The role of ERK2 in germinal center B cell selection

Abstract

Abstract The regulation of programmed cell death is a crucial control point for the maintenance of B cell tolerance in the germinal center (GC) and involves the coordination of several intracellular signaling pathways. Dysregulation of these pathways can lead to the survival of autoreactive B cells, resulting in autoimmune disease. The mitogen-activated protein kinase (MAPK) pathway is involved in the transduction of both survival and apoptotic signals received through the B cell receptor (BCR) and the Fas receptor (CD95), respectively. Extracellular signal regulated kinases 1 and 2 (ERK1/2) are important effectors of this pathway and play a major role in the B cell selection process. Though it is known that ERK2 specifically regulates the pro-apoptotic protein, Bmf, its function in GC B cells remains poorly understood. Our lab has developed a novel mouse model in which the deletion of Erk2 is accompanied by the expression of the fluorescent reporter protein, eYFP, allowing us to identify and isolate viable Erk2 Δ B cells using flow cytometry. Preliminary data using this model has shown that Erk2Δ B cells exhibit impaired survival ex vivo and express several activation-associated surface markers. This suggests that ERK2 plays a major role in facilitating GC B cell selection. Thus we hypothesize that Erk2 Δ B cells are impaired in their ability to participate in the GC reaction. We are currently investigating the ability of Erk2 Δ B cells to respond to activating and pro-apoptotic stimuli in vitro as well as to differentiate in to antibody-secreting plasma cells. Our results will contribute to a better understanding of the molecular programs involved in B cell selection, potentially offering new approaches to treating B cell-driven autoimmune diseases.