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: 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
• 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' 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

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。电流 治疗通常依赖于广谱免疫抑制药物来减少炎症， 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寿命细胞。 与类风湿性关节炎和克罗恩病等疾病中的器官损伤相关的性质， 狼疮性肾炎在许多小鼠中，激活FcγRs的缺失，IgG的受体保护器官免受损伤 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 自身免疫性疾病我们已经证明IgG免疫复合物在血管内的沉积触发了 在肾小球肾炎模型中，中性粒细胞通过自身Fcγ R快速捕获，随后发生肾损伤， 提示中性粒细胞Fcγ R是IgG沉积和器官损伤之间的关键环节。是什么 活化的中性粒细胞的命运？中性粒细胞可以转分化为树突状细胞（DC），以响应 在发炎的小鼠和人中观察到体外细胞因子和具有DC标志物（nDC）的中性粒细胞 组织中这表明中性粒细胞印迹可能超越炎症的急性阶段。基于 根据小鼠模型和狼疮患者血液中的初步数据，我们提出以下建议。中性粒细胞FcγR 与多价IgG复合抗原的接合诱导中性粒细胞转分化为 免疫原性、抗原交叉呈递nDC，其引发T细胞依赖性获得性免疫和器官 损伤，这有助于从急性向慢性自身免疫性疾病的转变。这一假设将 使用我们的人源化FcγR小鼠、中性粒细胞报告小鼠、自身免疫靶点的小鼠模型 器官损伤和系统性红斑狼疮（SLE）患者血液与转录组谱分析相结合， 功能测定和多光子活体显微术。在具体目标中，我们建议理解 FcγR依赖性中性粒细胞向DC转化的分子基础，nDC命运的演变， IgG介导的炎症过程中的运输和免疫原性概况以及nDC在免疫应答中的作用。 促进器官损伤。在这里，我们将重点放在肾毒性肾炎，肾小球肾炎的模型， 模拟狼疮肾炎和T细胞介导的肾小管间质性肾炎的效应期， 是导致终末期肾病的主要原因，但完全预期我们的研究结果将更广泛地适用于 其他IgG介导的自身免疫性疾病。成功完成我们的目标将导致 一个独特的群体的强大的抗原呈递细胞，发展从中性粒细胞暴露于 自身抗体-IC，并可能提供证据表明它们建立了一个前馈回路， 从而增加了转变为慢性自身免疫性疾病的风险。我们预计，这将奠定 为阐明自身免疫性疾病治疗干预的新点奠定基础。