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

项目概要/摘要 系统性红斑狼疮（SLE）是一种毁灭性的自身免疫性疾病，其中全身普遍存在的自身抗体 核抗原引起多个器官的炎症和组织损伤。SLE的治疗已经改善 在过去30年里取得了相当大的进步，但这些进步依赖于现有的药物，但不足 有效性和显著毒性。尽管一些新的治疗方法正在进入2期和3期试验，但只有 一种适度有效的生物制剂目前被FDA批准用于治疗活动性SLE。因此，必须 免疫学知识的进步可用于改善SLE患者的治疗和生活质量。 自身抗体的产生是系统性红斑狼疮发病机制的核心，但关于自身抗体的起源仍存在许多问题 产生它们的浆细胞。很明显，自身抗体的产生可以先于疾病的发作， SLE的发作通常与新一波的浆细胞增殖有关。我们的自身免疫 卓越中心提案的核心假设是， 个体患者中自身抗体的诱导和来源将使我们能够定义 在人类SLE中负责耐受性丧失的失调机制，并将形成适当治疗的基础。 临床试验的患者分层和选择。为此，我们将采用新技术， 一项有意义的研究，在一个自然的剧目中的少量人类细胞，以重新审视有关起源的基本问题， 和自身抗体的调节。一个关键的工具是一种新的荧光核抗原制剂， 由Diamond实验室开发，可用于识别和分离自身反应性B细胞， 总B细胞群的一小部分。这将有助于使用下一代测序技术， 免疫球蛋白基因来分析自身反应性B细胞的特异性库。主要项目将 描述SLE患者的自身反应性浆细胞，并询问其起源和转录 特征，以确定个体患者中可能特异于 自身反应性B细胞，与保护细胞免受微生物抗原。合作项目将 检查接受TNF抑制剂治疗的患者引发狼疮相关自身免疫的机制 治疗炎症性关节炎该试点项目将解决转录，代谢和功能多样性， SLE患者的循环T滤泡辅助细胞，并询问是否有可能恢复正常的B细胞 这些细胞的辅助功能通过改变T细胞代谢。我们的建议得到了密切的科学支持， 通过与下一代测序专家的合作， 方法和数据分析，并通过强大的临床基础设施，将增加临床深度，并确保及时 所有三项研究的患者招募。

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.