Speckmann, C. (2023) C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib. Clinical immunology (Orlando, Fla.). 256:109777109777.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping