High-resolution deconvolution of selection effects on the composition of the B cell repertoire

选择对 B 细胞库组成的影响的高分辨率反卷积

• 批准号: 10224256
• 负责人: Bryan Briney
• 金额: $ 48.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224256
• 关键词: Address; Affect; Affinity; Antibodies; Antibody Repertoire; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocytes; Binding; Cell Lineage; Cells; Clone Cells; Communicable Diseases; Data Set; Development; Early identification; Epitopes; Financial Hardship; Genetic; Genetic Recombination; High-Throughput Nucleotide Sequencing; Human; Immune Tolerance; Immune system; Individual; Knowledge; Laboratories; Memory; Modification; Molecular Profiling; Nature; Pathogenicity; Pattern; Personal Satisfaction; Phenotype; Plasma Cells; Process; Proteins; Research; Resolution; Shapes; Societies; Specificity; Techniques; V(D)J Recombination; autoreactive B cell; autoreactivity; central tolerance; peripheral tolerance; prevent; single cell analysis; vaccine development

Project Summary The random nature of V(D)J recombination, whose primary purpose is to produce antibodies that bind a broad range of potential targets, often inadvertently creates antibodies that recognize self antigens. Such autoreactive antibodies are often associated with autoimmune diseases that adversely affect the wellbeing of millions and represent a significant financial burden on society. During early development, mechanisms exist for managing autoreactive B cells, including deletion, modification, or silencing. In the periphery, B cells undergoing affinity maturation are subject to peripheral tolerance mechanisms to prevent acquisition of high affinity autoreactivity. Indeed, a myriad of selection and tolerance mechanisms, spanning the entirety of the B cell lineage from early pro-B cells to long-lived plasma cells, exert massive influence on the composition of the human antibody repertoire. Although the repertoire-shaping effects of selection and tolerance are thought to be quite large, we still have only a limited understanding of the ways in which B cell repertoire composition is regulated by selection. The long-term research focus of my laboratory is to use high-throughput sequencing to gain a more complete understanding of the development, maturation and function of the human B cell repertoire. Continuing technological advances, including emerging single-cell analysis techniques, allow the construction of increasingly detailed molecular profiles for large numbers of individual cells. The extremely high resolution of such datasets will allow study of the humoral immune system at an unprecedented level of depth and detail. Over the next five years, we will leverage these advances to address significant knowledge gaps in the following areas. (1) Discovery of specific features or feature patterns encoded by B cell receptors that are selectively depleted or modified by central tolerance. (2) Identification of early B cell development checkpoints at which selection and tolerance homogenize the repertoires of different individuals. (3) Characterization of global patterns of affinity maturation which, independent of any particular antigen, globally shape the composition of the memory repertoire. A more complete understanding of the processes and mechanisms that shape the B cell repertoire is vitally important and broadly relevant to ongoing research in infectious disease, autoimmunity, and rational vaccine development.

项目摘要 V（d）J重组的随机性质，其主要目的是产生结合宽的抗体 潜在靶标的范围通常会无意间产生识别自抗原的抗体。这样的 自动反应性抗体通常与自身免疫性疾病相关，这些疾病会对福祉产生不利影响 数百万，代表了社会的重大财务负担。在早期开发过程中，存在机制 用于管理自动反应性B细胞，包括删除，修改或沉默。在外围，B细胞 经历亲和力成熟是否受到外围耐受性机制，以防止获得高 亲和力自动反应性。实际上，跨越整个B的无数选择和宽容机制 细胞谱系从早期的pro-B细胞到长寿命的浆细胞，对成分产生巨大影响 人类抗体库。尽管选择和耐受性的曲目形成效应被认为是 很大，我们仍然对B细胞曲目组成的方式有限 由选择调节。 我实验室的长期研究重点是使用高通量测序以获得更完整的 了解人B细胞库的发展，成熟和功能。继续 技术进步，包括新兴的单细胞分析技术，允许构建 越来越详细的单个细胞分子曲线。非常高的分辨率 这样的数据集将允许研究体验的深度和细节水平。 在接下来的五年中，我们将利用这些进步来解决重大知识差距 以下区域。 （1）发现由B细胞受体编码的特定特征或特征模式 通过中央公差有选择地耗尽或修饰。 （2）识别早期B细胞开发检查点 选择和耐受性使不同个体的曲目均匀。 （3）表征 全球亲和力成熟的模式，与任何特定的抗原无关，在全球范围内塑造 记忆曲目的组成。对过程和机制的更完整理解 塑造B细胞曲目至关重要，并且与正在进行的传染病研究中有关 自身免疫性和理性疫苗开发。