Functional alteration of follicular helper T cells in SLE

SLE 患者滤泡辅助 T 细胞的功能改变

• 批准号: 9903211
• 负责人: Sun Jung Kim
• 金额: $ 24.16万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 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/9903211
• 关键词: Address; Age; Animal Model; Antigen-Antibody Complex; Autoantibodies; Autoantigens; Autoimmune Diseases; B cell differentiation; B-Cell Activation; B-Lymphocytes; BLR1 gene; Biological Assay; Blood; CCR6 gene; CD4 Positive T Lymphocytes; CXCR3 gene; Cells; Cellular Metabolic Process; Collection; Consultations; Data; Dendritic Cells; Deposition; Development; Disease; Exhibits; Flow Cytometry; Frequencies; Funding Mechanisms; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genetic Variation; Glucose; Goals; Helper-Inducer T-Lymphocyte; Human; Immunotherapy; In Vitro; Individual; Inflammation; Infrastructure; Interferon Type II; Interleukin-17; Interleukin-4; Interruption; Lupus; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; PRDM1 gene; Pathogenicity; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma Cells; Population Heterogeneity; Production; Publishing; Research; Rheumatoid Arthritis; SLC2A1 gene; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; Testing; Therapeutic Agents; Tissues; Toll-like receptors; base; chemokine receptor; data management; druggable target; genetic risk factor; inhibitor/antagonist; metabolic profile; metabolomics; mouse model; outcome forecast; peripheral blood; precision medicine; programmed cell death protein 1; response; risk variant; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; trend

Pilot Project Summary/Abstract The pathogenic potential of TFH is well-described in animal models of lupus and an increased frequency of circulating TFH is associated with disease activity in human patients. Among the risk genes for SLE are several genes associated with metabolic abnormalities that cause increased metabolic activity in T cells. This pilot project is an exploratory project based on the hypothesis that subsets of TFH in SLE patients will have different metabolic alterations that increase their capacity to provide help to B cells. Such cells may be therapeutically targeted by agents that alter cell metabolism. To address these hypotheses, the pilot project proposes two aims; Aim 1 will determine the metabolic profile of CD4+ TFH subsets from SLE patients, and Aim 2 will determine metabolic plasticity of TFH cells. Peripheral blood TFH are a heterogeneous population of CD4+ T cells and express IL-21 but subsets have also been identified that express IFNγ, IL-4 or IL-17. Metabolic characterization of these subsets has not yet been performed. We have a hypothesis that TFH cells of SLE patients have altered metabolism and TFH subsets with increased metabolism have an increased capacity to provide B cell help. We will examine 5 different subsets of peripheral TFH based on their expression of PD-1 and the chemokine receptors CXCR5, CCR6 and CXCR3 and examine their metabolic function before and after cell activation using flow cytometry and colorimetric methods that will define their ability to take up glucose, their glycolytic function, their mitochondrial mass and the presence of mitochondrial depolarization. Differences in transcriptome will be determined using RNA-Seq and the ability of each subset to induce B cell differentiation determined. It is already known that TH1, TH2 and TH17 cells have different metabolic requirements and that the different TFH subsets have different functions with respect to their ability to help B cells differentiate into plasma cells. These studies will specifically characterize the metabolic profile of TFH subsets and should generate hypotheses about potential therapies that can be used to interrupt TFH function in a way that could advance precision medicine. As proof of principle, selected metabolic modulators will then be used to determine whether any metabolic functions can be normalized in a subset specific manner and whether this alters T cell helper activity. The pilot project will assist in characterization of TFH proposed by the collaborative project; these two projects are synergistic and could expand under different funding mechanisms to examine how conventional immunotherapies, including TNF inhibitors alter TFH metabolism and function. There is also the potential to relate TFH subsets to the phenotypic characterization of the ANA response proposed in the Principle Project. The pilot project will also benefit from the infrastructure of the ACE project, particularly the access to well characterized patients, uniform methods for blood collection and storage, prioritized access to statistical consultation and a data management plan.

试点项目摘要/摘要 TFH的致病潜力在狼疮动物模型中得到了很好的描述，并且频率增加 循环中TFH的数量与人类患者的疾病活动性有关。系统性红斑狼疮的风险基因包括 与代谢异常有关的几个基因导致T细胞代谢活性增加。这 试点项目是一个基于假设的探索性项目，即SLE患者的TFH亚群将 不同的代谢变化增加了它们为B细胞提供帮助的能力。这样的细胞可以是 以改变细胞新陈代谢的药物为治疗靶点。为了解决这些假设，试点项目 提出两个目标；目标1将确定SLE患者CD4+TFH亚群的代谢情况；目标1将确定SLE患者CD4+TFH亚群的代谢 2将决定TFH细胞的代谢可塑性。 外周血TFH是一种异质性的CD4+T细胞群，表达IL-21，但亚群 也被发现表达干扰素γ、IL-4或IL-17。这些亚群的代谢特征还没有 但却被执行了。我们有一个假设，SLE患者的TFH细胞代谢发生了改变，TFH 新陈代谢增强的亚群提供B细胞帮助的能力增强。我们将检查5个 外周TFH的不同亚群基于其PD-1和趋化因子受体CXCR5的表达， 应用流式细胞术检测CCR6和CXCR3在细胞活化前后的代谢功能 比色法将确定它们吸收葡萄糖的能力，它们的糖酵解功能，它们的 线粒体质量和线粒体去极化的存在。转录组的差异将是 用RNA-Seq法测定各亚群诱导B细胞分化的能力。它是 已知TH1、TH2和TH17细胞有不同的代谢需求，不同的TFH 亚群在帮助B细胞分化为浆细胞的能力方面具有不同的功能。这些 研究将具体描述TFH亚群的代谢特征，并应产生以下假设 可以用来中断TFH功能的潜在疗法，可以促进精准医学的发展。 作为原则的证明，选定的代谢调节剂将被用来确定是否有任何代谢 功能可以以子集特定的方式标准化，以及这是否会改变T细胞辅助活动。 试点项目将协助确定合作项目提出的TFH的特征；这两个 项目是协同的，可以在不同的供资机制下扩大，以审查如何常规 免疫疗法，包括肿瘤坏死因子抑制剂，会改变TFH的代谢和功能。还有一种可能是 将TFH亚集与原理项目中提出的ANA反应的表型特征联系起来。 试点项目还将受益于ACE项目的基础设施，特别是进入油井的通道 特色化的患者，统一的血液采集和存储方法，优先获得统计数据 咨询和数据管理计划。