ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis.
Stephanie GuilletTomi LazarovNatasha JordanBertrand BoissonMaria TelloBarbara CraddockTing ZhouChihiro NishiRohan BarejaHairu YangFrédéric Rieux-LaucatRosa Irene Fregel LorenzoSabrina D DyallDavid IsenbergDavid D'CruzNico LachmannOlivier ElementoAgnes VialeNicholas D SocciLaurent AbelShigekatzu NagataMorgan HuseW Todd MillerJean-Laurent CasanovaFrederic GeissmannPublished in: medRxiv : the preprint server for health sciences (2024)
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 systemic lupus erythematosus (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, non-receptor tyrosine kinases (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.
Keyphrases
- systemic lupus erythematosus
- disease activity
- tyrosine kinase
- endothelial cells
- copy number
- stem cells
- anti inflammatory
- mouse model
- high glucose
- early onset
- end stage renal disease
- induced apoptosis
- high throughput
- cell death
- induced pluripotent stem cells
- newly diagnosed
- genome wide
- signaling pathway
- pluripotent stem cells
- rheumatoid arthritis
- prognostic factors
- multiple sclerosis
- type diabetes
- binding protein
- electronic health record
- cell cycle arrest
- diabetic rats
- metabolic syndrome
- dna methylation
- oxidative stress
- stress induced
- bone marrow
- single cell
- high fat diet induced