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Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK

V. Kanderova, T. Svobodova, S. Borna, M. Fejtkova, V. Martinu, J. Paderova, M. Svaton, J. Kralova, E. Fronkova, A. Klocperk, S. Pruhova, MA. Lee-Kirsch, L. Hornofova, M. Koblizek, P. Novak, O. Zimmermannova, Z. Parackova, A. Sediva, T. Kalina, A....

. 2022 ; 149 (4) : 1464-1472.e3. [pub] 20210915

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22018986

BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.

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$a Kanderova, Veronika $u CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK / $c V. Kanderova, T. Svobodova, S. Borna, M. Fejtkova, V. Martinu, J. Paderova, M. Svaton, J. Kralova, E. Fronkova, A. Klocperk, S. Pruhova, MA. Lee-Kirsch, L. Hornofova, M. Koblizek, P. Novak, O. Zimmermannova, Z. Parackova, A. Sediva, T. Kalina, A. Janda, J. Kayserova, M. Dvorakova, M. Macek, P. Pohunek, P. Sedlacek, A. Poh, M. Ernst, T. Brdicka, O. Hrusak, J. Lebl
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$a BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.
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$a Svobodova, Tamara $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Borna, Simon $u Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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$a Fejtkova, Martina $u CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Martinu, Vendula $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Paderova, Jana $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Svaton, Michael $u CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Kralova, Jarmila $u Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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$a Fronkova, Eva $u CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Klocperk, Adam $u Department of Immunology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Pruhova, Stepanka $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Lee-Kirsch, Min Ae $u Molecular Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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$a Hornofova, Ludmila $u Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Koblizek, Miroslav $u Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Novak, Petr $u Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University, Institute of Microbiology of the Czech Academy of Sciences, Vestec, Czech Republic
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$a Parackova, Zuzana $u Department of Immunology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Sediva, Anna $u Department of Immunology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Janda, Ales $u Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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$a Dvorakova, Marcela $u Department of Radiology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Macek, Milan $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Pohunek, Petr $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Sedlacek, Petr $u CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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$a Poh, Ashleigh $u School of Cancer Medicine, La Trobe University, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, Australia
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$a Ernst, Matthias $u School of Cancer Medicine, La Trobe University, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, Australia
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$a Brdicka, Tomas $u Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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$a Hrusak, Ondrej $u CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic. Electronic address: ondrej.hrusak@lfmotol.cuni.cz
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$a Lebl, Jan $u Department of Pediatrics, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, Prague, Czech Republic
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