CD138 Regulates Competition of Antibody Secreting Cells for Survival

长寿抗体分泌细胞(LLASCs)本质上是重要的免疫效应细胞 分泌高亲和力抗体，预防感染。与现场直播形成对比 减毒病毒可以提供终身免疫，基于蛋白质的疫苗已知 诱导不佳的LLASCs，通常需要多次增强才能产生足够的抗体效价。这个 控制LLASC产量的因素人们知之甚少，但对所有人来说都是至关重要的 基于体液的疫苗。LLASCs的存活主要由可溶性细胞因子介导，如 4月份在骨髓中，IL-6在次级淋巴组织中。免疫后，抗体 分泌细胞(ASCs)表达不同水平的CD138，其功能尚不清楚，因为 可结合100+蛋白，CD138-/-无明显表型。然而，我们最近 发表了一项研究，最终详细说明了CD138在有效抗体反应中的直接作用 控制免疫后ASC的成熟和存活。LLASC表达最高水平 CD138在所有细胞中的表达，与新生的ASCs相比，ASCs表达中间 CD138水平。我们认为CD138的高表达为LLASCs提供了更高的 IL-6和APRIL的结合和积累，这是有限的，导致竞争性 比新的ASCs更具生存优势。在目标1中，我们将在此测试此竞争模型 Grant，它可以解释糟糕的疫苗反应以及LLASCs是如何维持的 时间和重复的免疫反应。在目标2中，我们将探索在以下情况下增加CD138的方法 接种疫苗以提高ASC存活率和长期免疫力。在目标3和4中，我们将探索 CD138在病理状态下发挥作用。

Long-lived antibody secreting cells (LLASCs) are critical immune effector cells constitutively secreting high affinity antibody providing prophylaxis against infections. In contrast to live attenuated viruses which can provide lifelong immunity, protein-based vaccines are known to poorly induce LLASCs, often requiring multiple boosting to generate sufficient antibody titer. The factors that control LLASC production are poorly understood, but are critically important for all humoral-based vaccines. Survival of LLASCs is chiefly mediated by soluble cytokines, such as APRIL in the BM, and IL-6 in secondary lymphoid tissues. After immunization, antibody secreting cells (ASCs) express variable levels of CD138, and its function was unclear, since it can bind 100+ proteins, and CD138-/- have no overt phenotype. However, we have recently published a study that finally details a direct role for CD138 for potent antibody responses, by controlling ASC maturation and survival after immunization. LLASCs express the highest level of CD138 among all cells, in comparison to newly minted ASCs, which express intermediate levels of CD138. We proposed that high expression of CD138 provides LLASCs with higher binding and accumulation of IL-6 and APRIL, which are limiting, leading to a competitive advantage over new ASCs for survival. In Aim 1, we will test this competition model in this grant, which can explain poor vaccine responses as well as how LLASCs are maintained over time and repeated immune responses. In Aim 2 we will explore ways to increase CD138 after vaccination to enhance ASC survival and long term immunity. In Aims 3 & 4, we will explore CD138 function in pathological conditions.