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

摘要 风湿性关节炎（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都具有 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 发展慢性炎症反应，还包括骨髓细胞群，中性粒细胞和其他先天性 白细胞这两种疾病在家族中聚集，并且共享许多密切相关的风险等位基因，这表明 相关免疫机制。开发针对狼疮的靶向疗法一直令人沮丧， 许多治疗方法可以减少RA的疾病活动，但TNF形式的大量未满足需求 反应不足;而且没有治愈方法。 基于RA/SLE AMP联合体，单细胞RNA-seq和CyTOF分析具有表型特征。 并在转录水平上鉴定了许多存在于炎症肾脏中的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，我们选择了一组重要的细胞群， 在这两种疾病的相关组织中富集。鉴于B细胞和抗体产生的重要性， 我们关注年龄（或自身免疫）相关B细胞（ABC B细胞）和B辅助性T细胞的新亚群 包括滤泡辅助性T细胞（Tfh）和最近在项目1中发现的外周辅助性T细胞（Tph）。 该项目的重点是确定ABC与其他B细胞群的关系，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细胞富集于 狼疮肾和类风湿关节炎滑膜允许他们在疾病之间的比较。项目2审查小说 巨噬细胞炎症状态发现狼疮肾，并寻求确定主要的激活因子， 这些转录因子驱动细胞状态变化，以达到炎症性CM4状态， 肾炎项目3研究了驱动RA炎症的成纤维细胞基质。人口 炎性亚层CD90 + DR+成纤维细胞在RA中显著扩增，并参与维持 炎症项目3研究了Notch梯度和Notch信号在驱动分化中的作用。 以及滑膜和肾脏中该群体的活化及其在炎性关节炎中的作用。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 通过综合成像分析。通过利用计算的同步专家管道， 系统免疫学单细胞RNA测序和图像分析核心，从两种疾病中收集的数据 并且组织可以被有效地比较。所有3个项目都侧重于确定 产生在相关组织中直接发现的重要细胞状态。在一起，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， 为治疗干预开辟了新的途径。

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.