Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE

RA 和 SLE 炎症组织中免疫细胞和成纤维细胞的分化

• 批准号: 10427141
• 负责人: Michael B. Brenner
• 金额: $ 249.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/10427141
• 关键词: Abnormal Cell; Affect; Age; Anatomy; Animal Model; Antibody Formation; Antigenic Specificity; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Lymphocytes; Blood; Cell Communication; Cells; Chronic; Clinical; Complement; Data; Development; Disease; Disease Clusterings; Family; Fibroblasts; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Image; Image Analysis; Immune; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Institutes; Joints; Kidney; Laboratories; Lesion; Leukocytes; Lupus; Lupus Nephritis; Medicine; Methods; Mus; Myeloid Cells; NOTCH3 gene; Nature; Nephritis; Organ; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Population; Production; Reaction; Rheumatoid Arthritis; Role; Signal Transduction; Stromal Cells; Synovial Membrane; Synovitis; System; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; Therapeutic; Therapeutic Intervention; Tissues; Virulence Factors; Work; base; cell type; computational pipelines; experimental study; high dimensionality; human disease; imaging approach; imaging platform; immunopathology; in vivo; insight; interest; macrophage; monocyte; neutrophil; notch protein; novel; programs; recruit; risk variant; single cell analysis; single cell technology; single-cell RNA sequencing; targeted treatment; transcription factor; transcriptome; transcriptome sequencing

ABSTRACT Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are different diseases clinically and the most important tissue damage occurs in joints and kidneys, respectively. Yet, both SLE and RA share a central common theme of adaptive T and B cell interactions that result in autoantibody production. Both tissues develop chronic inflammatory reactions that also include myeloid cell populations, neutrophils and other innate leukocytes. The two diseases cluster in families and share a number of closely related risk alleles suggesting related immune mechanisms. Developing targeted therapies for lupus has been frustrating and while a number of therapies can reduce disease activity in RA, a large unmet need exists in the form of TNF inadequate responders; and there is no cure. Based on the RA/SLE AMP consortium, single cell RNA-seq and CyTOF analysis has phenotypically and transcriptionally identified many unexpected cell types and cell states present in the inflamed kidney in lupus nephritis and RA synovitis. Here, we select a set of important cell populations specific to, or highly enriched in, the involved tissues in both diseases. Given the importance of B cells and antibody production, we focus on the novel subset of age (or autoimmunity) associated B cells (ABC B cells) and B helper T cells including both T follicular helper (Tfh) and the recently discovered T peripheral helper (Tph) T cells in Project 1. The project focuses on defining the relationship of ABC to other B cell populations and examines the role of Tph and Tfh cells in driving ABC B cells and their cross-talk. ABC B cells and Tph/Tfh cells are enriched in both lupus kidney and RA synovium allowing their comparison across diseases. Project 2 examines novel macrophage inflammatory states found in lupus kidney and seeks to define the main activating factors and transcription factors that drive cell state changes to achieve the inflammatory CM4 state that predominates in nephritis. Project 3 examines the fibroblastic stroma that drives inflammation in RA. A population of inflammatory sublining CD90+DR+ fibroblasts is profoundly expanded in RA and implicated in perpetuating inflammation. Project 3 examines the role of a Notch gradient and Notch signaling in driving the differentiation and activation of this population in synovium and kidney and its role in inflammatory arthritis. All 3 projects interact to examine the cell types of interest across diseases, to determine which cells are interacting most closely by integrated imaging analysis. By utilizing the synchronized expert pipelines of the Computational Systems Immunology Core for single cell RNA-seq and image analysis, the data gathered from both diseases and tissues can be effectively compared. All 3 projects focus on determining the drivers and transitions that yield the important cell states that have been discovered directly in the involved tissues. Together, the program will provide new insights into the tissue immunopathology in these human autoimmune diseases and help to unfold new avenues for therapeutic intervention.

抽象的 类风湿性关节炎（RA）和系统性红斑狼疮（SLE）在临床上是不同的疾病 最重要的组织损伤分别发生在关节和肾脏。然而，SLE 和 RA 都有一个共同点 导致自身抗体产生的适应性 T 细胞和 B 细胞相互作用的中心共同主题。两种组织 产生慢性炎症反应，还包括骨髓细胞群、中性粒细胞和其他先天性炎症反应 白细胞。这两种疾病在家族中聚集，并具有许多密切相关的风险等位基因，表明 相关的免疫机制。开发狼疮靶向疗法一直令人沮丧，尽管 许多疗法可以降低 RA 的疾病活动度，但 TNF 的形式存在大量未满足的需求 响应者不足；并且没有治愈方法。 基于 RA/SLE AMP 联盟，单细胞 RNA-seq 和 CyTOF 分析具有表型 并通过转录鉴定了发炎肾脏中存在的许多意想不到的细胞类型和细胞状态 狼疮性肾炎和RA滑膜炎。在这里，我们选择一组特定于或高度特定的重要细胞群 富含两种疾病所涉及的组织。鉴于 B 细胞和抗体产生的重要性， 我们专注于年龄（或自身免疫）相关 B 细胞（ABC B 细胞）和 B 辅助 T 细胞的新子集 包括项目 1 中的滤泡辅助性 T (Tfh) 和最近发现的外周辅助性 T (Tph) T 细胞。 该项目的重点是定义 ABC 与其他 B 细胞群的关系，并检查 ABC 的作用 Tph 和 Tfh 细胞驱动 ABC B 细胞及其串扰。 ABC B 细胞和 Tph/Tfh 细胞富含 狼疮肾和 RA 滑膜可以进行跨疾病比较。项目 2 审查小说 狼疮肾中发现的巨噬细胞炎症状态，并试图确定主要的激活因素和 驱动细胞状态变化以达到在炎症中占主导地位的 CM4 状态的转录因子 肾炎。项目 3 检查引起 RA 炎症的成纤维细胞基质。人口为 炎性亚衬 CD90+DR+ 成纤维细胞在 RA 中深度扩增，并与永久存在有关 炎。项目 3 研究了 Notch 梯度和 Notch 信号在驱动分化中的作用 滑膜和肾脏中该群体的激活及其在炎症性关节炎中的作用。所有 3 个项目 相互作用以检查跨疾病的感兴趣的细胞类型，以确定哪些细胞相互作用最多 通过综合成像分析紧密结合。通过利用计算的同步专家管道 用于单细胞 RNA 测序和图像分析的系统免疫学核心，从两种疾病收集的数据 和组织可以有效地进行比较。所有 3 个项目都专注于确定驱动因素和转型 产生直接在相关组织中发现的重要细胞状态。一起，节目 将为这些人类自身免疫性疾病的组织免疫病理学提供新的见解，并有助于 开辟治疗干预的新途径。