Defining the cellular origin of pathogenic autoantibodies

定义致病性自身抗体的细胞起源

• 批准号: EP/Y031091/1
• 负责人: Amalie Grenov
• 金额: $ 23.84万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY031091%2F1
• 关键词: Defining; cellular; origin; pathogenic; autoantibodies

B cell-derived autoantibodies are found in practically all autoimmune diseases, and in many of them they are pathogenic. While globally immunosuppressive or immune cell-depleting therapies improved clinical outcomes, they often fail to remove the pathogenic B cell subsets and to improve the most severe clinical manifestations. Development of more effective therapies requires understanding of how and from which subsets autoreactive B cells arise.Despite significant advances in our understanding of B cell maturation and tolerance, there is still conflicting evidence on the role of germinal centers (GC) in pathogenic autoantibody production. While some studies have identified selective mutations in autoreactive B cells indicative of GC-origin, others have shownthat autoantibody formation can occur in GC-depleted environments.In this proposed work, mouse models of human autoimmune disease and novel antibody-tagging tools will be integrated with human patient cohorts todetermine the origin and GC-dependence of autoantibody-producing B cells.To understand the diversity or possible convergence of different pathogenic routes to disease, I will use mice carrying human variants that cover most of thespectrum of human monogenic systemic autoimmune disease. Crossing of these mice with mice expressing Cre-induced Flag-tagged antibody light-chainsallows tracking the origin of autoantibodies to specific B cell subsets. Using GC-specific inducible Cre models and ELISA-based detection, I will delineate GCcontributionto autoantibody formation across disease stages. In parallel, I will characterise autoreactive B cell subsets in human patient cohorts based on singlecelltranscriptomics and analysis of clonal sharing. This will further identify whether autoantibody-producing cells are GC-experienced.The knowledge acquired in this proposal will provide solid foundations for the design of more targeted therapies that can eliminate autoreactive B cells.

B细胞衍生的自身抗体几乎存在于所有自身免疫性疾病中，并且在许多自身免疫性疾病中它们是致病性的。虽然整体免疫抑制或免疫细胞耗竭疗法改善了临床结果，但它们往往无法去除致病性 B 细胞亚群并改善最严重的临床表现。开发更有效的疗法需要了解自身反应性 B 细胞亚群如何产生以及由哪些亚群产生。尽管我们对 B 细胞成熟和耐受性的理解取得了重大进展，但关于生发中心 (GC) 在致病性自身抗体产生中的作用仍然存在相互矛盾的证据。虽然一些研究已经确定了表明 GC 起源的自身反应性 B 细胞中的选择性突变，但其他研究表明，自身抗体的形成可能发生在 GC 耗尽的环境中。在这项拟议的工作中，将整合人类自身免疫性疾病的小鼠模型和新型抗体标记工具与人类患者队列一起确定产生自身抗体的 B 细胞的起源和 GC 依赖性。为了了解不同致病途径的多样性或可能的趋同性，我将使用携带人类变异体的小鼠，这些变异体涵盖了大部分人类单基因系统性自身免疫性疾病的谱系。将这些小鼠与表达 Cre 诱导的 Flag 标记抗体轻链的小鼠杂交，可以追踪特定 B 细胞亚群自身抗体的起源。使用 GC 特异性诱导 Cre 模型和基于 ELISA 的检测，我将描述 GC 对跨疾病阶段自身抗体形成的贡献。与此同时，我将基于单细胞转录组学和克隆共享分析来表征人类患者群体中的自身反应性 B 细胞亚群。这将进一步确定产生自身抗体的细胞是否经历过GC。该提案中获得的知识将为设计更多能够消除自身反应性B细胞的靶向疗法提供坚实的基础。