Englander Institute for Precision Medicine

ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis.

TitleACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis.
Publication TypeJournal Article
Year of Publication2024
AuthorsGuillet S, Lazarov T, Jordan N, Boisson B, Tello M, Craddock B, Zhou T, Nishi C, Bareja R, Yang H, Rieux-Laucat F, Lorenzo RIrene Freg, Dyall SD, Isenberg D, D'Cruz D, Lachmann N, Elemento O, Viale A, Socci ND, Abel L, Nagata S, Huse M, W Miller T, Casanova J-L, Geissmann F
JournalElife
Volume13
Date Published2024 Nov 21
ISSN2050-084X
KeywordsAdult, Animals, Autoantibodies, c-Mer Tyrosine Kinase, Disease Models, Animal, Efferocytosis, Female, Humans, Lupus Erythematosus, Systemic, Macrophages, Male, Mice, Phagocytosis, Protein-Tyrosine Kinases
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.

DOI10.7554/eLife.96085
Alternate JournalElife
PubMed ID39570652
PubMed Central IDPMC11581429
Grant ListAnnee Recherche / / Assistance Publique - Hôpitaux de Paris /
R01 AI124349 / AI / NIAID NIH HHS / United States
5R01AI124349-03 / / National Institute of Allergy and Infectious Diseases /
JPMJCR14M4 / / Core Research for Evolutional Science and Technology /
P30CA008748 / CA / NCI NIH HHS / United States
1R01AI130345-01 / / National Institute of Allergy and Infectious Diseases /
R01 AI130345 / AI / NIAID NIH HHS / United States
R01 CA058530 / CA / NCI NIH HHS / United States
R01-AI087644 / / National Institute of Allergy and Infectious Diseases /
DEA20140630127 / / Fondation pour la Recherche Médicale /
CA58530 / CA / NCI NIH HHS / United States
No. 15H05785 / / Grants-in-Aid for Scientific Research /
Fellowship / ARC_ / Arthritis Research UK / United Kingdom
R01 AI087644 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States

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