# IgD‐Expressing Mature B Cells Exhibit Enhanced Sensitivity to Glucocorticoid‐Induced Cell Death

## TL;DR

Mature B cells that express IgD are more likely to die when exposed to glucocorticoids, which could help explain how these drugs affect immune responses.

## Contribution

The study reveals that IgD-expressing B cells are uniquely sensitive to glucocorticoid-induced death, which is GR-dependent and impacts B cell survival and activation.

## Key findings

- IgDhi B cells are more sensitive to glucocorticoid-induced cell death compared to IgMhi B cells.
- GR agonists like Dexamethasone and Prednisolone selectively deplete IgDhi follicular B cells.
- IgMhi B cells show increased resistance to GC-induced death and express higher levels of survival-related genes.

## Abstract

Glucocorticoids (GCs) regulate diverse physiological processes, comprising metabolism, immune responses, stress adaptation, and inflammation. Synthetic GCs are widely used for their powerful anti‐inflammatory and immunosuppressive effects, in the treatment of autoimmune diseases, allergies, and inflammation. Here, we investigated the role of the glucocorticoid receptor (GR) in B cell development and survival using both B cell‐specific GR‐deficient mice and continuous in vivo GR agonist treatments. Deletion of the GR in B cells altered splenic B cell subpopulations, increasing follicular and CD21lo B cells and leading to the accumulation of IgM−/IgD− B cells. In vivo treatment with GR agonists, such as Dexamethasone (Dex) and Prednisolone (Pred), selectively depleted IgDhi follicular while enriching IgMhi marginal zone B cells. IgMhi B cells, which were more resistant to GC‐induced cell death, showed an increased expression of IL‐10 and genes involved in survival, suggesting a potential regulatory function. In vitro, B cell activation via CpG or lipopolysaccharide (LPS) altered IgM/IgD expression and B cell sensitivity to GR agonists, thereby leading to improved B cell survival and increased plasma cell differentiation. Together, these findings suggest that IgD downregulation and IgM upregulation are critical for B cell survival under GC exposure and that GR agonists promote the enrichment of IgMhi cells resistant to apoptosis.

Our study shows that mature B cells expressing IgD exhibit significantly higher sensitivity to glucocorticoid (GC)‐induced cell death. This elevated sensitivity is specifically dependent on GC receptor (GR) expression and is accompanied by enhanced activation as well as terminal differentiation of B cells. Our findings elucidate how exogenous GCs affect B cell survival and suggest that their endogenous counterparts regulate B cell homeostasis and activation.