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Regulation, function and localization of monocytes in autoimmune tissues

自身免疫组织中单核细胞的调节、功能和定位

基本信息

批准号：
10598099
负责人：
Nir Hacohen
金额：
$ 53.05万
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：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598099
关键词：
Address Affect Animal Disease Models Animal Model Anti-Inflammatory Agents Antigen-Antibody Complex Apoptotic Autoimmune Autoimmunity Automobile Driving B-Cell Activation B-Lymphocytes Cell Communication Cell physiology Cells Clinical Coculture Techniques Cytotoxic T-Lymphocytes DIF factor Data Dimensions Disease Educational process of instructing Endothelium Environmental Risk Factor Extravasation FCGR3B gene Fibroblasts Generations Genes Genetic Risk Genetic study Human Image Image Analysis Immune Immune response Immunology In Vitro Infiltration Inflammation Inflammatory Kidney Lesion Link Location Lupus Lupus Nephritis Lymphocyte Maps Measures Methods Microscopy Monitor Necrosis Nucleic Acids Pathologic Pathology Pathway interactions Patients Phagocytosis Physiological RNA Reagent Regulation Resolution Role Sampling Signal Transduction Stains Structure System Systemic Lupus Erythematosus T-Cell Activation Testing Tissues Transcript Virulence Factors Visualization Work cell type cohort cytokine differential expression exhaustion experimental study genetic association genetic variant genome wide association study high dimensionality human tissue imaging study kidney cell monocyte novel overexpression patient stratification programs repaired risk variant single-cell RNA sequencing tissue repair transcription factor transcriptome sequencing

项目摘要

A central challenge in autoimmunity is to discover the cells and pathways that drive pathological immune responses in humans. Previous studies of human samples were limited by low-dimensional single cell methods or high-dimensional bulk methods confounded by cell mixtures. By sequencing RNA of thousands of single cells from lupus nephritis kidneys, we found 21 unique immune cell states, many of which were also found in synovial tissue of RA patients. In Project 2, we will focus on 3 monocyte states that we observe in lupus nephritis kidneys, which likely arise from patrolling blood monocytes that enter the kidney. While these monocytes share expressed genes with the previously described M1/M2 spectrum of monocyte states, they express distinct functional modules and do not map directly to those states. To better understand these disease-associated monocyte states, we will perform experiments to address three hypotheses. First, we hypothesize that monocyte inflammation, phagocytosis, and tissue repair programs in lupus nephritis kidneys are regulated by fibroblasts and tissue-derived factors. With Project 3, we will co-culture primary monocytes with activated/inflammatory fibroblasts together with known local pathogenic factors and determine changes in cellular functions, including phagocytosis, cytokine secretion, endothelial extravasation, T/B cell activation (with Project 1) and other functions. Preliminary data show that fibroblasts and a proposed pathogenic factor, necrotic cells, strongly induce monocyte differentiation. Second, we hypothesize that TFs expressed in lupus monocytes will induce differentiation and expression of disease-associated gene inflammation and tissue repair programs. We will overexpress candidate TFs (based on their expression and genetic association with lupus) in monocytes and assess inflammation, phagocytosis, and differentiation. Preliminary studies show that the TF overexpression is feasible, impacts differentiation, and if successful, would allow reliable in vitro generation of differentiated monocytes for functional studies. Third, to address monocyte roles in lupus nephritis kidneys, we hypothesize that the proximity of monocytes, fibroblasts and tissue lesions, along with expression of fibroblast-induced monocyte gene programs, will reflect cell-cell interactions and functions of monocytes in patient kidneys. Using automated staining, microscopy and image analysis (with the Computational Systems Immunology Core) of kidney sections from up to 205 clinically-annotated lupus nephritis patients, we will visualize and assess co- localization of monocytes, fibroblasts, tissue structures/lesions. Preliminary data shows close contacts between monocytes and fibroblasts and feasibility of scaling our imaging studies to the full cohort. By building on a more accurate definition of monocytes in human lupus nephritis kidneys, developing methods to study them in vitro and in human tissues, we will define the origin, differentiation pathways, functions and spatial locations of monocytes in lupus nephritis, provide a roadmap for mechanistic studies in animal models of disease and identify approaches to manipulate monocytes as potential therapies for lupus nephritis.

自身免疫的核心挑战是发现驱动病理性免疫的细胞和途径