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Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.
de Jesus, Adriana A; Chen, Guibin; Yang, Dan; Brdicka, Tomas; Ruth, Natasha M; Bennin, David; Cebecauerova, Dita; Malcova, Hana; Freeman, Helen; Martin, Neil; Svojgr, Karel; Passo, Murray H; Bhuyan, Farzana; Alehashemi, Sara; Rastegar, Andre T; Uss, Katsiaryna; Kardava, Lela; Marrero, Bernadette; Duric, Iris; Omoyinmi, Ebun; Peldova, Petra; Lee, Chyi-Chia Richard; Kleiner, David E; Hadigan, Colleen M; Hewitt, Stephen M; Pittaluga, Stefania; Carmona-Rivera, Carmelo; Calvo, Katherine R; Shah, Nirali; Balascakova, Miroslava; Fink, Danielle L; Kotalova, Radana; Parackova, Zuzana; Peterkova, Lucie; Kuzilkova, Daniela; Campr, Vit; Sramkova, Lucie; Biancotto, Angelique; Brooks, Stephen R; Manes, Cameron; Meffre, Eric; Harper, Rebecca L; Kuehn, Hyesun; Kaplan, Mariana J; Brogan, Paul; Rosenzweig, Sergio D; Merchant, Melinda; Deng, Zuoming; Huttenlocher, Anna; Moir, Susan L.
Afiliación
  • de Jesus AA; Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Chen G; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Yang D; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Brdicka T; Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • Ruth NM; Medical University of South Carolina, Charleston, SC, USA.
  • Bennin D; Departments of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA.
  • Cebecauerova D; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Malcova H; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Freeman H; Raigmore Hospital, Inverness, Scotland.
  • Martin N; Royal Hospital for Children, Glasgow, Scotland.
  • Svojgr K; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Passo MH; Medical University of South Carolina, Charleston, SC, USA.
  • Bhuyan F; Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Alehashemi S; Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Rastegar AT; Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Uss K; Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Kardava L; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Marrero B; Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Duric I; Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • Omoyinmi E; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  • Peldova P; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Lee CR; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Kleiner DE; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Hadigan CM; Clinical Center, National Institutes of Health, Bethesda, MD, USA.
  • Hewitt SM; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Pittaluga S; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Carmona-Rivera C; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Calvo KR; Clinical Center, National Institutes of Health, Bethesda, MD, USA.
  • Shah N; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Balascakova M; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Fink DL; Collaborative Clinical Research Branch/Neutrophil Monitoring Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
  • Kotalova R; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Parackova Z; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Peterkova L; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Kuzilkova D; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Campr V; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Sramkova L; Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic.
  • Biancotto A; Sanofi Oncology, Vitry, France.
  • Brooks SR; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Manes C; Yale University, New Haven, CT, USA.
  • Meffre E; Yale University, New Haven, CT, USA.
  • Harper RL; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Kuehn H; Clinical Center, National Institutes of Health, Bethesda, MD, USA.
  • Kaplan MJ; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Brogan P; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  • Rosenzweig SD; Clinical Center, National Institutes of Health, Bethesda, MD, USA.
  • Merchant M; AstraZeneca Research Based Biopharmaceutical Company, Waltham, MA, USA.
  • Deng Z; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Huttenlocher A; Departments of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA.
  • Moir SL; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Commun ; 14(1): 1502, 2023 03 17.
Article en En | MEDLINE | ID: mdl-36932076
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 ß2-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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Vasculitis / Familia-src Quinasas / Células Endoteliales Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Vasculitis / Familia-src Quinasas / Células Endoteliales Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos