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

0575264 - ÚMG 2024 RIV US eng J - Journal Article
de Jesus, A. A. - Chen, G. - Yang, D. - Brdička, Tomáš - Ruth, N. M. - Bennin, D. - Cebecauerová, D. - Malcová, H. - Freeman, H. - Martin, N. - Švojgr, K. - Passo, M. H. - Bhuyan, F. - Alehashemi, S. - Rastegar, A. T. - Uss, K. - Kardava, L. - Marrero, B. - Duric, Iris - Omoyinmi, E. - Peldová, P. - Lee, C. R. - Kleiner, D. E. - Hadigan, C. M. - Hewitt, S. M. - Pittaluga, S. - Carmona-Rivera, C. - Calvo, K. R. - Shah, N. - Balascaková, M. - Fink, D. L. - Kotalová, R. - Parackova, Z. - Peterková, L. - Kužílková, D. - Campr, V. - Šrámková, L. - Biancotto, A. - Brooks, S. R. - Manes, C. - Meffre, E. - Harper, R. L. - Kuehn, H. - Kaplan, M. J. - Brogan, P. - Rosenzweig, S. D. - Merchant, M. - Deng, Z. - Huttenlocher, A. - Moir, S. L. … Total 54 authors
Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.
Nature Communications. Roč. 14, č. 1 (2023), č. článku 1502. E-ISSN 2041-1723
R&D Projects: GA MŠMT LX22NPO5102
Institutional support: RVO:68378050
Keywords : ENDOTHELIAL-CELL PERMEABILITY * TYROSINE PHOSPHORYLATION * NEUTROPHIL RECRUITMENT * SRC * TRANSFORMATION
OECD category: Biochemistry and molecular biology
Impact factor: 16.6, year: 2022
Method of publishing: Open access
https://www.nature.com/articles/s41467-023-36941-y

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.
Permanent Link: https://hdl.handle.net/11104/0346202