ATR-mediated DNA damage responses underlie aberrant B cell activity in systemic lupus erythematosus
-
- Theodora Manolakou
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
-
- Dionysis Nikolopoulos
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
-
- Dimitrios Gkikas
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27, Athens, Greece.
-
- Anastasia Filia
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
-
- Martina Samiotaki
- Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Attica, Greece.
-
- George Stamatakis
- Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Attica, Greece.
-
- Antonis Fanouriakis
- Department of Rheumatology, Asklepieion General Hospital, Athens, Greece.
-
- Panagiotis Politis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27, Athens, Greece.
-
- Aggelos Banos
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
-
- Themis Alissafi
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27, Athens, Greece.
-
- Panayotis Verginis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 700 13 Heraklion, Greece.
-
- Dimitrios T. Boumpas
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
説明
<jats:p>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.</jats:p>
収録刊行物
-
- Science Advances
-
Science Advances 8 (43), 2022-10-28
American Association for the Advancement of Science (AAAS)