Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F23%3A00575264" target="_blank" >RIV/68378050:_____/23:00575264 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064203:_____/23:10458064 RIV/00216208:11130/23:10458064

Výsledek na webu

<a href="https://www.nature.com/articles/s41467-023-36941-y" target="_blank" >https://www.nature.com/articles/s41467-023-36941-y</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-023-36941-y" target="_blank" >10.1038/s41467-023-36941-y</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Popis výsledku v původním jazyce

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases, pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of beta 2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation, and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis. Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.

Název v anglickém jazyce

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Popis výsledku anglicky

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases, pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of beta 2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation, and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis. Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

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

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Svazek periodika

14

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

1502

Kód UT WoS článku

001040483800005

EID výsledku v databázi Scopus

2-s2.0-85150441908