Pathways of plasma cell differentiation in autoimmunity

自身免疫中浆细胞分化的途径

• 批准号: 8699294
• 负责人: Loren D Erickson
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-08 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699294
• 关键词: Adoptive Transfer; Affect; Antibodies; Antibody Formation; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Bone Marrow; Cell Count; Cell Survival; Cells; Cellular biology; Congenic Mice; Data; Development; Family; Generations; Goals; Homeostasis; Immune; Immune response; Knockout Mice; Life; Longevity; Lymphoid; Lymphoid Tissue; Maintenance; Mature Bone; Mediating; Modeling; Molecular; Mus; New Zealand; Organ; Pathway interactions; Physiological; Plasma Cells; Production; Property; Proteins; Recombinants; Regulation; Reporting; Role; Signal Transduction; Source; Staging; T-Lymphocyte; TALL-1 protein; Testing; Thinking; Time; Tissues; Transgenic Mice; Tumor Necrosis Factor Receptor; autoreactive B cell; bis(3-bis(4-chlorophenyl)methyl-4-dimethylaminophenyl)amine; cell type; design; effective therapy; member; mouse model; plasma cell differentiation; progenitor; receptor; research study; self-renewal

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.

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 受体家族的一员，我们的团队首先将其描述为 PC 上的关键受体，在结合其配体 BAFF 和 APRIL 后，介导 PC 在骨髓 (BM) 中的长期存活。这导致我们假设 BCMA 通过直接向成熟的 BM PC 传递促生存信号而对 PC 寿命产生内在影响，而 BM PC 作为抗体生产的长期来源。然而，通过 BCMA 的信号传导也可能影响产生 BM PC 的早期 B 细胞中间体，从而间接促进 BM 中产生抗体的 PC 的发育和持续存在。我们之前已经证明，通过产生独特的 BM 驻留细胞类型 PC 祖细胞（PCpre），可以在 T 细胞依赖性免疫反应中实现 BM PC 库的开发，该细胞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，该信号控制它们在 BM 中的维护以及它们向长寿命 PC 的分化。因此，BCMA 信号传导是特异性保护性抗体正常库的建立和稳定性所必需的。如果没有这种机制，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倾向小鼠模型中，与 BCMA 充足相比，BCMA 缺乏会导致 B 细胞淋巴细胞急剧增殖、PCpre 和长寿命 PC 在次级淋巴器官中积累、自身抗体产生增强、产生 BAFF 的细胞数量增加以及早期致死。 自身免疫倾向小鼠4。这些观察结果表明，在易患自身免疫的小鼠中，B 细胞上通过 BCMA 发出的信号有助于控制 B 细胞稳态并严格消除自身反应性 B 细胞。在本提案中，我们将使用转基因、同类和基因敲除小鼠的组合来表征 PC 分化途径的连续阶段的 BCMA 信号传导。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、先天免疫细胞的外源信号和 T 细胞有助于控制自身免疫易感小鼠中长寿命 PC 的异常发育和存活。