DEMORA: DEep spatial characterization of synovial MacrOphages in Rheumatoid Arthritis

风湿性关节炎（RA）是最常见的影响关节的自身免疫性疾病。疾病过程的主要部位是滑膜组织（ST），其中巨噬细胞在驱动炎症中发挥核心作用。在生理条件下，滑膜由一个薄的衬里和一个相对无细胞的亚衬里包含一些居民巨噬细胞，但在RA，ST变化相当大。根据细胞浸润的“数量/质量”，已经描述了三种不同的“病理型”：淋巴-骨髓性、弥漫-骨髓性和少免疫性。尽管量不同，但滑膜组织巨噬细胞（STM）存在于所有三种病理类型中。在过去的五年中，STM的单细胞分子分析揭示了表型和功能不同的簇的存在，导致一个新的STM分类的定义。在这里，我假设不同的STM簇塑造RA滑膜组织微环境，影响组织病理学和治疗反应。通过应用于现有的独特的生物资源>800 ST，尖端技术，如数字空间分析与单细胞RNA-seq和计算机反卷积集成，我的目标是：确定STM簇的位置/地形分布和特定“生态位”的存在（例如，异位内/异位周围淋巴结构、血管周围或神经）;鉴定与每种滑膜病理类型相关的STM簇并驱动病理类型转变;评估特定STM簇是否预测对抗风湿药物的临床反应，它们在治疗后如何变化，以及哪些子集出现在对多种药物难治的患者中。这种深入的STM表征RA ST将增强我们对慢性关节炎和治疗无反应机制的理解，整合和改进基于ST细胞/分子特征的预测算法，并可能提出新的治疗靶点。

Rheumatoid Arthritis (RA) is the most common autoimmune disease affecting the joints. The primary site of the disease process is the synovial tissue (ST), where macrophages play a central role in driving inflammation. In physiologic conditions, the synovial membrane consists of a thin lining and a relatively acellular sublining containing a few resident macrophages, but in RA, the ST changes considerably. Three different "pathotypes" have been described depending on the "quantity/quality" of the cellular infiltrate: lympho-myeloid, diffuse-myeloid, and pauci-immune. Although in different amounts, synovial tissue macrophages (STM) are present in all three pathotypes. In the last five years, single-cell molecular profiling of STM has revealed the existence of phenotypically and functionally distinct clusters, leading to the definition of a new STM taxonomy. Here, I hypothesize that different STM clusters shape the synovial tissue micro-environment in RA and influence tissue pathology and response to treatment. By applying to an existing unique bioresource of >800 ST, cutting-edge technology such as digital spatial profiling integrated with single-cell RNA-seq and in silico deconvolution, I aim to: determine the location/topographical distribution of STM clusters and the existence of specific "niche" (e.g., intra/peri-ectopic lymphoid structures, peri-vascular or nerve); identify STM clusters associated with each synovial pathotype and driving pathotypes transition; assess if specific STM clusters predict clinical response to anti-rheumatic drugs, how they change post-treatment, and which subsets emerge in patients refractory to multiple medications. This in-depth STM characterization in RA ST will enhance our understanding of the mechanisms sustaining chronic arthritis and non-response to treatments, integrate and improve predictive algorithms based on ST cellular/molecular signatures, and may suggest new therapeutic targets.