B cell Autoimmunity in Human SLE

人类 SLE 中的 B 细胞自身免疫

• 批准号: 8680422
• 负责人: Ignacio E. Sanz
• 金额: $ 54.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680422
• 关键词: Acute; Acute Disease; Address; Antibodies; Antibody Formation; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Bioinformatics; Cells; Cellular biology; Chronic; Clinical; Clinical Data; Clinical Trials; Collaborations; Diagnosis; Disease; Effector Cell; Epigenetic Process; Event; Flare; Flow Cytometry; Functional disorder; Generations; Heterogeneity; Human; Immune; Immunoglobulin-Secreting Cells; Life; Lupus; Maintenance; Maps; Memory; Mission; Molecular; Multiple Abnormalities; Phenotype; Pilot Projects; Plasma Cells; Play; Process; Production; Proteome; Proteomics; Relative (related person); Role; Serum; Signal Pathway; Systemic Lupus Erythematosus; Technology; Transcriptional Regulation; Work; autoreactive B cell; base; cell growth; cell type; density; design; driving force; effective therapy; epigenome; high throughput technology; innovation; insight; next generation sequencing; prevent; programs; systemic autoimmune disease; tool

DESCRIPTION (provided by applicant): B cells play central pathogenic roles in many human autoimmune diseases including Systemic Lupus Erythematosus (SLE). Understanding and effectively treating human autoimmunity will require a deep understanding of the antigenic, cellular and molecular events that contribute to the breakdown of B cell tolerance and the downstream events leading to acute clinical disease through the generation of effector cells and to chronic autoimmunity through the formation, maintenance and reactivation of long-lived autoimmune memory. The Emory Autoimmunity Center of Excellence (ACE) U19 proposes an integrated approach to elucidating these central questions through three highly synergistic projects and the use of state-of-the-art technology. The Principal Project (Dr. Sanz, PI), will elucidate the relative participation of naive and memory cells in the generation of antibody secreting cells expanded during acute lupus flares, the antigenic drives responsible for these expansions and the cellular basis of different types of lupus autoantibodies. The Collaborative Agenda (Dr. Boss, PI), will use transcriptional and epigenetic studies to map the signaling pathways responsible for the cellular events addressed in the Principal Project. In turn, these studies will provide a scientific and technological platform that the Emory ACE U19 will extend to other ACE centers to similarly study other immune cell types and human autoimmune diseases. Finally, the Pilot Project (Dr. Jacob, PI), will dissect the molecular determinants responsible for the survival of human long-lived plasma cells. The scientific mission of the Emory ACE U19 will be supported by a well-integrated Administrative Core led by Dr. Sanz who has served in a similar role for more than 10 years as PI of the Rochester ACE. The Emory ACE will also provide major input into the ACE Steering Committee actively contributing to developing the scientific agenda of the network and to the design and implementation of mechanistic studies both through the U19 Collaborative Agenda and the UMI-supported clinical trials. RELEVANCE: The Emory ACE U19 will pursue an integrated approach to the cellular and molecular mechanisms of B cell dysfunction in Human SLE. Through the Collaborative Project, it will enlarge its reach to study other immune cells and autoimmune diseases. The expected results should greatly enhance our ability to diagnose, treat and prevent autoimmune diseases. Principal Project: B Cells in Human SLE Project Leader: Ignacio Sanz DESCRIPTION: 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. RELEVANCE: This project will provide critical insight into the contribution of different B cells and antibody secreting cells to the autoantibody repertoire and disease process in human SLE. Together with the Collaborative Project, it will also study the epigenome and transcriptional program of autoimmune B cells.

描述（由申请人提供）：B细胞在包括系统性红斑狼疮（SLE）在内的许多人类自身免疫性疾病中起主要致病作用。理解和有效地治疗人类自身免疫将需要对抗原、细胞和分子事件的深入理解，所述抗原、细胞和分子事件促成B细胞耐受性的破坏，以及下游事件通过效应细胞的产生导致急性临床疾病，以及通过长期自身免疫记忆的形成、维持和再激活导致慢性自身免疫。埃默里自身免疫卓越中心（ACE）U19提出了一种综合方法，通过三个高度协同的项目和使用最先进的技术来阐明这些核心问题。主要项目（Dr. Sanz，PI）将阐明幼稚细胞和记忆细胞在急性狼疮发作期间扩增的抗体分泌细胞产生中的相对参与，负责这些扩增的抗原驱动以及不同类型狼疮自身抗体的细胞基础。合作议程（博士博斯，PI），将使用转录和表观遗传学研究来映射负责在主要项目中解决的细胞事件的信号通路。反过来，这些研究将提供一个科学和技术平台，Emory ACE U19将扩展到其他ACE中心，以类似地研究其他免疫细胞类型和人类自身免疫性疾病。最后，飞行员 项目（雅各布博士，PI），将解剖负责人类长寿浆细胞的生存的分子决定因素。 埃默里ACE U19的科学使命将得到由Sanz博士领导的一个整合良好的管理核心的支持，Sanz博士担任罗切斯特ACE的PI已经超过10年。埃默里大学ACE还将为ACE指导委员会提供重要投入，积极促进网络科学议程的制定，并通过U19合作议程和UMI支持的临床试验设计和实施机制研究。 相关性：Emory ACE U19将采用综合方法研究人类SLE中B细胞功能障碍的细胞和分子机制。通过合作项目，它将扩大其研究范围，以研究其他免疫细胞和自身免疫性疾病。预期的结果将大大提高我们诊断、治疗和预防自身免疫性疾病的能力。 主要项目：SLE患者的B细胞 项目负责人：伊格纳西奥·桑兹 描述：系统性红斑狼疮是一种系统性自身免疫性疾病，其特征是严重的B细胞异常和多种自身抗体产生。然而，尽管人类B细胞生物学领域取得了重大进展，但对SLE中B细胞活化、多样化和扩增的确切抗原和细胞机制仍知之甚少。此外，疾病异质性、不精确的B细胞表型和缺乏定义驱动自身反应性B细胞和血清自身抗体的产生和选择的抗原力所需的高通量技术阻碍了对急性疾病加重期间不同B细胞亚群的相对参与的精确理解。在当前的ACE周期中，我们已经建立了解决这些问题所需的工具，包括多维流式细胞术;下一代测序（NGS）;大规模单细胞抗体生成;以及用于高密度免疫学，转录和临床数据综合分析的生物信息学平台。此外，我们已经开始与专家组合作研究B细胞和ASC表观遗传学（Boss博士，合作议程PI）和分析血清抗体蛋白质组学（Cheung博士; CST）。在Emory ACE U19的这个主要项目中，我们提出在这些成就的基础上，通过以下具体目标来剖析B细胞和ASC亚群的参与：目标1。通过NGS和单细胞抗体产生的库分析，不同B细胞区室在SLE发作中的参与和抗原选择;目的2。短寿命和长寿命抗体分泌细胞对SLE血清自身抗体蛋白质组的相对贡献;目的3。SLE B细胞的表观遗传和转录控制与合作项目。拟议的工作与合作议程和试点项目高度协同，在提出的问题和实验方法方面具有高度创新性。本研究结果对我们了解自身免疫中B细胞的致病机制和设计更安全有效的治疗方案具有重要意义。 相关性：该项目将提供关键的洞察不同的B细胞和抗体分泌细胞的自身抗体库和疾病过程中的人类SLE的贡献。与合作项目一起，它还将研究自身免疫B细胞的表观基因组和转录程序。