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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.

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。当前的