ATR-mediated DNA damage responses underlie aberrant B cell activity in systemic lupus erythematosus
Theodora Manolakou, Dionysis Nikolopoulos, Dimitrios Gkikas, Anastasia Filia, Martina Samiotaki, George Stamatakis, Antonis Fanouriakis, Panagiotis Politis, Aggelos Banos, Themis Alissafi, Panayotis Verginis, Dimitrios T. Boumpas
Abstract
B cells orchestrate autoimmune responses in patients with systemic lupus erythematosus (SLE), but broad-based B cell-directed therapies show only modest efficacy while blunting humoral immune responses to vaccines and inducing immunosuppression. Development of more effective therapies targeting pathogenic clones is a currently unmet need. Here, we demonstrate enhanced activation of the ATR/Chk1 pathway of the DNA damage response (DDR) in B cells of patients with active SLE disease. Treatment of B cells with type I IFN, a key driver of immunity in SLE, induced expression of ATR via binding of interferon regulatory factor 1 to its gene promoter. Pharmacologic targeting of ATR in B cells, via a specific inhibitor (VE-822), attenuated their immunogenic profile, including proinflammatory cytokine secretion, plasmablast formation, and antibody production. Together, these findings identify the ATR-mediated DDR axis as the orchestrator of the type I IFN-mediated B cell responses in SLE and as a potential novel therapeutic target.