Neutrophil plasticity in autoimmune disease

自身免疫性疾病中的中性粒细胞可塑性

• 批准号: 10569637
• 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
• 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/10569637
• 关键词: Abbreviations; Acceleration; Acute; Antibodies; Antigen Presentation; 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; Cell Communication; Cell Differentiation process; Cells; Characteristics; Chronic Disease; Clinical; Complex; Coupled; Crohn' s disease; Cross Presentation; 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; NF-kappa B; Nephritis; Neutrophil Activation; Organ; Ovalbumin; Ovum; Patients; Phase; Phenotype; Polysaccharides; Population; Process; Property; Proteins; Reporter; Rheumatoid Arthritis; Risk; Role; Serum; Spleen; Systemic Lupus Erythematosus; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic Intervention; Tubulointerstitial Nephritis; Tumor Immunity; acquired immunity; antigen binding; autoimmune pathogenesis; cell killing; cell motility; chemokine receptor; chronic autoimmune disease; cytokine; differential expression; draining lymph node; human tissue; humanized mouse; immunogenic; imprint; in vivo; inhibitor; insight; intravital microscopy; mouse model; multi-photon; nephrotoxicity; neutrophil; novel; organ injury; phenotypic biomarker; prevent; programs; receptor; recruit; renal damage; response; single-cell RNA sequencing; tissue injury; trafficking; transcription factor; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics; transdifferentiation; uptake

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.

自身免疫性疾病是仅次于癌症和心脏病的第三大常见疾病。当前 治疗方法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病。中性粒细胞被认为是具有降解性的短期细胞。 与类风湿性关节炎和克罗恩病等疾病的器官损害有关的特性 狼疮性肾炎。Fc-γ受体活化缺失对许多小鼠的器官损伤有保护作用 自身免疫性疾病模型和FcγR SNP与类风湿性关节炎、狼疮等有关 自身免疫性疾病。我们已经证明，血管内免疫球蛋白免疫复合体的沉积会触发 在肾小球肾炎模型中，通过自身的Fcγ受体快速捕获中性粒细胞和随后的肾脏损伤， 提示中性粒细胞Fc-γ受体是免疫球蛋白沉积与器官损害之间的关键环节。什么是 激活的中性粒细胞的命运？中性粒细胞可转分化为树突状细胞(DC) 炎症小鼠和人的体外细胞因子和具有DC标记的中性粒细胞(NDC)的观察 纸巾。这表明中性粒细胞印记可能超出了炎症的急性期。基座 根据小鼠模型和狼疮患者血液的初步数据，我们提出了以下建议。中性粒细胞FcγR 与多价免疫球蛋白复合抗原结合诱导中性粒细胞转分化为 免疫原性、抗原交叉呈递NDCS，可诱导T细胞依赖获得性免疫和器官 损害，有助于从急性自身免疫性疾病向慢性自身免疫性疾病过渡。这一假说将 用我们的人源化FcγR小鼠，中性粒细胞报告小鼠，自身免疫靶标的小鼠模型进行测试 器官损伤和系统性红斑狼疮(SLE)患者血液结合转录组分析， 功能分析和多光子活体显微镜。在具体目标上，我们建议理解 FcγR依赖的中性粒细胞向DC转变的分子基础，NDC命运的演变， 免疫球蛋白介导的炎症过程中的转运和免疫原性变化及NDCS在脑内的作用 促进器官损伤。在这里，我们将重点介绍肾毒性肾炎，这是一种肾小球肾炎模型， 模拟狼疮性肾炎和T细胞介导的肾小管间质肾炎的效应期， 是终末期肾病的主要原因，但充分预期我们的结果将更广泛地适用于 其他免疫球蛋白介导的自身免疫性疾病。成功完成我们的目标将导致我们的角色 一个独特的强大的抗原提呈细胞群体，这些细胞是由暴露于 自身抗体-IC，并可能提供证据表明它们建立了一个前馈环路，从而加剧了炎症 从而增加了转变为慢性自身免疫性疾病的风险。我们预计这将为 为阐明自身免疫性疾病治疗干预的新观点奠定基础。