Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.
Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.
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DOI：
10.1038/s41467-023-36941-y
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发表时间：
2023-03-17
影响因子：
16.6
通讯作者：
Goldbach-Mansky, Raphaela
中科院分区：
文献类型：
--
作者：
de Jesus, Adriana A.;Chen, Guibin;Yang, Dan;Brdicka, Tomas;Ruth, Natasha M.;Bennin, David;Cebecauerova, Dita;Malcova, Hana;Freeman, Helen;Martin, Neil;Svojgr, Karel;Passo, Murray H.;Bhuyan, Farzana;Alehashemi, Sara;Rastegar, Andre T.;Uss, Katsiaryna;Kardava, Lela;Marrero, Bernadette;Duric, Iris;Omoyinmi, Ebun;Peldova, Petra;Lee, Chyi-Chia Richard;Kleiner, David E.;Hadigan, Colleen M.;Hewitt, Stephen M.;Pittaluga, Stefania;Carmona-Rivera, Carmelo;Calvo, Katherine R.;Shah, Nirali;Balascakova, Miroslava;Fink, Danielle L.;Kotalova, Radana;Parackova, Zuzana;Peterkova, Lucie;Kuzilkova, Daniela;Campr, Vit;Sramkova, Lucie;Biancotto, Angelique;Brooks, Stephen R.;Manes, Cameron;Meffre, Eric;Harper, Rebecca L.;Kuehn, Hyesun;Kaplan, Mariana J.;Brogan, Paul;Rosenzweig, Sergio D.;Merchant, Melinda;Deng, Zuoming;Huttenlocher, Anna;Moir, Susan L.;Kuhns, Douglas B.;Boehm, Manfred;Kramarzova, Karolina Skvarova;Goldbach-Mansky, Raphaela
嗜中性粒细胞炎症是许多单基因自身炎性疾病的标志;调节破坏性免疫细胞外渗到周围组织中的病理机制知之甚少。在这里，我们确定了三个不相关的男孩围产期发病的嗜中性皮肤小血管炎和全身炎症。两名患者在生命的第一年发生肝纤维化。下一代测序鉴定了Src家族酪氨酸激酶中的两种从头截短变体，林恩，p.Y508*，p.Q507* 和一种从头错义变体，p.Y508 F，其导致林恩激酶的组成性激活。功能研究显示，诱导的患者源性内皮细胞（iEC）上ICAM-1的表达增加，患者中性粒细胞上β2-整合素的表达增加，从而增加中性粒细胞粘附和血管跨内皮迁移（TEM）。TNF抑制治疗改善了全身炎症; Src激酶抑制剂达沙替尼治疗后，肝纤维化消退。我们的研究结果揭示了林恩激酶在调节炎症信号，调节微血管通透性和中性粒细胞募集以及促进肝纤维化中的关键作用。嗜中性粒细胞炎症是许多单基因自身炎性疾病的标志。作者在此报告了3例无血缘关系的男孩围产期发作的嗜中性皮肤小血管炎和全身性炎症的病例系列，并确定了Src家族酪氨酸激酶林恩的新生截短和错义变体。
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 β2-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.
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DOI：
10.1084/jem.20020515
发表时间：
2002-12-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hibbs ML;Harder KW;Armes J;Kountouri N;Quilici C;Casagranda F;Dunn AR;Tarlinton DM
通讯作者：
Tarlinton DM
影响因子：
7
作者：
Jin, Lily L.;Wybenga-Groot, Leanne E.;Moran, Michael F.
通讯作者：
Moran, Michael F.
影响因子：
16.1
作者：
Higashi T;Friedman SL;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
20.3
作者：
Han, Jingyan;Zhang, Guoying;Li, Zhenyu
通讯作者：
Li, Zhenyu
影响因子：
13.3
作者：
Louvrier, Camille;El Khouri, Elma;Giurgea, Irina
通讯作者：
Giurgea, Irina