Defining the cellular origin of pathogenic autoantibodies

B细胞衍生的自身抗体几乎存在于所有的自身免疫性疾病中，并且在其中许多疾病中它们是致病性的。虽然全面的免疫抑制或免疫细胞耗竭疗法改善了临床结果，但它们通常无法去除致病性B细胞亚群并改善最严重的临床表现。开发更有效的治疗方法需要了解自身反应性B细胞是如何以及从哪些亚群中产生的。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存在相互矛盾的证据。虽然一些研究已经确定了自身反应性B细胞中指示GC起源的选择性突变，但其他研究表明，自身抗体形成可以发生在GC耗尽的环境中。人类自身免疫性疾病的小鼠模型和新的抗体标记工具将与人类患者队列相结合，以确定自身抗体的起源和GC依赖性。为了了解疾病的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体的小鼠，这些变体涵盖了人类单基因系统性自身免疫性疾病的大部分谱。将这些小鼠与表达Cre诱导的Flag标记抗体轻链的小鼠杂交，可以追踪特异性B细胞亚群自身抗体的来源。使用GC特异性的诱导型Cre模型和基于ELISA的检测，我将描述GC在不同疾病阶段对自身抗体形成的贡献。与此同时，我将根据细胞转录组学和克隆共享分析，研究人类患者队列中的自身反应性B细胞亚群。这将进一步确定自身抗体产生细胞是否是GC经验的。在这个建议中获得的知识将为设计更有针对性的治疗方法，可以消除自身反应性B细胞提供坚实的基础。

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.