Service d'Hématologie, Oncologie et Rhumatologie pédiatrique, Cliniques universitaires Saint-Luc, Brussels, Belgium.
Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Ann Rheum Dis. 2023 Dec;82(12):1538-1546. doi: 10.1136/ard-2023-224068. Epub 2023 Jul 28.
Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.
RNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.
PCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.
In this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.
对未经治疗的早期类风湿关节炎（RA）患者的滑膜组织进行转录组分析，以探索无偏倚、数据驱动的方法定义临床相关亚组的能力。
对 74 例样本进行了 RNA-seq 分析，并在纳入时收集了疾病活动数据。基于最具变异性基因的表达，采用主成分分析（PCA）和无监督聚类定义患者聚类，然后进行途径分析和免疫细胞亚群相对丰度推断。对石蜡切片进行组织学评估和多重免疫荧光（用于 CD45、CD68、CD206）。
对该系列中（n=894）最具变异性基因的表达进行 PCA 分析并未将样本分为不同的组，而是产生了与基线疾病活动相关的连续体。根据这些基因的表达，定义了两个患者聚类（PtC1，n=52；PtC2，n=22）。PtC1 具有显著更高的疾病活动度和对甲氨蝶呤治疗反应的可能性，表现出免疫系统基因的上调；PtC2 表现出脂质代谢基因的上调，这些基因被描述为特征组织驻留或 M2 样巨噬细胞。与这些数据一致，M2 样：M1 样巨噬细胞比值与疾病活动评分呈负相关，与较低的滑膜免疫浸润和较薄的、富含 M2 样巨噬细胞的滑膜衬里层有关。
在这项大型早期未经治疗的 RA 系列研究中，我们表明滑膜转录组与临床疾病活动密切相关，并与滑膜炎症相关。有趣的是，较低的炎症和疾病活动与更高的 M2：M1 巨噬细胞比值相关，在滑膜衬里层尤为明显。这可能表明组织驻留巨噬细胞在 RA 中具有保护作用。
