Pathways of plasma cell differentiation in autoimmunity

描述(申请人提供)：自身免疫中浆细胞分化的途径。该项目的总体目标是直接评估BCMA在调节浆细胞(PC)存活和自身抗体发展中的作用。BCMA是肿瘤坏死因子受体家族的一员，我们的研究小组首次将其描述为PC上的一个关键受体，当它与其配体BAFF和APRIL结合时，介导它们在骨髓中的长期存活。这导致了我们的假设，即BCMA通过直接向成熟的BM PC传递支持生存的信号来影响PC的寿命，而成熟的BM PC作为抗体产生的长期来源。然而，通过BCMA的信号也可以影响早期的B细胞中间体，从而产生BM PC，从而间接地促进产生抗体的PC在BM中的发展和持续。我们先前已经证明，在T细胞依赖的免疫反应中，可以通过产生一种独特的BM驻留细胞类型PC前体(PCpre)来实现BM PC库的发展，该PC前体具有长期自我更新和向长寿命PC的终末分化的能力。 BM1-3。本申请中提供的新数据表明，PCPRE产生长寿命BM PC的能力取决于BAFF/APRIL。我们进一步假设，维持长寿命PC的能力部分是在PCPRE阶段实现的，特别是通过PCPRE中的BCMA信号，该信号控制着它们在BM中的维护以及它们与长寿命PC的区分。因此，BCMA信号对于建立和稳定正常的特异性、保护性抗体库是必需的。在缺乏这一机制的情况下，我们预测PC来源的稳定抗体产生的正常功能将被破坏。为了支持这一假设，我们最近报道，在LPR和新西兰来源的自身免疫倾向小鼠模型中，与BCMA充足的自身免疫倾向小鼠相比，BCMA缺乏会导致B细胞显著增殖，次级淋巴器官中PCpre和长寿PC的积累，自身抗体的产生增加，BAFF产生细胞的数量增加，以及早期死亡。这些观察表明，在有自身免疫倾向的小鼠中，通过B细胞上的BCMA发出的信号有助于控制B细胞的动态平衡和严格消除自身反应性B细胞。在这项提案中，我们将使用转基因、同源基因和基因敲除小鼠的组合来表征PC分化途径连续阶段的BCMA信号。这一策略将使我们能够确定BCMA在PC生物学中的生理作用，以及B细胞的内在变化、来自天然免疫细胞的外源信号和T细胞有助于控制自身免疫倾向小鼠长期存活的PC的异常发育和存活。

DESCRIPTION (provided by applicant): Pathways of plasma cell differentiation in autoimmunity. The overall goal of this project is to directly assess the role of BCMA in the regulation of plasma cell (PC) survival and the development of autoantibodies. BCMA is a member of the TNF receptor family and was first described by our group as a critical receptor on PCs that, upon binding its ligands BAFF and APRIL, mediates their long-term survival in the bone marrow (BM). This has led to our hypothesis that BCMA has an intrinsic effect on PC longevity by directly delivering pro-survival signals to mature BM PCs that serve as a long-term source for antibody production. However, signaling through BCMA could also affect earlier B cell intermediates that give rise to BM PCs and, thus, contribute indirectly to the development and persistence of antibody- producing PCs in the BM. We have previously demonstrated that the development of a reservoir of BM PCs could be achieved in a T cell-dependent immune response through the generation of a unique BM resident cell type, the PC progenitor (PCpre), with the capacity for both long-term self renewal and terminal differentiation to long-lived PCs in the BM1-3. New data provided in this application demonstrates that the ability of PCpre to give rise to long-lived BM PCs is dependent on BAFF/APRIL. We further hypothesize that the capacity to sustain long-lived PCs is achieved in part at the PCpre stage, specifically through BCMA signaling in PCpre, which controls both their maintenance in the BM and their differentiation to long-lived PCs. Thus, BCMA signaling is required for the establishment and stability of a normal repertoire of specific, protective antibodies. In the absence of this mechanism, we predicted that the normal functions of PC-derived stable antibody production in immune homeostasis would be disrupted. In support of this hypothesis, we recently reported that, in both the lpr and New Zealand-derived autoimmune-prone mouse models, BCMA deficiency causes dramatic B cell lymphoproliferation, accumulation of PCpre and long-lived PCs in secondary lymphoid organs, enhanced autoantibody production, increased numbers of BAFF-producing cells, and early lethality compared to BCMA- sufficient autoimmune-prone mice4. These observations suggest that, in autoimmune-prone mice, signals through BCMA on B cells help control B cell homeostasis and the stringent elimination of autoreactive B cells. In this proposal, we will use a combination of transgenic, congenic, and knockout mice to characterize BCMA signaling at sequential stages of the PC differentiation pathway. This strategy will allow us to determine the physiologic role of BCMA in PC biology as well as intrinsic alterations in B cells, exogenous signals from innate immune cells, and T cell help in controlling abnormal development and survival of long-lived PCs in autoimmune-prone mice.