Neutrophil plasticity in autoimmune disease

自身免疫性疾病中的中性粒细胞可塑性

基本信息

批准号：
10326852
负责人：
Tanya N Mayadas
金额：
$ 64.84万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326852
关键词：
Abbreviations Acute Antibodies Antigen-Antibody Complex Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Autoimmune Diseases Automobile Driving Autophagocytosis Behavior Biological Assay Blood Blood Vessels CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Categories Cells Characteristics Chronic Disease Clinical Complex Coupled Crohn&apos s disease Data Dendritic Cells Deposition Disease End stage renal failure Evolution Exposure to Fluorescein-5-isothiocyanate Frequencies Generations Genes Glomerulonephritis Goodpasture Syndrome Granulocyte-Macrophage Colony-Stimulating Factor Heart Diseases Human IgG Receptors Immune response Immunize Immunoglobulin G Immunosuppressive Agents In Vitro Inflammation Inflammatory Injections Injury Injury to Kidney Kidney Link Lupus Lupus Nephritis Malignant Neoplasms Mediating Modeling Molecular Mus Nephritis Neutrophil Activation Organ Ovalbumin Patients Phase Phenotype Polysaccharides Population Process Property Proteins Reporter Rheumatoid Arthritis Risk Role Serum Spleen Systemic Lupus Erythematosus T-Cell Proliferation T-Lymphocyte Testing Therapeutic Intervention Tubulointerstitial Nephritis Tumor Immunity acquired immunity antigen binding autoimmune pathogenesis base cell killing chemokine receptor chronic autoimmune disease cytokine differential expression draining lymph node human tissue humanized mouse immunogenic imprint in vivo inhibitor insight intravital microscopy migration mouse model nephrotoxicity neutrophil novel organ injury phenotypic biomarker prevent receptor recruit renal damage response single-cell RNA sequencing systemic autoimmune disease tissue injury trafficking transcription factor transcriptome transcriptome sequencing transcriptomics transdifferentiation uptake

项目摘要

Autoimmune disease is the third most common disease category after cancer and heart disease. Current therapies often rely on broad-spectrum immunosuppressive drugs to reduce inflammation and thus prevent permanent organ damage and chronic disease. Neutrophils are considered short-lived cells with degradative properties that associate with organ damage in diseases ranging from rheumatoid arthritis and Crohn’s to lupus nephritis. Deletion of activating FcγRs, receptors for IgG protects from organ damage in many mouse models of autoimmune diseases and FcγR SNPs are linked to rheumatoid arthritis, lupus and other autoimmune disorders. We have shown that IgG-immune complex deposition within blood vessels triggers rapid neutrophil capture via their own FcγRs and subsequent renal injury in a model of glomerulonephritis, suggesting that neutrophil FcγRs serve as a key link between IgG deposition and organ damage. What is the fate of activated neutrophils? Neutrophils can transdifferentiate into dendritic cells (DC) in response to cytokines in vitro and neutrophils with DC markers (nDC) are observed in inflamed mouse and human tissues. This suggests that the neutrophil imprint may go beyond the acute stages of inflammation. Based on preliminary data in mouse models and lupus patient blood we propose the following. Neutrophil FcγR engagement with multivalent IgG-complexed antigen induces neutrophil transdifferentiation into immunogenic, antigen cross-presenting nDCs that elicit T cell dependent acquired immunity and organ damage, which contributes to the transition from acute to chronic autoimmune disease. This hypothesis will be tested using our humanized FcγR mice, neutrophil reporter mice, mouse models of autoimmune target organ injury and systemic lupus erythematosus (SLE) patient blood coupled with transcriptome profiling, functional assays and multiphoton intravital microscopy. In specific aims, we propose to understand the molecular underpinnings of the FcγR dependent neutrophil to DC transition, the evolution of nDC fate, trafficking and immunogenic profile during the course of IgG mediated inflammation and the role of nDCs in promoting organ damage. Here, we will focus on nephrotoxic nephritis, a model of glomerulonephritis that mimics aspects of the effector phase of lupus nephritis, and T cell mediated tubulointerstitial nephritis, which are leading causes of end stage renal disease, but fully anticipate a broader applicability of our results to other IgG-mediated autoimmune diseases. Successful completion of our aims will lead to the characterization of a unique population of potent antigen presenting cells that develop from neutrophils exposed to autoantibody-ICs and may provide evidence that they establish a feed forward loop that fuels inflammation and thus increases the risk for transition to chronic autoimmune disease. We anticipate that this will lay the groundwork for elucidating novel points for therapeutic intervention in autoimmune disorders.

当前，自身免疫性疾病是继癌症和心脏病之后的第三大常见疾病。治疗通常依赖广谱免疫抑制药物来减少炎症，从而预防永久性器官损伤和慢性疾病中性粒细胞被认为是具有降解性的短命细胞。与类风湿性关节炎和克罗恩病等疾病的器官损伤相关的特性狼疮性肾炎中激活的 FcγR（IgG 受体）的缺失可以保护许多小鼠免受器官损伤。自身免疫性疾病模型和 FcγR SNP 与类风湿性关节炎、狼疮和其他疾病有关我们已经证明 IgG 免疫复合物沉积在血管内会引发自身免疫性疾病。在肾小球肾炎模型中，中性粒细胞通过其自身的 FcγR 快速捕获并随后造成肾损伤，表明中性粒细胞 FcγR 是 IgG 沉积和器官损伤之间的关键联系。活化的中性粒细胞的命运是否可以转分化为树突状细胞（DC）？在发炎的小鼠和人类体内观察到体外细胞因子和带有 DC 标记 (nDC) 的中性粒细胞这表明中性粒细胞印记可能超出了炎症的急性阶段。根据小鼠模型和狼疮患者血液的初步数据，我们提出以下建议。与多价 IgG 复合抗原结合诱导中性粒细胞转分化为具有免疫原性、抗原交叉呈递的 nDC，可引发 T 细胞依赖性获得性免疫和器官这个假设将使用我们的人源化 FcγR 小鼠、中性粒细胞报告小鼠、自身免疫靶点小鼠模型进行测试器官损伤和系统性红斑狼疮 (SLE) 患者血液以及转录组分析，功能测定和多光子活体显微镜在具体目标中，我们建议了解。 FcγR依赖性中性粒细胞向DC转变的分子基础，nDC命运的进化， IgG 介导的炎症过程中的运输和免疫原性特征以及 nDC 在其中的作用在这里，我们将重点关注肾毒性肾炎，这是一种肾小球肾炎模型。模拟狼疮性肾炎效应期和 T 细胞介导的肾小管间质性肾炎的各个方面，是终末期肾病的主要原因，但充分预期我们的结果具有更广泛的适用性成功完成我们的目标将导致其他 IgG 介导的自身免疫性疾病的表征。一组独特的强效抗原呈递细胞，由暴露于自身抗体 IC 并可能提供证据证明它们建立了加剧炎症的前馈循环从而增加转变为慢性自身免疫性疾病的风险。阐明自身免疫性疾病治疗干预新要点的基础。