Glutaredoxin2 reduces age-associated B cell differentiation through maintaining redox homeostasis

Yuan JiangChunli SunQilin HeShujun LiuShihao TianYan ZhangFubin Li^*Huihui Zhang^*

• School of Medicine, Shanghai Jiao Tong University, Shanghai, China

The redox system plays a pivotal role in autoimmune diseases and cancer, with oxidative stress and antioxidant adaptations driving pathological processes. Age/autoimmunity-associated B cells (ABCs), characterized by elevated ROS levels, are implicated in autoimmune disorders such as systemic lupus erythematosus (SLE). However, the mechanisms linking ROS to ABC differentiation remain unclear. Glutaredoxin 2 (Grx2), a key antioxidant enzyme, regulates redox homeostasis, but its role in autoimmune B cell biology is underexplored. Using wild-type and Grx2-knockout mice, we demonstrated that ABCs exhibit higher ROS levels than follicular B cells, and ROS is essential for their differentiation. In vitro, the antioxidant N-Acetyl-L-Cysteine (NAC) reduced ABC differentiation rate by 50%, showing ROS dependency in ABC differentiation. Grx2 deficiency amplified ROS levels and ABC proportions in aged mice, correlating with accelerated autoimmune pathology. In the SLE-prone ShipΔB model, Grx2 deletion exacerbated ABC differentiation, CD4+ T cell activation, and anti-dsDNA autoantibody titers, highlighting Grx2's role in restraining autoimmunity. These findings establish Grx2 as a redox checkpoint that limits ABC-driven autoimmunity by modulating ROS. The Grx2-ROS axis emerges as a therapeutic target for SLE and related chronic inflammatory diseases, offering a novel pathway to mitigate oxidative stress-mediated immune dysregulation.