Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
Summary Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. 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 reveal increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on 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. These findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 01. Okt. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.1101/2022.09.27.22280319 |
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| PPN (Katalog-ID): |
XBI037437011 |
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| 100 | 1 | |a de Jesus, Adriana A. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome |
| 264 | 1 | |c 2022 | |
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| 520 | |a Summary Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. 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 reveal increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on 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. These findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis. | ||
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