Development of Intestinal Polyreactive IgA B Cells

在稳态条件下，大部分肠道肠道微生物群被伊加抗体包被， 但是对付细菌抗原的巨大多样性的策略和机制， 仍然难以捉摸汇聚的研究表明，稳态伊加反应采用高度多反应性， 库结合广泛但不同的微生物群亚群。这些抗体反应是在 有限的T细胞帮助，具有低的体细胞突变率和很少的亲和力成熟。这种新视角 与粘膜免疫刺激引起的T细胞依赖性、高亲和力抗体应答的经典范例相反， 病原体，病原体和疫苗，并提供了一个简单的免疫解决方案的挑战， 微生物抗原复杂性。它还提出了几个基本问题，包括如何多反应 特异性是在伊加库中产生和选择的，以及它们如何与其他特异性共存或重叠。 免疫反应和疾病。该项目通过以下方式解决这些问题：（i）生成 使用CRISPR/Cas9技术的多反应性伊加基因敲入小鼠，以（ii）了解 多反应性伊加前体B细胞的分化和（iii）研究多反应性伊加在 肠内和肠外挑战背景下的克隆水平。这些研究将澄清一个主要的差距， 我们对多反应性B细胞库的理解，解决了对现有抗体教条的挑战， 具体性和宽容性，并发展新的知识、概念和工具，以更好地了解 肠道免疫、炎症性肠病和口服疫苗。

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.