COBRE: DMS: CHEMOKINE RESPONSIVENESS OF PLASMA CELLS IN AUTOIMMUNITY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。B淋巴细胞是免疫系统的主要细胞组成部分，其功能是产生被称为抗体的分泌蛋白，保护宿主免受病原体的侵害。这种以抗体为基础的保护的一个特点是，专门的B细胞，即浆细胞（PC）具有延长寿命的能力，这也是疫苗建立长期免疫的原因。在健康个体中，PC的持续存在是保护性体液免疫的资产，但在PC疾病中却是一个重要的负担。因此，了解决定PC发展和生存的因素在生物学和治疗方面都具有相当重要的意义。我们的实验室研究两种PC疾病：第一，是PC恶性肿瘤，多发性骨髓瘤（MM），第二，是抗体介导的自身免疫性疾病，系统性红斑狼疮。我们已经确定了一种快速生长、自我更新的细胞群——存在于骨髓（BM）中的数量很少——作为正常pc （PCpre）的前体。这些细胞可以自我更新，也可以最终分化为寿命很长的细胞。因此，这种细胞群具有与干细胞相似的特性，因为它们在骨髓中产生更多的祖细胞和大多数PCs。这一发现为我们目前确定控制这些PCpre的细胞和分子信号的工作奠定了基础。为此，我们确定TNF家族的新成员BCMA对终末期pc的生存至关重要。我们假设BCMA在PC发育的祖细胞阶段发挥作用，在这个阶段，决定是补充还是最终分化为分泌抗体的PC。这个模型是高度创新的，因为第一次知道了长寿命PC的细胞起源，因此可以靶向治疗PC疾病。我们的长期目标是了解如何控制PCpre。我们已经开始以三个具体目标为重点来处理这些问题。1)确定BCMA在正常PCpre自我更新和分化中的作用。2)建立BCMA-BAFF相互作用如何影响自反应性pc的发展和生存。3)探讨BCMA-BAFF相互作用在支持多发性骨髓瘤生存中的作用。我们计划使用各种小鼠模型来测试这些目标，因为PCpre可以进行基因修饰和分离，数量足以在体外和体内进行表征。综上所述，我们期望本文提出的研究结果能够增强我们对PCpre中BCMA功能的理解，并更好地了解首先发生耐受性丧失或转化的靶细胞群。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. B lymphocytes constitute a major cellular component of the immune system, whose function is to produce secreted proteins called antibodies that protect the host against pathogens. A hallmark of this antibody-based protection is the capacity of specialized B cells, plasma cells (PC), to have a prolonged lifespan and is the raison d'¿tre for vaccines to establish long-term immunity. In healthy individuals, the persistence of PCs is an asset for protective humoral immunity but is a significant liability in PC disorders. Thus, understanding the factors that determine PC development and survival takes on considerable importance in terms of both biology and therapeutics. Our laboratory studies two PC disorders: first, is the PC malignancy, multiple myeloma (MM) and second, is the antibody-mediated autoimmune disease, systemic lupus erythematosus. We have identified a rapidly growing, self-renewing cell population - present in low numbers in the bone marrow (BM) - as the precursors to normal PCs (PCpre). These cells can undergo self-renewal or can terminally differentiate to very long-lived PCs. Thus, this cell population has similar properties to stem cells since they give rise both to more progenitors and to the majority of PCs within the bone marrow. This discovery is the basis for our current work to determine the cellular and molecular signals that control these PCpre. To this end, we have determined that a newly-identified member of the TNF family, BCMA, is critical for the survival of end-stage PCs. We hypothesize that BCMA plays a role at the progenitor phase of PC development where decisions are made to either replenish or terminally differentiate to antibody-secreting PCs. This model is highly innovative because for the first time the cellular origin of long-lived PCs is known and therefore can be targeted in the treatment of PC disorders. Our long-range goal is to understand how PCpre are controlled. We have begun to address these questions by focusing on three specific aims. 1) To determine the function of BCMA in normal PCpre self-renewal and differentiation. 2) Establish how BCMA-BAFF interactions affect the development and survival of autoreactive PCs. 3) To investigate the role of BCMA-BAFF interactions in supporting the survival of multiple myeloma. We plan to test each of these aims using a variety of murine models, since PCpre can be genetically-modified and isolated in quantities sufficient for in vitro and in vivo characterization. Taken together, we expect that the results from the studies proposed here should enhance our understanding of BCMA function in PCpre, as well as provide a better understanding of the target cell population where loss of tolerance, or transformation, first occurs.