Biochemical Mechanisms for Sustained Humoral Immunity

项目总结 分泌抗体的浆细胞在健康和疾病中起着关键作用，但人们对此知之甚少。 关于控制抗体合成和分泌的生化机制或如何 这些途径与控制细胞存活的途径相交。此外，由于 强健的抗体分泌所固有的高代谢需求以及许多 浆细胞持续数十年，抑制浆细胞凋亡的途径是 很可能以独特的方式整合在一起。这个项目的中心是这样一种假设，即Long- 骨髓中活的浆细胞获得维持抗体分泌所需的信号 通过一种称为嘌呤能受体的细胞外ATP感应来避免细胞死亡 P2rX4。我们进一步假设eATP是在骨髓中局部产生的 浆细胞由成骨细胞通过缝隙连接蛋白Panx3表达。因此， 与我们的初步数据一致，抑制P2rX4或Panx3功能被预测为 导致耗尽长寿命的浆细胞并降低血清抗体效价，包括 用于疾病相关抗体。为了验证我们的假设，我们将：1)定义细胞固有 P2rX4调节的新生儿和长寿浆细胞的结果，以及2)定义细胞 EATP/Panx3调控长寿命浆细胞的外部来源和结果。 这些研究将为专门化生存提供独特和必要的见解。 长寿浆细胞使用的机制。这项工作支持了我们长期的 制定有效和具体禁用或耗尽的战略的目标 有问题的浆细胞。

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.