eLife (Nov 2024)
ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis
- Stephanie Guillet,
- Tomi Lazarov,
- Natasha Jordan,
- Bertrand Boisson,
- Maria Tello,
- Barbara Craddock,
- Ting Zhou,
- Chihiro Nishi,
- Rohan Bareja,
- Hairu Yang,
- Frederic Rieux-Laucat,
- Rosa Irene Fregel Lorenzo,
- Sabrina D Dyall,
- David Isenberg,
- David D'Cruz,
- Nico Lachmann,
- Olivier Elemento,
- Agnes Viale,
- Nicholas D Socci,
- Laurent Abel,
- Shigekazu Nagata,
- Morgan Huse,
- W Todd Miller,
- Jean-Laurent Casanova,
- Frédéric Geissmann
Affiliations
- Stephanie Guillet
- ORCiD
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States; Ecole doctorale Bio Sorbonne Paris Cité, Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Tomi Lazarov
- ORCiD
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
- Natasha Jordan
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London, United Kingdom
- Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States; University of Paris Cité, Imagine Institute, Paris, France
- Maria Tello
- ORCiD
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Barbara Craddock
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, United States
- Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New York, United States
- Chihiro Nishi
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Rohan Bareja
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical College, New York, United States
- Hairu Yang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- Frederic Rieux-Laucat
- University of Paris Cité, Imagine Institute, Paris, France
- Rosa Irene Fregel Lorenzo
- University of La Laguna, San Cristóbal de La Laguna, Spain
- Sabrina D Dyall
- Department of Biosciences and Ocean Studies, Faculty of Science, University of Mauritius, Reduit, Mauritius
- David Isenberg
- Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States
- David D'Cruz
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London, United Kingdom
- Nico Lachmann
- Centre for Rheumatology, Division of Medicine, University College London, The Rayne Building, London, United Kingdom
- Olivier Elemento
- Cary and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Meyer Cancer Center Weill Cornell Medical College, New York, United States
- Agnes Viale
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany
- Nicholas D Socci
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany; Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States
- Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States; University of Paris Cité, Imagine Institute, Paris, France
- Shigekazu Nagata
- ORCiD
- Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Morgan Huse
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
- W Todd Miller
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States; Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, United States
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States; University of Paris Cité, Imagine Institute, Paris, France; Howard Hughes Medical Institute, New York, United States; Lab of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick Children, Paris, France; Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
- Frédéric Geissmann
- ORCiD
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, United States; Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King’s College London and Louise Coote Lupus Unit, Guy’s and Thomas’ Hospitals, London, United Kingdom
- DOI
- https://doi.org/10.7554/eLife.96085
- Journal volume & issue
-
Vol. 13
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
Keywords
