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
{"title":"ACK1 和 BRK 非受体酪氨酸激酶缺陷与家族性系统性红斑狼疮有关，并参与流出细胞的形成","authors":"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","doi":"10.1101/2024.02.15.24302255","DOIUrl":null,"url":null,"abstract":"Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We report compound heterozygous deleterious variants in the kinase domains of the non-receptor tyrosine kinases (NRTK) TNK2/ACK1 in one multiplex family and PTK6/BRK in another. Experimental blockade of mouse ACK1 or BRK increases glomerular IgG deposits and circulating autoantibodies in an <em>in vivo</em> SLE model. In addition, we found that the patients’ ACK and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cells (hiPSC)-derived macrophages. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"254 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis\",\"authors\":\"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\",\"doi\":\"10.1101/2024.02.15.24302255\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We report compound heterozygous deleterious variants in the kinase domains of the non-receptor tyrosine kinases (NRTK) TNK2/ACK1 in one multiplex family and PTK6/BRK in another. Experimental blockade of mouse ACK1 or BRK increases glomerular IgG deposits and circulating autoantibodies in an <em>in vivo</em> SLE model. In addition, we found that the patients’ ACK and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cells (hiPSC)-derived macrophages. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis.\",\"PeriodicalId\":501527,\"journal\":{\"name\":\"medRxiv - Allergy and Immunology\",\"volume\":\"254 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-02-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"medRxiv - Allergy and Immunology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.02.15.24302255\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv - Allergy and Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.02.15.24302255","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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. Non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We report compound heterozygous deleterious variants in the kinase domains of the non-receptor tyrosine kinases (NRTK) TNK2/ACK1 in one multiplex family and PTK6/BRK in another. Experimental blockade of mouse ACK1 or BRK increases glomerular IgG deposits and circulating autoantibodies in an in vivo SLE model. In addition, we found that the patients’ ACK and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cells (hiPSC)-derived macrophages. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
