Early Growth Response Protein 2 (EGR2) regulation of B cell differentiation in lupus-prone mice

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease with an unidentified cause and no suitable treatment. It involves abnormal activation of B cells, which produce pathogenic autoantibodies that contribute to inflammation and tissue damage in multiple organs. Therapeutic depletion of B cells in human lupus patients had mixed success due to the complex heterogeneity of B cell subsets, differences in autoantibody production, and the persistence of antibody-secreting plasma cells (PCs). Our laboratory reported that the transcription factor Early Growth Response 2 (EGR2), a key regulator of immune cell function, was markedly upregulated in murine and human lupus lymphocytes. Further, we reported that conditional deletion of Egr2-/- in lymphocytes in lupus-prone B6/lpr mice suppressed pathogenic anti-dsDNA autoantibodies. Notably, Egr2-/- B6/lpr mice exhibited an increased germinal center B (GCB) cell population but a decreased PC subset, suggesting that GCB cells fail to progress into fully differentiated PCs. This finding reveals a novel and unexpected role of EGR2 in the transition from GCB cells to antibody-secreting PCs. These findings provide compelling evidence that EGR2 functions aberrantly in lupus, contributing to disease pathology by facilitating the generation of autoreactive PCs. To further investigate the novel role of EGR2 on B cells. In this project, we conducted extensive experiments using newly developed CD2Cre-Egr2-/- MRL-MpJ- Fas lpr mice, in which Egr2 is selectively deleted in CD2-expressing lymphocytes primarily in T cells and a subset of activated or mature B cells that express CD2. Our findings show that egr2 deletion in MRL/lpr mice leads to a significant reduction in marginal zone B cells and a trend reduction in antibody-secreting plasma cells, while follicular B cells remain largely unaffected. Germinal center B cells were found to be increased, mirroring previous results observed in Egr2-/- B6/lpr mice. However, we observed only a slight decrease in serum anti-dsDNA autoantibodies in Egr2-/- MRL/lpr mice, which was different from what we observed in Egr2-/- B6/lpr mice. Collectively, our data indicate that EGR2 plays a pivotal and previously underappreciated role in regulating late-stage B cell development in lupus. These findings suggest that EGR2 may contribute to lupus pathogenesis by facilitating the differentiation of autoreactive B cells into plasma cells, and it may represent a novel therapeutic target for modulating pathogenic B cell responses in SLE.