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

摘要 类风湿关节炎(RA)和系统性红斑狼疮(SLE)是临床上不同的疾病。 最重要的组织损伤分别发生在关节和肾脏。然而，SLE和RA都有一个共同的 导致自身抗体产生的适应性T和B细胞相互作用的中心共同主题。两种组织 出现慢性炎症反应，包括髓系细胞群、中性粒细胞和其他先天的 白细胞。这两种疾病聚集在一起，并分享一些密切相关的风险等位基因，提示 相关的免疫机制。开发针对狼疮的靶向疗法一直令人沮丧，虽然 许多治疗方法可以减少类风湿性关节炎的疾病活动性，大量未得到满足的需求以肿瘤坏死因子的形式存在 应对人员不足；而且没有治愈的办法。 基于RA/SLE AMP联合体，单细胞RNA-SEQ和CyTOF分析具有表型 并在转录上鉴定了在发炎的肾脏中存在的许多意想不到的细胞类型和细胞状态 狼疮性肾炎和类风湿性滑膜炎。在这里，我们选择了一组重要的特定于或高度 在这两种疾病中，受累组织都是富含的。鉴于B细胞和抗体产生的重要性， 我们专注于与年龄(或自身免疫)相关的B细胞(ABC B细胞)和B辅助T细胞的新亚群 包括项目1中的T滤泡辅助细胞(TFH)和最近发现的T外周辅助T细胞(TPH)。 该项目的重点是定义ABC与其他B细胞群体的关系，并检查 TPH和TFH细胞驱动ABC B细胞及其相互作用。ABC B细胞和TPH/Tfh细胞富含 狼疮肾和类风湿性关节炎滑膜都允许跨疾病进行比较。项目2考察小说 狼疮肾中发现巨噬细胞炎症状态，并试图确定主要激活因子和 驱动细胞状态改变以达到炎症CM4状态的转录因子，这种状态在 肾炎。项目3检查了驱动类风湿关节炎炎症的成纤维细胞间质。一群人 炎性亚表达CD90 DR成纤维细胞在类风湿关节炎中显著扩张并与永生化有关 发炎。项目3研究了凹槽梯度和凹槽信号在驱动分化中的作用 以及滑膜和肾脏中这种群体的激活及其在炎症性关节炎中的作用。所有3个项目 相互作用以检查疾病中感兴趣的细胞类型，以确定哪些细胞相互作用最多 通过集成的成像分析进行密切联系。通过利用计算的同步专家流水线 系统免疫学核心为单细胞RNA-SEQ和图像分析，从这两种疾病收集的数据 和组织可以有效地进行比较。所有3个项目都侧重于确定驱动因素和过渡 产生在相关组织中直接发现的重要细胞状态。总而言之，该计划 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。

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.