ATR-mediated DNA damage responses underlie aberrant B cell activity in systemic lupus erythematosus

Sci Adv. 2022 Oct 28;8(43):eabo5840. doi: 10.1126/sciadv.abo5840. Epub 2022 Oct 28.


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.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • B-Lymphocytes
  • DNA Damage
  • Humans
  • Lupus Erythematosus, Systemic* / metabolism


  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins