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

## TL;DR

This study shows that Glutaredoxin2 helps control age-related B cell changes linked to autoimmunity by managing oxidative stress.

## Contribution

The study reveals a novel role for Glutaredoxin2 in modulating age-associated B cell differentiation via redox regulation.

## Key findings

- Grx2 deficiency increases ROS levels and ABC proportions in aged mice, accelerating autoimmunity.
- NAC reduced ABC differentiation by 50%, showing ROS dependency in this process.
- Grx2 deletion in ShipΔB mice worsened autoimmunity and T cell activation.

## Abstract

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 oxidoreductase, regulates redox homeostasis, but its role in autoimmune B cell biology is underexplored.

Using wild-type and Grx2-knockout mice, we examined ROS levels and ABC differentiation. In vitro, ABC differentiation was induced with IL-21 and TLR7 agonist, and the effect of the antioxidant N-Acetyl-L-Cysteine (NAC) was assessed. The SLE-prone ShipΔB model crossed with Grx2−/− mice was used to evaluate autoimmune pathology.

ABCs exhibited higher ROS levels than follicular B cells, and NAC reduced ABC differentiation rate by 50%, demonstrating ROS dependency. Grx2 deficiency amplified ROS levels and ABC proportions in aged mice, correlating with accelerated autoimmunity. In ShipΔB mice, Grx2 deletion exacerbated ABC differentiation, CD4+ T cell activation, and anti-dsDNA autoantibody titers.

Grx2 acts as a redox checkpoint that limits ABC-driven autoimmunity by modulating ROS. The Grx2–ROS axis represents a potential therapeutic target for SLE and related chronic inflammatory diseases.