Molecular Regulation of B cells and T cells in Human SLE

人类 SLE 中 B 细胞和 T 细胞的分子调控

• 批准号: 10265747
• 负责人: Ignacio E. Sanz
• 金额: $ 37.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-26 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265747
• 关键词: Antigens; Antitumor Response; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B cell differentiation; B-Cell Development; B-Lymphocytes; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Patient; Categories; Cell physiology; Cells; Chronic; Clinical; Clinical Protocols; Clinical Research; Collaborations; Committee Members; Comparative Study; Development; Diagnosis; Disease; Effector Cell; Epigenetic Process; Evolution; Funding; Genetic Predisposition to Disease; Goals; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Individual; Knowledge; Lead; Leadership; Location; Lupus; Maintenance; Mission; Molecular; Onset of illness; Outcome; PD-1 blockade; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Physicians; Pilot Projects; Population; Process; Regulation; Resources; Scientist; Systemic Lupus Erythematosus; T-Lymphocyte; Translating; Universities; Virus Diseases; Work; arm; autoreactive B cell; base; clinical development; design; epigenetic regulation; epigenome; exhaustion; experience; immunogenic; imprint; innovation; novel; operation; personalized medicine; programs; response; self-renewal; stem; stem-like cell

The overarching objective of the Emory Autoimmunity Center of Excellence (ACE) U19 is to decipher the molecular programs responsible for the aberrant effector immune responses that lead to autoimmune disease. Specifically, based on the work performed by the Emory ACE during the current funding cycle, we postulate that epigenetic regulation of effector B cell differentiation and function is a critical pathogenic component of Systemic Lupus Erythematosus (SLE). Further, we contend that disease-related epigenetic imprinting is first established at early stages of B cell development and then maintained throughout the differentiation of naïve cells into their effector progeny upon activation by antigens and co- stimulatory pathways. Finally, we propose that SLE will also be characterized by abnormal regulation of other critical effector immune responses, namely CD8 T cells and in particular, the stem-like population responsible for the maintenance of antigen-specific responses in chronic viral infections and anti-tumor responses in patients treated with checkpoint inhibitors. The fundamental goals of the Emory ACE are: 1) to understand B cells and CD8 T cells dysregulation in human SLE; and 2) to assemble a scientific and technological platform that engages other ACE U19 and UM1 Centers to perform similar studies in other immune cells and autoimmune disorders. The specific aims of the Emory ACE U19 are: Aim 1: To establish an Administrative Core (I. Sanz, Core Director) for the successful operation of the ACE U19 Scientific Program and its interaction with the ACE Network; Aim 2: To develop a highly integrated Emory ACE U19 Scientific Program comprised of the following components: Principal Project (Sanz, PI): Mechanisms of B cell dysregulation in human SLE; Collaborative Project (Boss, PI): Epigenetic regulation of autoimmune responses; Pilot Project (Ahmed, PI): Characterization of stem-like CD8 T cells in SLE. The expected results will unravel disease pathogenesis; segment patients; design personalized therapies; and develop biomarkers of disease onset, evolution, and outcome. Our efforts will naturally dovetail with the mission of the UM1 ACEs centers and contribute greatly to the charter mission of the ACE network.

埃默里自身免疫卓越中心(ACE)U19的首要目标是 破译负责异常效应器免疫反应的分子程序 导致自身免疫性疾病。具体地说，基于Emory ACE所做的工作 在当前的资金周期中，我们假设效应器B细胞的表观遗传调节 辨证与功能是系统性红斑狼疮的重要致病因素 红斑狼疮(SLE)。此外，我们认为与疾病相关的表观遗传印记是第一个 在B细胞发育的早期阶段建立，然后在整个 幼稚细胞在抗原和辅助剂的激活下分化为效应子代 刺激通路。最后，我们提出系统性红斑狼疮也将以异常为特征 调节其他关键效应者的免疫反应，即CD8T细胞，尤其是， 负责维持体内抗原特异性反应的干细胞群 接受检查点抑制剂治疗的患者的慢性病毒感染和抗肿瘤反应。 Emory ACE的基本目标是：1)了解B细胞和CD8 T细胞 人类系统性红斑狼疮的调节失调；以及2)组装一个科学和技术平台， 聘请其他ACE U19和UM1中心在其他免疫细胞中进行类似的研究 和自身免疫性疾病。Emory ACE U19的具体目标是：目标1：建立 ACE U19成功运行的管理核心(I.Sanz，核心总监) 科学计划及其与ACE网络的相互作用；目标2：开发一个高度 Emory ACE U19综合科学计划由以下组件组成： 主要项目(SANZ，PI)：人类系统性红斑狼疮B细胞失调的机制 项目(Boss，PI)：自身免疫反应的表观遗传调节；试点项目(Ahmed，PI)： 系统性红斑狼疮患者干细胞样CD8T细胞的特征预期的结果将揭开疾病的面纱 发病机制；细分患者；设计个性化治疗；开发生物标记物 疾病的发生、发展和结局。我们的努力自然会与联合国的使命相吻合 UM1 ACES中心，并为ACE网络的特许使命做出了巨大贡献。