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在所有自身免疫性疾病中都发现，在许多自身免疫性疾病中，它们具有致病性。虽然全球免疫抑制或免疫细胞缺乏疗法改善了临床结果，但它们通常无法去除病原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如何以及从哪些子集自动反应性B细胞出现。尽管在我们对B细胞成熟和耐受性的理解方面取得了重大进展，但仍存在有关生发中心（GC）在致病自身抗体产生中的作用的证据。 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或可能收敛到不同致病性途径到疾病，我将使用携带人类变种的小鼠，这些变体涵盖了人类单基因自身免疫性疾病的大部分光谱。这些小鼠与表达CRE诱导的FLAG标记的抗体轻链的小鼠交叉，跟踪自身抗体的起源于特定B细胞亚群。使用GC特异性诱导CRE模型和基于ELISA的检测，我将跨疾病阶段划定gccontribution至自身抗体的形成。同时，我将基于单次转录组学和克隆共享分析的人类患者队列中的自动反应性B细胞子集表征。这将进一步确定是否具有GC体验的自身抗体细胞。该提案中获得的知识将为设计更具靶向疗法的设计提供可靠的基础，以消除自动反应性B细胞。