Regulation of B cells by Selenium

硒对 B 细胞的调节

基本信息

批准号：
9890924
负责人：
Girish S Kirimanjeswara
金额：
$ 39.3万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-11 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890924
关键词：
Acute Address Animal Model Animals Antibody Response Antibody-Producing Cells Antigen Presentation Pathway Antigens Antioxidants Autoimmune Diseases B cell differentiation B-Cell Activation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Biological Assay Bone Marrow Calcium Signaling Cell Compartmentation Cell Differentiation process Cell Line Cell physiology Cells Chronic Defect Development Diet Dietary Selenium Disease Disease Progression Dose Endocytosis Flow Cytometry Frequencies Genes Genetic Homeostasis Human Immune Immune response Immunoglobulin M Immunoglobulins Impairment Incidence Influenza vaccination Knock-out Lead MHC Class II Genes Malignant Neoplasms Measures Memory Micronutrients Modeling Monitor Mus Oxidation-Reduction Peripheral Phosphorylcholine Play Production Reactive Oxygen Species Receptor Signaling Receptors, Antigen, B-Cell Regulation Role Secondary to Selenium Signal Transduction Source Spleen Stromal Cells Supplementation System T-Lymphocyte Tissue Model Tissues Tularemia Wild Type Mouse antigen processing base cell mediated immune response experimental study in vitro Assay in vivo macrophage mouse model nutrition pathogen protein folding public health relevance response selenocysteine-tRNA selenoprotein trafficking

项目摘要

DESCRIPTION (provided by applicant): The essential micronutrient selenium (Se) is known to play a significant role in immune homeostasis and immune responses. Thus far, the majority of studies have focused on the effect of Se on either T cells or macrophages. In addition to these cells, B cells are well known for their involvement in immune homeostasis, yet the role of Se and selenoproteins in B cells has largely been understudied. There are evidence that Se may influence humoral responses in humans and animals. A few recent studies have noted the potential role of selenoproteins in B cell calcium signaling and protein folding. However, no studies to date have addressed the role of Se in B-cell receptor (BCR) signaling and its downstream effects such as B cell differentiation, proliferation, and immunoglobulin secretion. Redox status of B cells influences the B cell functions and differentiation. Given the central role of selenoproteins in regulating the redox status of cells, we hypothesized that selenoproteins influence B cell development and functions by regulating the redox status of cells. Preliminary studies indicated that BCR endocytosis and antigen trafficking to MHC class II compartments are significantly impaired in Se-deficient B cells. Defects in BCR endocytosis and antigen processing in Se-deficient B cells were associated with the higher levels of cellular ROS. Interestingly, BCR endocytosis and antigen degradation were accelerated in B cells isolated from Se-supplemented mice, suggesting that B cells functions could be enhanced by dietary Se-supplementation. The proposed study will be the first to establish the role of selenoproteins in B cell functions and development with the following specific aims: Specific Aim 1: Establish the role of selenoproteins in B cell antigen processing and presentation. To determine the contributions of selenoproteins to antigen processing and presentation, BCR endocytosis & signaling, antigen trafficking, degradation, and presentation will be measured in Se-deficient, Se-adequate and Se-supplemented B cells. Specific Aim 2: Examine the role of selenoproteins in B cell differentiation and development. Since we observed a significant reduction the frequency and number of B cells in the spleen of TrspB mice, B cell developmental stages in bone marrow and B cell subsets in peripheral tissues in TrspB mice will be compared with that of wild-type (WT) littermate controls. Specific Aim 3: Investigate the effect of Se in B cell-mediated immune responses. Immunoglobulin synthesis and secretion will be measured by in vitro assays using TrspB B cells. In addition, disease progression in models of acute tularemia and chronic bordetellosis, will be monitored in TrspB mice. The proposed studies will have a major impact on the field by addressing three critical questions: 1) What is the contribution of selenoproteins to the functions and development of B cells? 2) How do selenoproteins influence the memory response? 3) Does dietary Se supplementation lead to better humoral immune responses, which could have high translational value. The significance of the proposed studies is that they will lead to a better understanding of the contributions of Se and selenoproteins to B cell homeostasis.

描述（由申请人提供）：已知必需微量营养素硒 (Se) 在免疫稳态和免疫反应中发挥重要作用，迄今为止，大多数研究都集中在 Se 对 T 细胞或巨噬细胞的影响。除了这些细胞外，B 细胞因其参与免疫稳态而闻名，但 Se 和硒蛋白在 B 细胞中的作用在很大程度上尚未得到充分研究。有证据表明 Se 可能会影响体液反应。最近的一些研究已经注意到硒蛋白在 B 细胞钙信号传导和蛋白质折叠中的潜在作用，但迄今为止还没有研究探讨硒在 B 细胞受体 (BCR) 信号传导及其下游影响中的作用。由于B细胞的分化、增殖和免疫球蛋白的分泌，对B细胞的功能和分化起着核心作用。为了研究硒蛋白在调节细胞氧化还原状态中的作用，我们发现硒蛋白通过调节细胞氧化还原状态来影响 B 细胞的发育和功能。初步研究表明，在缺硒的 B 细胞中，BCR 内吞作用和向 MHC II 类区室的抗原运输显着受损。缺硒 B 细胞中 BCR 内吞作用和抗原加工的缺陷与细胞 ROS 水平较高有关。在从补充硒的小鼠中分离出的 B 细胞中，这一过程加速，表明通过膳食补充硒可以增强 B 细胞功能。这项研究将是第一个确定硒蛋白在 B 细胞功能和发育中的作用的研究，其具体目标如下。：具体目标 1：确定硒蛋白在 B 细胞抗原加工和呈递中的作用确定硒蛋白对抗原加工和呈递、BCR 内吞作用和信号传导、抗原运输、降解和呈递的贡献。将在缺硒、硒充足和补充硒的 B 细胞中进行测量。具体目标 2：检查硒蛋白在 B 细胞分化和发育中的作用，因为我们观察到脾脏中 B 细胞的频率和数量显着减少。 TrspB 小鼠的骨髓中的 B 细胞发育阶段和外周组织中的 B 细胞亚群将与野生型 (WT) 同窝小鼠对照进行比较具体目标 3：将使用 TrspB B 细胞进行体外测定，研究 Se 对 B 细胞介导的免疫反应的影响。此外，还将在 TrspB 小鼠中监测急性兔热病和慢性博氏菌病模型中的疾病进展。拟议的研究将通过解决三个关键问题对该领域产生重大影响：1）硒蛋白对 B 细胞的功能和发育有何贡献？硒蛋白会影响记忆反应吗？ 3) 膳食补充硒是否会导致更好的体液免疫反应，这可能具有很高的转化价值，这些研究的意义在于它们将有助于更好地了解硒和硒蛋白对 B 的贡献。细胞稳态。