{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:39:51Z","timestamp":1772156391880,"version":"3.50.1"},"posted":{"date-parts":[[2024,2,19]]},"group-title":"Allergy and Immunology","reference-count":133,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>in vivo<\/jats:italic>\n                  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\u2019 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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Loss of function variants of human ACK1 and BRK kinase underlie systemic lupus erythematosus in young patients from multiplex families and disrupt the anti-inflammatory response of macrophages to apoptotic cells.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.02.15.24302255","type":"posted-content","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T12:10:12Z","timestamp":1708344612000},"source":"Crossref","is-referenced-by-count":0,"title":["ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis"],"prefix":"10.64898","author":[{"given":"Stephanie","family":"Guillet","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6312-0080","authenticated-orcid":false,"given":"Tomi","family":"Lazarov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natasha","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"Boisson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Tello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Craddock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chihiro","family":"Nishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohan","family":"Bareja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hairu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7858-7866","authenticated-orcid":false,"given":"Frederic","family":"Rieux-Laucat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2951-6508","authenticated-orcid":false,"given":"Rosa Irene Fregel","family":"Lorenzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina D.","family":"Dyall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Isenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"D\u2019Cruz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nico","family":"Lachmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Elemento","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnes","family":"Viale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas D.","family":"Socci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Abel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9758-8426","authenticated-orcid":false,"given":"Shigekazu","family":"Nagata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan","family":"Huse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.","family":"Todd Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Laurent","family":"Casanova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-2468","authenticated-orcid":false,"given":"Frederic","family":"Geissmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024060900201150000_2024.02.15.24302255v2.1","unstructured":"Dall\u2019Era, M. in Current Rheumatology Diagnosis and Treatment. 3rd ed. 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