Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
Adriana A. de Jesus, Guibin Chen, Dan Yang, Tomáš Brdička, Natasha M. Ruth, David A. Bennin, Dita Cebecauerová, Hana Malcová, Helen Freeman, Neil Martin, Karel Švojgr, Murray H. Passo, Farzana Bhuyan, Sara Alehashemi, Andre Rastegar, Katsiaryna Uss, Lela Kardava, Bernadette Marrero, Iris Đurić, Ebun Omoyinmi, Petra Peldová, Chyi‐Chia Richard Lee, David E. Kleiner, Colleen Hadigan, Stephen M. Hewitt, Stefania Pittaluga, Carmelo Carmona‐Rivera, Katherine R. Calvo, Nirali N. Shah, Miroslava Balaščaková, Danielle Fink, Radana Kotalová, Zuzana Paračková, Lucie Peterková, Daniela Kužílková, Vít Campr, Lucie Šrámková, Angélique Biancotto, Stephen R. Brooks, Cameron Manes, Eric Meffre, Rebecca L. Harper, Hye Sun Kuehn, Mariana J. Kaplan, Paul Brogan, Sergio D. Rosenzweig, Melinda S. Merchant, Zuoming Deng, Anna Huttenlocher, Susan Moir, Douglas B. Kuhns, Manfred Boehm, Karolina Škvárová Kramarzová, Raphaela Goldbach‐Mansky
Abstract
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.