A novel CD4+ T cell helper population in Lupus Nephritis

狼疮性肾炎中的新型 CD4 T 细胞辅助群体

基本信息

批准号：
10159209
负责人：
Maria Virginia Pascual
金额：
$ 25.43万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159209
关键词：
Affect Antigen-Antibody Complex Apoptotic Area Autoantibodies Autoimmune Diseases Autoimmune Responses B-Lymphocyte Subsets B-Lymphocytes Binding Proteins Biological Markers Blood CD4 Positive T Lymphocytes CXCR3 gene Cell Compartmentation Cells Characteristics Childhood Citric Acid Clinical Complement Cutaneous DNA Data Dendritic Cells Disease Electron Transport Event Exposure to Frequencies Generations Genes Genetic Transcription Goals Heart Helper-Inducer T-Lymphocyte Homing Human Immune Immune system Immunoglobulin-Secreting Cells Impairment Inflammation Interferon Type I Interferons Interleukin-1 Interleukin-10 Kidney Lead Life Link Longitudinal Studies Lupus Nephritis Mitochondrial DNA Mus Mutation Myeloid Cells Nephritis Nucleic Acids Oxides Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Plasmablast Population Production Property Reporting Resources Role Succinates Syndrome Systemic Lupus Erythematosus T-Lymphocyte Tissues Transcript Up-Regulation Urine Virulence Factors Work autoreactive B cell autoreactivity cell killing cell type cellular targeting cohort cytokine cytotoxic epigenome extracellular genetic variant hypoxia inducible factor 1 improved insight neutrophil new therapeutic target novel novel marker programmed cell death protein 1 programs protein complex renal damage systemic autoimmunity transcriptome

项目摘要

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by breakdown of tolerance to nucleic acids (NAs) and widespread inflammation. While nucleosomal DNA released from apoptotic cells is considered an important initiator of the autoimmune response in SLE, we and others have reported that live neutrophils might contribute to disease pathogenesis by releasing protein-bound oxidized mitochondrial DNA (Ox mtDNA) that activate plasmacytoid dendritic cells (pDCs) to produce Interferon (IFN). Our new data support that Ox MtDNA-activated pDCs prime and polarize naive CD4+ T cells towards a distinctive phenotype characterized by a Tr1-like cytokine profile (IFN, IL10), high expression of PD1 and the upregulation of a cytotoxic program. These cells generate mtROS through reverse electron transfer (RET) fueled by the citric acid metabolite succinate. Importantly, they help B cells through a unique and novel cytokine/metabolite combination: IL10 and succinate. Moreover, extrafollicular (CXCR5neg) CD4+ T helper cells with similar characteristics (Th10) are expanded in SLE patient’s blood and found in the tubulointerstitial areas of proliferative lupus nephritis (PLN) patients where they often associate with B cells. Indeed, we hypothesize that these CD4+ T cells contribute to extrafollicular autoantibody production and kidney damage and that they represent a valuable biomarker of PLN. Here, we propose: 1) to characterize the blood CD4+ T helper cell compartment of SLE patients and to determine, in longitudinal studies, the value of Th10 cells as a biomarker of Lupus nephritis; 2) to identify the mechanisms and cellular targets involved in Th10 cell-B cell help, determine whether unique B cell subsets respond to the cytokine/metabolite combination and whether autoreactive B cells are preferentially selected under these conditions; 3) to determine whether the interaction between succinate-producing Th10 cells and myeloid cells contributes to SLE pathogenesis. Overall, we expect that these studies will provide valuable insights into the role of this new T cell population in SLE. Furthermore, this work may identify useful biomarkers to stratify LN and new ways to interfere with Th10 cell generation/activation and ultimately improve the outlook of our patients.

系统性红斑狼疮 (SLE) 是一种自身免疫性疾病，其特征是核小体 DNA 释放时对核酸 (NA) 和广泛炎症的耐受性。来自凋亡细胞的细胞因子被认为是 SLE 自身免疫反应的重要引发剂，我们和其他人报道，活中性粒细胞可能通过以下方式促进疾病发病机制：释放蛋白质结合的氧化线粒体 DNA (Ox mtDNA)，激活类浆细胞我们的新数据支持 Ox MtDNA 激活的树突状细胞 (pDC)。 pDC 启动并极化初始 CD4+ T 细胞，使其形成独特的表型，其特征是 Tr1 样细胞因子谱（IFN、IL10）、PD1 高表达和细胞毒性物质上调这些细胞通过柠檬酸推动的反向电子转移（RET）产生 mtROS。重要的是，它们通过独特而新颖的方式帮助 B 细胞。细胞因子/代谢物组合：IL10 和琥珀酸盐此外，滤泡外 (CXCR5neg) CD4+。具有相似特征的 T 辅助细胞 (Th10) 在 SLE 患者的血液中扩增并发现在增殖性狼疮肾炎 (PLN) 患者的肾小管间质区域，它们经常事实上，我们发现这些 CD4+ T 细胞有助于滤泡外细胞的形成。自身抗体的产生和肾脏损伤，它们是 PLN 的一个有价值的生物标志物。在这里，我们建议：1) 表征 SLE 患者血液 CD4+ T 辅助细胞区室并在纵向研究中确定 Th10 细胞作为狼疮性肾炎生物标志物的价值； 2) 确定Th10细胞-B细胞帮助中涉及的机制和细胞靶标，确定独特的 B 细胞亚群是否对细胞因子/代谢物组合有反应以及是否在这些条件下优先选择自身反应性B细胞；3)确定是否产生琥珀酸的 Th10 细胞和骨髓细胞之间的相互作用导致 SLE 总的来说，我们期望这些研究将为了解其作用提供有价值的见解。此外，这项工作可能会识别出有用的生物标志物来进行分层。 LN 和干扰 Th10 细胞生成/激活并最终改善我们患者的前景。