Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F22%3A10432141" target="_blank" >RIV/00216208:11130/22:10432141 - isvavai.cz</a>
Alternative codes found
RIV/00064203:_____/22:10432141 RIV/00216224:14740/22:00128769
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=EhJos27VtJ" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=EhJos27VtJ</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.jaci.2021.07.046" target="_blank" >10.1016/j.jaci.2021.07.046</a>
Alternative languages
Result language
angličtina
Original language name
Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK
Original language description
BACKGROUND: Inborn errors of immunity (IEI) 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 IEI, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We 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 TNFα 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 (JAK) 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSION: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of IEI.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30102 - Immunology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Allergy and Clinical Immunology
ISSN
0091-6749
e-ISSN
1097-6825
Volume of the periodical
149
Issue of the periodical within the volume
4
Country of publishing house
US - UNITED STATES
Number of pages
9
Pages from-to
1464-1472
UT code for WoS article
000820784100013
EID of the result in the Scopus database
2-s2.0-85119213084