Synovial Tissue Heterogeneity in Japanese Patients With Rheumatoid Arthritis Elucidated Using a <scp>Cell‐Type</scp> Deconvolution Approach
S. Nakajima, Haruka Tsuchiya, Mineto Ota, Megumi Ogawa, Saeko Yamada, Ryochi Yoshida, Junko Maeda, Harumi Shirai, Taro Kasai, Jun Hirose, Keita Ninagawa, Yuichiro Fujieda, Takeshi Iwasaki, Yoshimi Aizaki, Hiroshi Kajiyama, Masakazu Matsushita, Eiryo Kawakami, Naoto Tamura, Toshihide Mimura, Koichiro Ohmura, Akio Morinobu, Tatsuya Atsumi, Yoshiya Tanaka, Tsutomu Takeuchi, Sakae Tanaka, Tomohisa Okamura, Keishi Fujio
Abstract
OBJECTIVE: Recent advances in single-cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to stratify the synovium from East Asian patients with RA by immune cell compositions and gain insight into the inflammatory drivers of each synovial phenotype. METHODS: Synovial tissues were obtained from East Asian patients in Japan with RA (n = 41) undergoing articular surgery. The cellular composition was quantified by a deconvolution approach using a public single-cell-based reference. Inflammatory pathway activity was calculated by gene set variation analysis, and chromatin accessibility was evaluated using assay of transposase accessible chromatin-sequencing. RESULTS: monocytes, and plasmablasts. In addition, tumor necrosis factor (TNF)-α, interferons (IFNs), and IL-6 signaling were highly activated in this subtype, and the expression of various chemokines was significantly enhanced. Moreover, we found an open chromatin region overlapping with RA risk locus rs9405192 near the IRF4 gene, suggesting the genetic background influences the development of this inflammatory synovial state. The other two subtypes were characterized by increased IFNs and IL-6 signaling, and expression of molecules associated with degeneration, respectively. CONCLUSION: This study adds insights into the synovial heterogeneity in East Asian patients and shows a promising link with predominant inflammatory signals. Evaluating the site of inflammation has the potential to lead to appropriate drug selection that matches the individual pathology.