Virginia Research Day 2021

Faculty Research Biomedical

04 EGR2 Differentially Regulates Plasma Cell Differentiation and Function in Normal C57BL/6 Mice and Autoimmune-Prone B6/lpr Mice

Rujuan Dai; Bettina Heid; Zhuang Wang; Christopher M Reilly; S Ansar Ahmed Corresponding author: Rdai05@vt.edu Department of Biomedical Sciences and Pathobiology, VMCVM, Virginia Tech Via College of Osteopathic Medicine-Virginia Campus

The major phenomenon of autoimmune disease such as lupus is the production of autoantibodies that target self-organs. High affinity IgG autoantibodies are thought to arise through GC responses, which is important for the differentiation of autoantibody- secreting plasma cells (PCs). The signaling pathways from which PCs originate may determine PCs lifespan, the characteristics of the autoreactive antibodies and sensitivity to B cell-depletion therapeutics. In a normal physiological setting, the PCs produce protective antibodies against bacterial and viral infection. Whereas in autoimmune disease, the PCs produce pathogenic autoantibodies against self-antigens. Major transcription factors that regulate the critical developmental checkpoint during GC response and PC differentiation have been identified. In this study, we investigated the role of transcription factor Early growth response protein 2 (EGR2) in regulating B cell development, deafferentation and function.

EGR2 is a zinc finger transcription factor that belongs to the early growth response ( Egr ) gene family. Recent studies have shown that EGR2 is required for the induction of T cell anergy, and it plays an important role in T cell immunity and autoimmunity. However, there is limited knowledge about the role of EGR2 in B cell development and function. We have recently reported that EGR2 was upregulated in human patients with autoimmune lupus and several murine lupus models including MRL -lpr, B6- lpr , and B6.sle123. To investigate further the immune regulatory role of EGR2 in autoimmune context, we derived CD2-CreEGR2-/-B6- lpr (EGR2-/-B6- lpr ) mice with EGR2 deficiency in both T and B cells. We found that in B6- lpr mice, EGR2 depletion significantly reduced serum levels of anti-dsDNA autoantibodies, total IgG, IgG1, IgG2a, and IgM. Furthermore, in B6- lpr mice, depletion of EGR2 promoted GCB development, but suppressed the differentiation of PCs, particular long-live plasma cells (LLPCs). In

contrast to autoimmune-prone B6-lpr mice, in wild type B6 mice, EGR2 depletion significantly increased anti-dsDNA autoantibodies, accompanying with a significant increase of GCB cell development and a trend of increase in PCs differentiation. In both B6 and B6-lpr mice, EGR2 depletion had no significant effect on the B cell development at early development stage (Pre-Pro-B, Pro-B, and Pre-B). Together, our data demonstrated that EGR2 has a differential role in regulating GCB transition into plasma cell during late B cell development. Ongoing study is to define the molecular and cellular mechanism underlying the aberrant role of EGR2 in regulating PC differentiation and function in B6- lpr mice.

This study was funded in part by the VCOM One Health Seed Grant.

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