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.

2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic

AstraZeneca Research Based Biopharmaceutical Company Waltham MA USA

Clinical Center National Institutes of Health Bethesda MD USA

Collaborative Clinical Research Branch Neutrophil Monitoring Laboratory National Institute of Allergy and Infectious Diseases National Institutes of Health Frederick MD USA

Departments of Pediatrics and Medical Microbiology and Immunology University of Wisconsin Madison Madison WI USA

Great Ormond Street Hospital for Children NHS Foundation Trust London UK

Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA

Laboratory of Leukocyte Signaling Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Medical University of South Carolina Charleston SC USA

National Cancer Institute National Institutes of Health Bethesda MD USA

National Heart Lung and Blood Institute National Institutes of Health Bethesda MD USA

National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda MD USA

Raigmore Hospital Inverness Scotland

Royal Hospital for Children Glasgow Scotland

Sanofi Oncology Vitry France

Translational Autoinflammatory Diseases Section National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA

Yale University New Haven CT USA

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