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

Kapp F. G., Kretschmer S., Beckmann C. C., Wäsch L., Molitor A., Carapito R., ...Daha Fazla

CLINICAL IMMUNOLOGY, cilt.256, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 256
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1016/j.clim.2023.109777
  • Dergi Adı: CLINICAL IMMUNOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Autoinflammation, CDC42, JAK inhibition, NOCARH, Ruxolitinib, Type I interferonopathy
  • Erciyes Üniversitesi Adresli: Evet

Özet

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.