Pathways of plasma cell differentiation in autoimmunity

描述（由申请人提供）：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TNF受体家族的成员，并且首先由我们的小组描述为PC上的关键受体，其在结合其配体BAFF和APRIL后介导其在骨髓（BM）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提供促生存信号对PC寿命具有内在影响，所述成熟的BM PC作为抗体产生的长期来源。然而，通过BCMA的信号传导也可以影响产生BM PC的早期B细胞中间体，因此，间接有助于BM中产生抗体的PC的发展和持续。我们以前已经证明，通过产生独特的BM驻留细胞类型，PC祖细胞（PCpre），可以在T细胞依赖性免疫应答中实现BM PC储库的发育，所述BM驻留细胞类型具有长期自我更新和终末分化为长寿命PC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信号传导，该信号传导控制它们在BM中的维持和它们向长寿命PC的分化。因此，BCMA信号传导对于特异性保护性抗体的正常库的建立和稳定性是必需的。在缺乏这种机制的情况下，我们预测PC衍生的稳定抗体产生在免疫稳态中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和新西兰衍生的自身免疫易感小鼠模型中，BCMA缺乏导致显著的B细胞淋巴增殖，次级淋巴器官中PCpre和长寿命PC的积累，增强的自身抗体产生，产生BAFF的细胞数量增加，以及与BCMA充足的自身免疫易感小鼠相比的早期致死率4。这些观察结果表明，在自身免疫易感小鼠中，通过B细胞上的BCMA的信号有助于控制B细胞稳态和自身反应性B细胞的严格消除。在这个建议中，我们将使用转基因，同源，和敲除小鼠的组合来表征BCMA信号在PC分化途径的连续阶段。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细胞的内在改变、来自先天免疫细胞的外源性信号和T细胞帮助控制自身免疫易感小鼠中长寿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.