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

Adriana A. de Jesus, Guibin Chen, Dan Yang, Tomas Brdicka, Natasha M. Ruth, David Bennin, Dita Cebecauerova, Hana Malcova, Helen Freeman, Neil Martin, Karel Svojgr, Murray H. Passo, Farzana Bhuyan, Sara Alehashemi, Andre T. Rastegar, Katsiaryna Uss, Lela Kardava, Bernadette Marrero, Iris Duric, Ebun Omoyinmi, Petra Peldova, Chyi-Chia Richard Lee, David E. Kleiner, Colleen M. Hadigan, Stephen M. Hewitt, Stefania Pittaluga, Carmelo Carmona-Rivera, Katherine R. Calvo, Nirali Shah, Miroslava Balascakova, Danielle L. Fink, Radana Kotalova, Zuzana Parackova, Lucie Peterkova, Daniela Kuzilkova, Vit Campr, Lucie Sramkova, Angelique Biancotto, Stephen R. Brooks, Cameron Manes, Eric Meffre, Rebecca L. Harper, Hyesun Kuehn, Mariana J. Kaplan, Paul Brogan, Sergio D. Rosenzweig, Melinda Merchant, Zuoming Deng, Anna Huttenlocher, Susan L. Moir, Douglas B. Kuhns, Manfred Boehm, Karolina Skvarova Kramarzova and Raphaela Goldbach-Mansky ()
Additional contact information
Adriana A. de Jesus: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health
Guibin Chen: National Heart, Lung, and Blood Institute, National Institutes of Health
Dan Yang: National Heart, Lung, and Blood Institute, National Institutes of Health
Tomas Brdicka: Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences
Natasha M. Ruth: Medical University of South Carolina
David Bennin: University of Wisconsin-Madison
Dita Cebecauerova: Charles University/University Hospital Motol
Hana Malcova: Charles University/University Hospital Motol
Helen Freeman: Raigmore Hospital
Neil Martin: Royal Hospital for Children
Karel Svojgr: Charles University/University Hospital Motol
Murray H. Passo: Medical University of South Carolina
Farzana Bhuyan: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health
Sara Alehashemi: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health
Andre T. Rastegar: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health
Katsiaryna Uss: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health
Lela Kardava: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Bernadette Marrero: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health
Iris Duric: Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences
Ebun Omoyinmi: Great Ormond Street Hospital for Children NHS Foundation Trust
Petra Peldova: Charles University/University Hospital Motol
Chyi-Chia Richard Lee: National Cancer Institute, National Institutes of Health
David E. Kleiner: National Cancer Institute, National Institutes of Health
Colleen M. Hadigan: Clinical Center, National Institutes of Health
Stephen M. Hewitt: National Cancer Institute, National Institutes of Health
Stefania Pittaluga: National Cancer Institute, National Institutes of Health
Carmelo Carmona-Rivera: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Katherine R. Calvo: Clinical Center, National Institutes of Health
Nirali Shah: National Cancer Institute, National Institutes of Health
Miroslava Balascakova: Charles University/University Hospital Motol
Danielle L. Fink: Collaborative Clinical Research Branch/Neutrophil Monitoring Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Radana Kotalova: Charles University/University Hospital Motol
Zuzana Parackova: Charles University/University Hospital Motol
Lucie Peterkova: Charles University/University Hospital Motol
Daniela Kuzilkova: Charles University/University Hospital Motol
Vit Campr: Charles University/University Hospital Motol
Lucie Sramkova: Charles University/University Hospital Motol
Angelique Biancotto: Sanofi Oncology
Stephen R. Brooks: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Cameron Manes: Yale University
Eric Meffre: Yale University
Rebecca L. Harper: National Heart, Lung, and Blood Institute, National Institutes of Health
Hyesun Kuehn: Clinical Center, National Institutes of Health
Mariana J. Kaplan: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Paul Brogan: Great Ormond Street Hospital for Children NHS Foundation Trust
Sergio D. Rosenzweig: Clinical Center, National Institutes of Health
Melinda Merchant: AstraZeneca Research Based Biopharmaceutical Company
Zuoming Deng: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Anna Huttenlocher: University of Wisconsin-Madison
Susan L. Moir: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Douglas B. Kuhns: Collaborative Clinical Research Branch/Neutrophil Monitoring Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Manfred Boehm: National Heart, Lung, and Blood Institute, National Institutes of Health
Karolina Skvarova Kramarzova: Charles University/University Hospital Motol
Raphaela Goldbach-Mansky: Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36941-y

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