ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis
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.
Authors
- Bertrand Boisson (ORCID: https://orcid.org/0000-0001-5240-3555)
- David D’Cruz (ORCID: https://orcid.org/0000-0002-6983-8421)
- Rohan Bareja (ORCID: https://orcid.org/0000-0002-0635-7743)
- Tomi Lazarov (ORCID: https://orcid.org/0000-0002-6312-0080)
- Nico Lachmann (ORCID: https://orcid.org/0000-0002-4245-1497)
- Morgan Huse (ORCID: https://orcid.org/0000-0001-9941-7719)
- Chihiro Nishi
- Nicholas D. Socci (ORCID: https://orcid.org/0000-0002-8254-6925)
- Jean‐Laurent Casanova (ORCID: https://orcid.org/0000-0002-7782-4169)
- W. Todd Miller (ORCID: https://orcid.org/0000-0002-6566-0064)
- Rosa Fregel (ORCID: https://orcid.org/0000-0002-2951-6508)
- Sabrina D. Dyall
- Ting Zhou (ORCID: https://orcid.org/0000-0003-1423-1507)
- S. Guillet (ORCID: https://orcid.org/0000-0002-9038-6765)
- Olivier Elemento (ORCID: https://orcid.org/0000-0002-8061-9617)
- Hairu Yang (ORCID: https://orcid.org/0000-0002-9420-878X)
- Agnès Viale (ORCID: https://orcid.org/0000-0001-8644-9017)
- María Tello‐Lafoz (ORCID: https://orcid.org/0000-0001-8909-6800)
- David Isenberg (ORCID: https://orcid.org/0000-0001-9514-2455)
- Frédéric Rieux‐Laucat (ORCID: https://orcid.org/0000-0001-7858-7866)
- Frédéric Geissmann (ORCID: https://orcid.org/0000-0001-5029-2468)
- Laurent Abel (ORCID: https://orcid.org/0000-0001-7016-6493)
- Shigekazu Nagata (ORCID: https://orcid.org/0000-0001-9758-8426)
- Barbara P. Craddock
- Natasha Jordan
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- Universidad de La Laguna (ES)
- King's College London (GB)
- Université Paris Cité (FR)
- Cornell University (US)
- Great Ormond Street Hospital (GB)
- Hospital for Sick Children (CA)
- Lander Institute (IL)
- Medizinische Hochschule Hannover (DE)
- Sorbonne Paris Cité (FR)
- SickKids Foundation (CA)
- Molecular Oncology (United States) (US)
- Institut des Maladies Génétiques Imagine (FR)
- University College London (GB)
- Osaka International University (JP)
- Stony Brook University (US)
- University of Mauritius (MU)
- Rockefeller University (US)
- The University of Osaka (JP)
Publication Details
- Journal
- eLife
- Published
- 2024-11-21
- DOI
- https://doi.org/10.7554/elife.96085.3
- Citations
- 5
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- Arthritis Research UK
- Assistance Publique - Hôpitaux de Paris
- Fondation pour la Recherche Médicale
- Japan Society for the Promotion of Science
- National Institute of Allergy and Infectious Diseases
- Core Research for Evolutional Science and Technology