ACK1 and BRK Non-receptor Tyrosine Kinase Deficiencies Are Associated with Familial Systemic Lupus and Involved in Efferocytosis

Overview

Journal medRxiv

Date 2024 Jun 17

PMID 38883731

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 DCruz

Nico Lachmann

Olivier Elemento

Agnes Viale

Nicholas D Socci

Laurent Abel

Shigekazu Nagata

Morgan Huse

W Todd Miller

Jean-Laurent Casanova

Frederic Geissmann

Affiliations

Soon will be listed here.

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 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 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.

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