Plasma Cell Regulation by Purinergic Receptors

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Project summary Plasma cells that secrete antibodies against self-antigens pose a considerable threat to human health. Moreover, because many plasma cells are exceptionally long-lived, strategies are needed to deplete long-lived plasma cells (LLPCs) that secrete pathogenic antibodies. This project centers on the hypothesis that LLPCs in bone marrow generate requisite survival signals by sensing extracellular ATP with specific members of the purinergic receptor (P2rX) family. Hence, we propose that compounds that selectively poison relevant purinergic receptors will deplete LLPCs. To test our hypothesis, we will: 1) Establish the impact of P2rX inhibitors on LLPC generation and maintenance, and 2) Determine the role of the purinergic receptor P2rX4 in early plasma cell induction and LLPC maintenance. These studies will provide unique and needed insights into the specialized survival mechanisms employed by LLPCs. This work supports our long-term objective of developing strategies to effectively and specifically disable or deplete problematic plasma cells.