Pathways of plasma cell differentiation in autoimmunity

自身免疫中浆细胞分化的途径

• 批准号: 8605829
• 负责人: Loren D Erickson
• 金额: $ 47.11万
• 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/8605829
• 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）：自身免疫中等离子体细胞分化的途径。该项目的总体目标是直接评估BCMA在调节浆细胞（PC）生存和自身抗体发展中的作用。 BCMA是TNF受体家族的成员，我们组首先将其描述为PC上的关键受体，该受体在结合其配体Baff和April时，介导了其在骨髓（BM）中的长期生存。这导致了我们的假设，即BCMA通过直接向成熟的BM PC传递亲生信号对PC寿命具有内在影响，该信号是抗体生产的长期来源。然而，通过BCMA的信号传导也可能影响早期的B细胞中间体，从而引起BM PC，因此间接促进了BM中抗体生产PC的发育和持续性。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细胞依赖性免疫反应中开发BM PC的储层，并具有长期自我更新和终极与长期自我更新的能力，并在长期寿命中与长期寿命。 BM1-3。本应用程序中提供的新数据表明，PCPRE产生长期BM PC的能力取决于BAFF/4月。我们进一步假设，维持长期PC的能力是在PCPRE阶段的一部分，特别是通过PCPRE中的BCMA信号传导，该信号控制了它们在BM中的维护以及它们与长寿命PC的分化。因此，BCMA信号是建立和稳定性的特定保护性抗体所必需的。在没有这种机制的情况下，我们预测免疫稳态中PC衍生的稳定抗体产生的正常功能将被破坏。为了支持这一假设，我们最近报告说，在LPR和新西兰衍生的自身免疫性小鼠模型中，BCMA缺乏症会导致急剧B细胞淋巴细胞增生，PCPRE和长期寿命的PC在次生淋巴机构中的长期PC的积累，并且足够的自动抗体生产，并增加了Bafff of Bafffornation的数量，并与之相比。自身免疫性易免疫小鼠4。这些观察结果表明，在自身免疫性的小鼠中，通过B细胞上的BCMA信号有助于控制B细胞稳态，并严格消除自动反应性B细胞。在此提案中，我们将使用转基因，先天和基因敲除小鼠的组合来表征PC分化途径的顺序阶段的BCMA信号传导。该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，先天免疫细胞的外源信号，而T细胞有助于控制自发免疫性pc的长期PC的异常发育和生存。