Targeting follicular helper CD4 T cells in SLE

靶向 SLE 中的滤泡辅助 CD4 T 细胞

基本信息

批准号：
10667605
负责人：
Laurence Morel
金额：
$ 46.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667605
关键词：
Address Adoptive Transfer Affinity Antibodies Antigens Autoantibodies Autoimmune Autoimmunity B cell differentiation B-Cell Activation B-Lymphocytes CD4 Positive T Lymphocytes Cells Cellular Metabolic Process Chronic Deoxyglucose Disease Disease model Energy-Generating Resources Enzymes Explosion FRAP1 gene Frequencies Funding Genetic Glucose Glutamine Glycolysis Glycolysis Inhibition Goals Hypoxia Immune Immunity Immunization Immunoglobulin Class Switching Immunoglobulin G Immunophenotyping Influenza Knowledge Lupus Metabolic Metabolism Modeling Mus Norleucine Oxidative Phosphorylation Pathogenesis Pathogenicity Pathway interactions Patients Population Production Program Sustainability Proliferating Proteins Publishing Role Signal Transduction Structure of germinal center of lymph node Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Time Tissues Translating autoreactive B cell autoreactivity cell type ds-DNA etomoxir experimental study fatty acid oxidation genetic approach in vivo inhibitor lupus prone mice metabolomics mouse model pathogen pharmacologic preservation response single-cell RNA sequencing therapeutic target transcriptomics

Address Adoptive Transfer Affinity Antibodies Antigens Autoantibodies Autoimmune Autoimmunity B cell differentiation B-Cell Activation B-Lymphocytes CD4 Positive T Lymphocytes Cells Cellular Metabolic Process Chronic Deoxyglucose Disease Disease model Energy-Generating Resources Enzymes Explosion FRAP1 gene Frequencies Funding Genetic Glucose Glutamine Glycolysis Glycolysis Inhibition Goals Hypoxia Immune Immunity Immunization Immunoglobulin Class Switching Immunoglobulin G Immunophenotyping Influenza Knowledge Lupus Metabolic Metabolism Modeling Mus Norleucine Oxidative Phosphorylation Pathogenesis Pathogenicity Pathway interactions Patients Population Production Program Sustainability Proliferating Proteins Publishing Role Signal Transduction Structure of germinal center of lymph node Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Time Tissues Translating autoreactive B cell autoreactivity cell type ds-DNA etomoxir experimental study fatty acid oxidation genetic approach in vivo inhibitor lupus prone mice metabolomics mouse model pathogen pharmacologic preservation response single-cell RNA sequencing therapeutic target transcriptomics

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项目摘要

Project Summary/Abstract High affinity class-switched autoantibodies (autoAb) are the major pathogenic effector molecules in lupus. They are generated by B cells that differentiate through either the germinal center (GC) or the extrafollicular (EF) pathways. The frequency of follicular helper (Tfh) cells and EF helper (eTf) CD4+ T cells are expanded in lupus in direct correlation with disease activity. The EF pathway has been best characterized in the MRL/lpr lupus- prone mice with AM14 BCR Tg B cells, which have been used as a model of autoreactive B cells activated through dual BCR and TLR9 signals. Overall, the GC and EF pathways are crucial nodes of lupus pathogenesis and lupus-prone mice present validated models for mechanistic studies of these pathways. We and others have shown that the metabolism of immune cells was altered in lupus patients and mice, and that some of these alterations offer therapeutic targets. Relatively little is known on the metabolic programs that sustain either autoreactive or immunization-induced (Imm-) GC B cells and Tfh cells, and nothing is known about the metabolism of EF activation. We have shown during the first cycle of funding that the production of anti-dsDNA IgG but not Imm-Abs, was glucose-dependent. In contrast, both autoAbs and Imm-Abs were eliminated by the inhibition of glutaminolysis. These results obtained with bulk polyclonal populations treated with metabolic inhibitors his led us to hypothesize that autoAbs and Imm-Abs have different metabolic requirements through the GC stage, which could be ultimately translated in their selective targeting. In this competitive renewal, we propose to use auto- and Imm-Ig-specific B and T cells, as well as GC B and Tact-specific deletions of metabolic enzymes to determine the intrinsic metabolic requirements of autoreactive and Imm-GC B and Tfh cells at the antigen- and cell-specific levels. We also propose to address the metabolic requirements of EF activation of autoreactive B cells. Using unique mouse models and a combination of scRNA-Seq and deep metabolomic analyses, we propose three specific aims to determine the requirements in glucose (1), glutamine (2), and FAO (3) for autoAb vs. Imm-Ab production, and to identify the corresponding mechanisms. These experiments will help to define the specific metabolic requirements of the B and CD4+ T cells that participate in the production of lupus autoAbs. This knowledge may ultimately identify means to eliminate autoAb production while preserving protective humoral autoimmunity.

项目摘要/摘要高亲和力开关自身抗体（AUTOAB）是狼疮中主要的致病效应分子。他们由B细胞通过生发中心（GC）或毛囊外（EF）产生的B细胞产生途径。卵泡辅助器（TFH）细胞和EF辅助（ETF）CD4+ T细胞的频率在狼疮中膨胀与疾病活动直接相关。 EF途径在MRL/LPR Lupus- 俯卧的小鼠具有AM14 BCR TG B细胞，这些小鼠已被用作自动反应性B细胞的模型通过双BCR和TLR9信号。总体而言，GC和EF途径是狼疮发病机理的关键节点和狼疮易发的小鼠提出了验证的模型，用于这些途径的机械研究。我们和其他人有表明狼疮患者和小鼠的免疫细胞代谢发生了改变，其中一些更改提供治疗靶标。在维持的代谢方案中，知之甚少自动反应性或免疫诱导的（IMM）GC B细胞和TFH细胞，对此一无所知 EF激活的代谢。我们在第一个资金周期表明，抗DSDNA的产生 IgG但不是Imm-Abs，是葡萄糖依赖性的。相比之下，自动ab和imm-abs均由抑制谷氨酰胺分解。这些用代谢处理的散装多克隆人群获得的结果抑制剂他的抑制剂使我们假设自动ab和imm-abs具有不同的代谢要求 GC阶段，最终可以在其选择性定位中翻译。在这种竞争性的续约中，我们建议使用自动和IMM-IG特异性B和T细胞，以及GC B以及代谢的特定于触觉缺失酶确定自动反应性和IMM-GC B和TFH细胞的内在代谢需求抗原和细胞特异性水平。我们还建议解决EF激活的代谢要求自动反应性B细胞。使用独特的鼠标模型以及SCRNA-SEQ和深层代谢组的组合分析，我们提出了三个具体目的，以确定葡萄糖（1），谷氨酰胺（2）和粮农组织（3）用于自动AutoAB与IMM-AB生产，并确定相应的机制。这些实验将有助于定义参与的B和CD4+ T细胞的特定代谢需求狼疮自动动作的生产。这些知识最终可能确定消除自动生产的方法同时保留保护性的体液自身免疫。