Biochemical Mechanisms for Sustained Humoral Immunity

Project summary Antibody-secreting plasma cells play critical roles in health and disease, yet little is known about the biochemical mechanisms controlling antibody synthesis and secretion or how these pathways intersect with pathways controlling cell survival. Furthermore, due to the high metabolic demands inherent to robust antibody secretion and the tendency for many plasma cells to persist for decades, pathways restraining apoptosis in plasma cells are likely to be integrated in unique ways. This project centers on the hypothesis that long- lived plasma cells in bone marrow obtain requisite signals to maintain antibody secretion and avoid cell death by sensing extracellular ATP with a purinergic receptor known as P2rX4. We further hypothesize that eATP is produced locally in the bone marrow for plasma cells by osteoblastic cells via the gap junction protein known as Panx3. Thus, consistent with our preliminary data, inhibition of P2rX4 or Panx3 function is predicted to cause the depletion of long-lived plasma cells and reduce serum antibody titers including for disease-associated antibodies. To test our hypothesis, we will: 1) Define cell intrinsic P2rX4-regulated outcomes for newborn and long-lived plasma cells, and 2) Define cell extrinsic sources and outcomes for eATP/Panx3 regulation of long-lived plasma cells. These studies will provide unique and needed insights into the specialized survival mechanisms employed by long-lived plasma cells. This work supports our long-term objective of developing strategies to effectively and specifically disable or deplete problematic plasma cells.