Heterogeneous pathways to autoantibody production: implications for prognosis and therapeutic targeting

项目摘要/摘要 系统性红斑狼疮(SLE)是一种破坏性的自身免疫性疾病，其自身抗体无处不在 核抗原会引起多个器官的炎症和组织损伤。系统性红斑狼疮的治疗有了进步 在过去的30年里有很大的进步，但这些进展依赖于现有的药物，而不是 有效率和显著毒性。尽管几种新疗法正在进入第二阶段和第三阶段的试验，但只有 目前FDA批准了一种适度有效的生物制剂用于治疗活动期SLE。因此，当务之急是 应用免疫学知识的进展来改善SLE患者的治疗和生活质量。 自身抗体的产生是SLE发病机制的核心，但关于SLE的起源仍有许多问题 产生它们的浆细胞。很明显，自身抗体的产生可以在疾病发生之前很多时候出现。 多年来，系统性红斑狼疮的爆发往往与新一波浆细胞增殖有关。我们的自身免疫力 卓越中心提案的中心假设是，对机制的更好理解 对个体患者自身抗体的诱导和来源的研究将使我们能够确定 调节失调的机制导致人类系统性红斑狼疮耐受性丧失，并将形成适当的 临床试验的患者分层和选择。为此，我们将应用新技术，使 对本地保留的少量人类细胞进行有意义的研究，以重温有关起源的基本问题 以及对SLE自身抗体的调节。一个重要的工具是一种新的荧光核抗原制剂， 由钻石实验室开发，可用于鉴定和分离仅代表A细胞的自身反应性B细胞 B细胞总数的一小部分。这将有助于使用下一代测序 免疫球蛋白基因来分析自身反应性B细胞的特异性谱系。主要项目将 确定SLE患者自身反应性浆细胞的特征并询问其来源和转录 档案，以期确定个体患者中可能特异的激活途径 自身反应性B细胞，与抵抗微生物抗原的细胞相比。协作项目将 研究接受肿瘤坏死因子抑制剂治疗的患者启动狼疮相关自身免疫的机制 治疗炎症性关节炎。试点项目将解决转录、代谢和功能的多样性 系统性红斑狼疮患者外周血中T滤泡辅助细胞能否恢复正常B细胞 通过改变T细胞新陈代谢来帮助这些细胞发挥功能。我们的建议得到了密切的科学支持 三个首席研究人员之间的互动，通过与下一代测序专家的合作 方法和数据分析，以及强大的临床基础设施，这将增加临床深度并确保 招募所有三项研究的患者。

Project Summary/Abstract Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which autoantibodies to ubiquitous nuclear antigens cause inflammation and tissue damage in multiple organs. The treatment of SLE has improved considerably over the past 30 years, but these advances have relied on existing medications with insufficient efficacy and significant toxicities. Although several new therapeutics are advancing to Phase 2 and 3 trials, only one modestly effective biologic is currently FDA approved for treating active SLE. It is imperative, therefore, that advances in immunologic knowledge be applied to improve the treatment and quality of life of SLE patients. Autoantibody production is central to the pathogenesis of SLE but many questions remain about the origins of the plasma cells that produce them. It is clear that autoantibody production can precede disease onset by many years, and that flares of SLE are often associated with a new wave of plasma cell proliferation. Our Autoimmunity Center of Excellence proposal is centered on the hypothesis that an improved understanding of the mechanisms of induction and source of autoantibodies in individual patients will allow us to define the spectrum of dysregulated mechanisms responsible for loss of tolerance in human SLE and will form the basis for appropriate patient stratification and selection for clinical trials. To this end, we will apply new technologies that allow meaningful study of small numbers of human cells in a native repertoire to revisit basic questions about the origin and regulation of autoantibodies in SLE. A crucial tool is a new fluorescent nuclear antigen preparation, developed by the Diamond lab that can be used to identify and isolate autoreactive B cells that represent only a small fraction of the total B cell population. This will facilitate the use next generation sequencing of immunoglobulin genes to analyze the repertoire specifically of autoreactive B cells. The Principal Project will characterize autoreactive plasma cells from patients with SLE and ask about their origins and transcriptional profile, with a view to identifying distinct pathways of activation in individual patients that may be specific to autoreactive B cells, compared with cells that protect against microbial antigens. The Collaborative Project will examine mechanisms for the initiation of lupus-related autoimmunity in patients being treated with TNF inhibitors for inflammatory arthritis. The Pilot Project will address the transcriptional, metabolic and functional diversity of circulating T follicular helper cells in patients with SLE and ask whether it is possible to restore normal B cell helper function of these cells by altering T cell metabolism. Our proposal is bolstered by close scientific interactions among the three lead investigators, by collaborations with experts in next generation sequencing methods and data analysis and by a robust clinical infrastructure that will add clinical depth and ensure timely recruitment of patients for all three studies.