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）存活和自身抗体产生中的作用。BCMA是TNF受体家族的一员，本研究小组首次将其描述为pc上的一个关键受体，通过与其配体BAFF和APRIL结合，介导其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传递促生存信号，作为抗体产生的长期来源，对PC寿命具有内在影响。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，从而间接促进BM中产生抗体pc的发展和持续。我们之前已经证明，通过产生一种独特的BM驻留细胞类型，PC祖细胞（PCpre），可以在T细胞依赖的免疫应答中实现BM PC储存库的发展，PC祖细胞具有长期自我更新和向长寿命PC的终端分化的能力

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.