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

被引：0

作者：

Guillet, Stephanie ^{[1
,2
]}

Lazarov, Tomi ^{[1
]}

Jordan, Natasha ^{[4
,5
,21
]}

Boisson, Bertrand ^{[6
,7
]}

Tello, Maria ^{[1
]}

Craddock, Barbara ^{[8
]}

Zhou, Ting ^{[8
]}

Nishi, Chihiro ^{[9
]}

Bareja, Rohan ^{[10
]}

Yang, Hairu ^{[1
]}

Rieux-Laucat, Frederic ^{[7
]}

Fregel Lorenzo, Rosa Irene ^{[11
]}

Dyall, Sabrina D. ^{[12
]}

Isenberg, David ^{[13
]}

D'Cruz, David ^{[4
,5
]}

Lachmann, Nico ^{[14
]}

Elemento, Olivier ^{[10
]}

Viale, Agnes ^{[15
]}

Socci, Nicholas D. ^{[15
,16
]}

Abel, Laurent ^{[6
,7
]}

Nagata, Shigekazu ^{[9
]}

Huse, Morgan ^{[1
]}

Miller, W. Todd ^{[16
,17
]}

Casanova, Jean-Laurent ^{[6
,7
,18
,19
,20
]}

Geissmann, Frederic ^{[1
,3
,4
,5
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Immunol Program, 1275 York Ave, New York, NY 10021 USA

[2] Univ Paris Descartes Sorbonne Paris Cite, Ecole Doctorale Bio Sorbonne Paris Cite, Paris, France

[3] Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA

[4] Kings Coll London, Ctr Mol & Cellular Biol Inflammat, London, England

[5] Guys & Thomas Hosp, Louise Coote Lupus Unit, London, England

[6] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY USA

[7] Univ Paris Cite, Imagine Inst, Paris, France

[8] Mem Sloan Kettering Canc Ctr, SKI Stem Cell Res Core, New York, NY USA

[9] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Lab Biochem & Immunol, Osaka, Japan

[10] Weill Cornell Med Coll, Meyer Canc Ctr, Inst Computat Biomed, Cary & Israel Englander Inst Precis Med, New York, NY USA

[11] Univ La Laguna, San Cristobal De Laguna, Spain

[12] Univ Mauritius, Dept Biosci & Ocean Studies, Fac Sci, Reduit, Mauritius

[13] Mem Sloan Kettering Canc Ctr, Bioinformat Core, New York, NY USA

[14] UCL, Div Med, Ctr Rheumatol, Rayne Bldg, London, England

[15] Hannover Med Sch, Inst Expt Hematol, REBIRTH Cluster Excellence, Hannover, Germany

[16] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY USA

[17] SUNY Stony Brook, Dept Physiol & Biophys, Sch Med, Stony Brook, NY USA

[18] Howard Hughes Med Inst, New York, NY USA

[19] Necker Hosp Sick Children, Lab Human Genet Infect Dis, INSERM, Paris, France

[20] Necker Hosp Sick Children, Dept Pediat, Paris, France

[21] Cambridge Univ Hosp, Dept Rheumatol, Cambridge, England

来源：

ELIFE | 2024年 / 13卷

关键词：

systemic lupus; genetic diseases; ACK1; BRK; CANCER-ASSOCIATED MUTATIONS; APOPTOTIC CELLS; AUTOIMMUNE-DISEASE; RESIDENT MACROPHAGES; CRYSTAL-STRUCTURES; IMPAIRED UPTAKE; ERYTHEMATOSUS; CLEARANCE; PHAGOCYTOSIS; PREVALENCE;

D O I：

10.7554/eLife.96085

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：32

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