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

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 IgDhigh follicular B cells while enriching IgDlow marginal zone B cells. IgDlow (IgMhigh) B cells, which were more resistant to glucocorticoid-induced cell death, showed increased expression of IL-10 and genes involved in survival, suggesting a potential regulatory function. In vitro, B cell activation via CpG or 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 IgDlow (IgMhigh) cells resistant to apoptosis.