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: 9980447
• 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/9980447
• 关键词: Address; Affect; Affinity; Antibodies; Antibody Repertoire; Antigens; Area; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell repertoire; 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; Receptors, Antigen, B-Cell; 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.

项目概要 V(D)J 重组的随机性质，其主要目的是产生结合广泛的抗体 一系列潜在靶标，通常会无意中产生识别自身抗原的抗体。这样的 自身反应性抗体通常与自身免疫性疾病有关，对健康产生不利影响 数以百万计，给社会带来了沉重的经济负担。在早期发展过程中，存在机制 用于管理自身反应性 B 细胞，包括删除、修改或沉默。在外周，B细胞 经历亲和力成熟的人受到外周耐受机制的影响，以防止获得高 亲和自身反应性。事实上，有无数的选择和耐受机制，跨越了整个 B 从早期原 B 细胞到长寿浆细胞的细胞谱系，对细胞的组成产生巨大影响 人类抗体库。尽管选择和宽容的剧目塑造效应被认为是 虽然相当大，但我们对 B 细胞库组成方式的了解仍然有限 通过选择来调节。 我实验室的长期研究重点是利用高通量测序来获得更完整的信息 了解人类 B 细胞库的发育、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 大量单个细胞的分子谱越来越详细。极高的分辨率 这些数据集将使体液免疫系统的研究达到前所未有的深度和细节。 在接下来的五年中，我们将利用这些进步来解决该领域的重大知识差距 以下领域。 (1) 发现由 B 细胞受体编码的特定特征或特征模式 通过中枢耐受选择性地耗尽或修饰。 (2) 早期B细胞发育检查点的识别 选择和宽容使不同个体的技能同质化。 (3) 表征 亲和力成熟的全局模式，独立于任何特定抗原，全局塑造 记忆库的组成。更全面地了解其过程和机制 塑造 B 细胞库至关重要，并且与正在进行的传染病研究广泛相关， 自身免疫和合理的疫苗开发。