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

Adriana Almeida de JesusGuibin ChenDan YangTomas BrdickaNatasha M RuthDavid BenninDita CebecauerovaHana MalcovaHelen FreemanNeil MartinKarel SvojgrMurray H PassoFarzana BhuyanSara AlehashemiAndre T RastegarKatsiaryna UssLela KardavaBernadette MarreroIris ĐurićEbun OmoyinmiPetra PeldovaChyi-Chia Richard LeeDavid E KleinerColleen M HadiganStephen M HewittStefania PittalugaCarmelo Carmona-RiveraKatherine R CalvoNirali N ShahMiroslava BalascakovaDanielle L FinkRadana KotalovaZuzana ParackovaLucie PeterkovaDaniela KuzilkovaVit CamprLucie SramkovaAngelique BiancottoStephen R BrooksCameron ManesEric MeffreRebecca L HarperHye Sun KuehnMariana J KaplanPaul BroganSergio D RosenzweigMelinda MerchantZuoming DengAnna HuttenlocherSusan L MoirDouglas B KuhnsManfred BoehmKarolina Skvarova KramarzovaRaphaela Goldbach Mansky
Published in: Nature communications (2023)
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.
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