Development of Intestinal Polyreactive IgA B Cells

肠道多反应性 IgA B 细胞的发育

• 批准号: 10543053
• 负责人: ALBERT S. BENDELAC
• 金额: $ 49.84万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-17 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543053
• 关键词: Address; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody Specificity; Antigens; Autoimmune Diseases; Autoimmunity; B cell differentiation; B cell repertoire; B-Cell Development; B-Lymphocytes; Bacterial Antigens; Binding; Bone Marrow; CRISPR/Cas technology; Cell Compartmentation; Cell Lineage; Cells; Development; Disease; Epitopes; Equilibrium; Exclusion; Flagellin; Gene Expression Profiling; Generations; Genes; HIV; Homeostasis; Human; Immune response; Immunity; Immunoglobulin A; Immunoglobulin M; Immunologics; Immunology; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Influenza; Intestines; Knock-in; Knock-in Mouse; Knowledge; Microbe; Modeling; Mucous Membrane; Mutation; Pattern; Peripheral; Phenotype; Physiological; Plasma Cells; Polysaccharides; Population; Production; Property; Risk; Role; Self Tolerance; Signal Transduction; Site; Somatic Mutation; Specificity; Structure; Surface; System; T-Lymphocyte; Testing; Vaccine Design; Vaccines; commensal bacteria; commensal microbes; improved; in vivo; intestinal homeostasis; microbial; microbiota; neutralizing monoclonal antibodies; novel; novel strategies; oral vaccine; pathobiont; pathogen; response; tool

A large fraction of the intestinal commensal microbiota is coated with IgA antibodies in homeostatic conditions, but the strategy and the mechanisms deployed to confront the immense diversity of bacterial antigens have remained elusive. Converging studies indicate that homeostatic IgA responses employ a highly polyreactive repertoire to bind broad but distinct subsets of microbiota. These antibody responses develop in the presence of limited T cell help, with low rate of somatic mutations and little affinity maturation. This new perspective contrasts with the classical paradigm of T cell-dependent, high-affinity antibody responses elicited by mucosal pathobionts, pathogens and vaccines, and provides a simple immunological solution to the challenge of microbiota antigenic complexity. It also raises several fundamental issues, including how polyreactive specificities are generated and selected in the IgA repertoire, and how they coexist or overlap with other immune responses during homeostasis and disease. This project addresses these issues by (i) generating polyreactive IgA knock-in mice using CRISPR/Cas9 technology to (ii) understand the development and differentiation of polyreactive IgA precursor B cells and (iii) to study the function of polyreactive IgA at the clonal level in the context of intestinal and extraintestinal challenges. These studies will clarify a major gap in our understanding of polyreactive B cell repertoires, address a challenge to existing dogmas of antibody specificity and tolerance, and develop new knowledge, concepts and tools for a better understanding of intestinal immunity, inflammatory bowel diseases and oral vaccines.

在稳态条件下，肠道共生微生物区系的很大一部分被IgA抗体覆盖， 但是，为应对细菌抗原的巨大多样性而部署的策略和机制 仍然难以捉摸。趋同研究表明，动态平衡的免疫球蛋白A反应采用高度多反应 结合广泛但不同的微生物亚群的谱系。这些抗体反应是在 T细胞帮助有限，体细胞突变率低，亲和力成熟少。这一新视角 与传统的依赖T细胞的高亲和力抗体反应模式不同 病原体、病原体和疫苗，并提供了一种简单的免疫学解决方案 微生物区系抗原性复杂性。它还提出了几个基本问题，包括如何多反应 在IgA曲目中生成和选择特定项，以及它们如何与其他项共存或重叠 动态平衡和疾病期间的免疫反应。该项目通过(I)生成 使用CRISPR/Cas9技术的多反应性IgA敲入小鼠(II)了解其发展和 多反应性IgA前体B细胞的分化及(III)多反应性IgA在B细胞分化中的作用 在肠道和肠外挑战的背景下的克隆水平。这些研究将澄清一个主要的差距 我们对多反应B细胞谱系的理解，解决了对现有抗体教条的挑战 专一性和容忍性，并开发新的知识、概念和工具，以更好地理解 肠道免疫、炎症性肠病和口服疫苗。