The biochemical pathways through which activated B cells initiate antibody synthesis and secretion while simultaneously undergoing cell division are unknown. Current models predict that early plasma cells generate the organelle structures needed for robust antibody secretion by activating the unfolded protein response (UPR) in response to increased antibody synthesis and through a mitosis-dependent process. This project centers on an alternative model where activated B cells prepare for plasma cell function by enacting the UPR well before increased antibody synthesis and independently of mitosis. Hence we propose that induction of the UPR in B cells is as much proactive as it is reactive. We will test this new model while also dissecting the past observations that marginal zone B cells generate plasma cells much faster than most B cells. We propose three specific aims: 1) Define biochemical pathways coordinating very early PC differentiation, 2) Define the role of constitutive mTORC1 signaling in MZ B cell differentiation, and 3) Uncouple mitosis and early PC differentiation.
The factors underlying the generation of antibody secreting plasma cells are not understood. These studies will define novel biochemical pathways that facilitate antibody synthesis and secretion. These studies have direct implications for strategies to manipulate antibody immune responses.