Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00064203:_____/22:10432141 RIV/00216224:14740/22:00128769

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Allergy and Clinical Immunology

ISSN

0091-6749

e-ISSN

1097-6825

Svazek periodika

149

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

9

Strana od-do

1464-1472

Kód UT WoS článku

000820784100013

EID výsledku v databázi Scopus

2-s2.0-85119213084