Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
34536415
DOI
10.1016/j.jaci.2021.07.046
PII: S0091-6749(21)01395-6
Knihovny.cz E-zdroje
- Klíčová slova
- SRC-family kinase, autoinflammation, cutaneous vasculitis, hematopoietic cell kinase, inborn error of immunity, inflammatory cytokines, pulmonary hemorrhage, reactive oxygen species, ruxolitinib,
- MeSH
- lidé MeSH
- plíce MeSH
- protoonkogenní proteiny c-hck genetika metabolismus MeSH
- protoonkogenní proteiny genetika MeSH
- skupina kinas odvozených od src-genu * genetika MeSH
- vaskulitida * genetika patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- HCK protein, human MeSH Prohlížeč
- protoonkogenní proteiny c-hck MeSH
- protoonkogenní proteiny MeSH
- skupina kinas odvozených od src-genu * MeSH
BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.
Department of Pediatrics and Adolescent Medicine University Medical Center Ulm Ulm Germany
Department of Pediatrics Horovice Hospital Horovice Czech Republic
Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic
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