Development of Intestinal Polyreactive IgA B Cells

肠道多反应性 IgA B 细胞的发育

基本信息

批准号：
10078246
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
项目类别：
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/10078246
关键词：
Address Affinity Antibodies Antibody Affinity Antibody Response Antibody Specificity Antigens Autoimmune 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 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

项目摘要

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，很大一部分肠道共生微生物群被 IgA 抗体覆盖，但应对细菌抗原的巨大多样性所采用的策略和机制已经仍然难以捉摸。综合研究表明，稳态 IgA 反应采用高度多反应性结合广泛但独特的微生物群子集的库。这些抗体反应在存在的情况下发生 T 细胞的帮助有限，体细胞突变率低，亲和力成熟度低。这个新视角与粘膜引起的 T 细胞依赖性、高亲和力抗体反应的经典范例形成对比病原体、病原体和疫苗，并为应对以下挑战提供了简单的免疫学解决方案微生物群抗原的复杂性。它还提出了几个基本问题，包括多反应性如何 IgA 库中产生和选择的特异性，以及它们如何与其他特异性共存或重叠稳态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) 了解发育和多反应性 IgA 前体 B 细胞的分化，以及 (iii) 研究多反应性 IgA 在肠道和肠外挑战背景下的克隆水平。这些研究将澄清一个主要差距我们对多反应性 B 细胞库的理解，解决了对现有抗体教条的挑战特异性和宽容性，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。