B cells in human SLE

人类 SLE 中的 B 细胞

• 批准号: 8842272
• 负责人: Ignacio E. Sanz
• 金额: $ 39.46万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8842272
• 关键词: Acute Disease; Address; Antibodies; Antibody Formation; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Bioinformatics; Cells; Cellular biology; Clinical Data; Collaborations; Disease; Epigenetic Process; Flare; Flow Cytometry; Generations; Heterogeneity; Human; Immunoglobulin-Secreting Cells; Life; Multiple Abnormalities; Phenotype; Pilot Projects; Process; Production; Proteome; Proteomics; Relative (related person); Serum; Systemic Lupus Erythematosus; Transcriptional Regulation; Work; autoreactive B cell; density; design; driving force; effective therapy; epigenome; high throughput technology; innovation; insight; next generation sequencing; programs; systemic autoimmune disease; tool

SLE is a systemic autoimmune disease characterized by profound B cell abnormalities and multiple autoantibody production. However, despite major advances in the field of human B cell biology, the precise antigenic and cellular mechanisms that underlie the activation, diversification and expansion of B cells in SLE remain poorly understood. Moreover, a precise understanding of the relative participation of different B cell subsets during acute disease exacerbations has been hampered by disease heterogeneity, imprecise B cell phenotyping and the lack of high-throughput technologies needed to define the antigenic forces driving the generation and selection of autoreactive B cells and serum autoantibodies. During the current ACE cycle we have established the tools required to address these questions including multi-dimensional flow cytometry; next generation sequencing (NGS); large scale single cell antibody generation; and bioinformatics platforms for the integrative analysis of high-density immunological, transcriptional and clinical data. Moreover, we have initiated collaborations with expert groups for the study of B cell and ASC epigenetics (Dr. Boss, Collaborative Agenda PI) and for the analysis of serum antibody proteomics (Dr. Cheung; CST). In this Principal Project of the Emory ACE U19, we proposed to build on these accomplishments to dissect the participation of B cell and ASC subsets through the following specific aims: Aim 1. Participation and antigenic selection of different B cell compartments in SLE flares using repertoire analysis by NGS and single cell antibody production; Aim 2. Relative contribution of short-lived and long-lived antibody secreting cells to the SLE serum autoantibody proteome; and Aim 3. Epigenetic and transcriptional control of SLE B cells in conjunction with the Collaborative Project. The work proposed is highly synergistic with the Collaborative Agenda and the Pilot Project and has a high degree of innovation in terms of the questions asked and the experimental approach. The expect results should be of far-reaching significance for our understanding of the pathogenic mechanisms acting upon B cells in human autoimmunity and for the rationale design of safer and more effective therapies.

SLE是一种系统性自身免疫性疾病，其特征是B细胞异常和多个 自身抗体生产。但是，尽管人类B细胞生物学领域取得了重大进展，但精确 抗原和细胞机制是B细胞激活，多样化和扩展的基础的抗原和细胞机制 SLE仍然很了解。此外，对不同b的相对参与的精确理解 急性疾病期间的细胞子集加剧了疾病异质性的阻碍，不精确b 细胞表型和缺乏定义抗原力驱动所需的高通量技术 自动反应性B细胞和血清自身抗体的产生和选择。在当前的王牌期间 周期我们已经建立了解决这些问题所需的工具，包括多维流量 细胞仪；下一代测序（NGS）；大型单细胞抗体产生；和生物信息学 用于高密度免疫，转录和临床数据的综合分析的平台。 此外，我们已经与专家小组进行了合作，以研究B细胞和ASC表观遗传学 （Boss博士，合作议程PI）和用于血清抗体蛋白质组学的分析（Cheung; CST）。 在Emory Ace U19的这个主要项目中，我们提议以这些成就为基础来剖析 B细胞和ASC子集的参与通过以下特定目的：AIM 1。参与和 使用NGS和 单细胞抗体产生；目标2。短寿命和长寿抗体分泌的相对贡献 细胞到SLE血清自身抗体蛋白质组；和目标3。SLE B的表观遗传和转录控制 单元格与协作项目结合。提出的工作与 协作议程和试点项目，就问题而言具有高度的创新 问和实验方法。对我们的期望结果应该具有深远的意义 了解作用于人类自身免疫性B细胞的致病机制和 更安全，更有效疗法的理由设计。