ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1139

Comprehensive Single-cell Profiling of Diverse Circulating Immune Cells in Idiopathic Inflammatory Myopathies Identifies a Novel Pathogenic Subset of Monocytes

Shinji Izuka1, Toshihiko Komai2, Hayato Yuuki2, Ikuko Ueda3, Manabu Fujimoto4, Hiroyuki Fukui5, Masaru Takeshita6, Natsuka Umezawa7, Shinsuke Yasuda7, Mitsutaka Yasuda8, Yuichiro Fujieda9, Tatsuya Atsumi9, Takeshi Iwasaki10, Akio Morinobu10, Yuya Kondo11, Isao Matsumoto11, Toshio Kawamoto12, Masakazu Matsushita12, Naoto Tamura13, Taro Iwamoto14, Hiroshi Nakajima14, Ken Yoshida15, Takeo Isozaki16, Nobuyuki Yajima16, Keiichi Sakurai17, Kimito Kawahata17, Yasuyuki Kamata18, Kojiro Sato18, Yoshiya Tanaka19, Akari Suzuki20, Kazuhiko Yamamoto21, Tomohisa Okamura22 and Keishi Fujio2, 1Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Tokyo, Japan, 2Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Bunkyo, Tokyo, Japan, 3Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan., Suita, Japan, 4Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan., Suita, Osaka, Japan, 5Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan., Tokyo, Japan, 6Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan, 7Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan., Tokyo, Japan, 8Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan., Sapporo, Japan, 9Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan, Sapporo, Japan, 10Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Kyoto, Japan, 11Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan., Tsukuba, Japan, 12Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan., Tokyo, Japan, 13Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan, 14Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan., Chiba, Japan, 15Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan., Tokyo, Japan, 16Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan., Tokyo, Japan, 17Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan., Kawasaki, Japan, 18Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Tochigi, Japan., Tochigi, Japan, 19Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan, 20Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan., Kanagawa, Japan, 21Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan., Kawasaki, Japan, 22Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Japan., Bunkyo, Tokyo, Japan

Meeting: ACR Convergence 2024

Keywords: , , , ,

Session Information

Date: Sunday, November 17, 2024

Title: Muscle Biology, Myositis & Myopathies – Basic & Clinical Science Poster II

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases, making it crucial to identify distinct pathological processes to improve a treatment strategy. Transcriptomic analyses have revealed increased type I interferon signatures in dermatomyositis and oxidative phosphorylation in antisynthetase syndrome (1). However, differences among disease phenotypes and activity states remain unclear. This study aims to elucidate these variations at a single-cell resolution, providing insights into disease establishment and exacerbation in IIM patients.

Methods: We collected peripheral blood mononuclear cells (PBMCs) from myositis-specific antibody (MSA)-positive IIM patients, including those positive for antibodies against anti-aminoacyl-tRNA synthetase (ARS), melanoma differentiation-associated gene 5 (MDA5), Mi-2, and transcriptional intermediary factor 1-γ (TIF1-γ), as well as healthy controls (HC) from multiple centers across Japan (Figure 1). We conducted single-cell RNA sequencing (scRNA-seq) on CD45+ live cells using the ‘Chromium Single Cell Gene Expression’ platform (10X Genomics), and the libraries were sequenced on the Illumina Novaseq 6000. We evaluated the International Myositis Assessment & Clinical Studies Group Disease Activity Core Set Measures to define disease activity. We explored transcriptomic signatures associated with disease activity and clinical manifestations by conducting transcriptomic analyses.

Results: scRNA-seq was performed on over 480,000 cells from 77 IIM patients and 23 age- and sex-matched HCs. Principal component analysis (PCA) revealed that the cell proportion of CD14+ monocytes had the highest factor loading in PC1. After reclustering of myeloid cell subsets, RNASE2high and MX1high CD14+ monocytes exhibited higher proportions in active IIM patients within the five clusters of classical monocyte subsets. Additionally, differentially expressed gene (DEG) analysis identified type I interferon-stimulated genes (ISGs) when comparing active vs. non-active patients and non-active vs. HC, particularly in the monocyte subsets of anti-MDA5 antibody-positive patients, suggesting ISG association with both disease exacerbation and establishment. Gene set variation analysis showed that active disease was characterized by a shift towards pro-inflammatory profiles, with elevated expression of inflammatory cytokines and chemokines. Cellular compositions of RNASE2high CD14+ monocytes were correlated with multiple components of the Myositis Disease Activity Assessment Tool (MDAAT) across all IIM phenotypes. Specifically, MX1high CD14+ monocytes were correlated with skin MDAAT in dermatomyositis patients.

Conclusion: Our study identified distinct disease-state and disease-activity signatures, particularly highlighting the roles of monocytes and ISGs in disease exacerbation and establishment. These findings enhance our understanding of IIM pathogenesis and could inform targeted therapy development.

Reference
[1] Sugimori Y, et al. ACR Open Rheumatol. 2023;5:93-102

Supporting image 1

Figure 1. Overview of this study

Disclosures: S. Izuka: Eisai, 6; T. Komai: AbbVie/Abbott, 6, Eli Lilly, 6, GlaxoSmithKlein(GSK), 5, 6; H. Yuuki: None; I. Ueda: None; M. Fujimoto: AbbVie, 5, 6, Amgen, 6, Boheringer-Ingerheim, 6, Janssen Pharma, 6, Japan Blood Products Organization, 6, Maruho, 5, 6, Novartis, 6, Sanofi, 6, Sun Pharma, 5, Taiho Pharma, 5, UCB Japan, 6; H. Fukui: None; M. Takeshita: None; N. Umezawa: Abbvie, 6, Astellas Pharma, 6, Boehringer Ingelheim, 6, Kyowa Kirin, 2; S. Yasuda: AbbVie/Abbott, Tanabe-Mitsubishi, Ono Pharmaceutical, Lilly, GSK, Astrazeneka, 6, Asahi-kasei, Chugai, Ayumi, Behringer, 5, 6, Immunoforge, 1; M. Yasuda: None; Y. Fujieda: MEDICAL & BIOLOGICAL LABORATORIES CO., LTD, 5, medical&biological laboratories, 5; T. Atsumi: AbbVie, 6, Alexion Inc., 6, Asahi-Kasei Co., 6, Astellas Pharma Inc., 6, AstraZeneca, 2, 6, Bayer Yakuhin, 6, Bristol-Myers Squibb(BMS), 6, Chugai Pharmaceutical Co., Ltd., 6, Daiichi Sankyo Co., Ltd., 6, Eisai Co. Ltd., 6, Eli Lilly Japan K.K., 6, Gilead Sciences K.K., 6, GSK, 2, 5, Janssen, 6, Mitsubishi Tanabe Pharma Co., 6, Nippon Boehringer Ingelheim Co., Ltd., 2, 6, Nippon Shinyaku Co., Ltd., 6, Novartis, 2, 6, Otsuka, 2, Pfizer, 6, Taiho Pharmaceutical Co. Ltd., 6, UCB, 6; T. Iwasaki: None; A. Morinobu: None; Y. Kondo: None; I. Matsumoto: None; T. Kawamoto: Astellas Pharma, 6, Chugai Pharmaceutical., 6, Eisai, 6; M. Matsushita: None; N. Tamura: AbbVie/Abbott, 6, Asahikasei, 5, AstraZeneca, 6, Ayumi, 5, Bristol-Myers Squibb(BMS), 5, 6, Cell Exosome Therapeutics, 5, Chugai, 6, Esai, 6, GlaxoSmithKlein(GSK), 2, 5, Janssen, 6, Japan Boehringer-Ingelheim, 6, Japan Eli Lilly, 5, Novartis, 2, 6, Taisyo, 6, Tanabe Mitsubishi, 6; T. Iwamoto: AstraZeneca, 6, GlaxoSmithKlein(GSK), 6; H. Nakajima: None; K. Yoshida: AbbVie/Abbott, 6, 6, 6, Asahi Kasei Pharma Corporation, 6, 6, Astellas Pharma Inc., 6, Boehringer-Ingelheim, 6, 6, 6, 6, Chugai Pharmaceutical Co., Ltd., 6, Eisai Co., Ltd., 6, 6, 6, Taisho Pharmaceutical Co., Ltd., 6, Takeda Pharmaceutical Co., 6, 6, Takeda Pharmaceutical Co., Ltd., 6; T. Isozaki: AbbVie, 6, Asahi Kasei Pharma, 5, 6, Astellas Pharma, 6, Eisai, 6, Eli Lilly Japan, 6, Gilead Sciences, 6, Janssen Pharmaceutical, 6, Novartis Pharma, 6, Pfizer, 6, Sanofi, 6, Taiho Pharmaceutical, 6, UCB Japan, 6; N. Yajima: None; K. Sakurai: Asahi Kasei Pharma, 6, AstraZeneca, 6, Chugai Pharmaceutical, 6, Eisai, 6, Eli Lilly Japan, 6, GlaxoSmithKline, 6, Janssen Pharmaceutical, 6, Nippon Shinyaku, 6, Taisho Pharmaceutical, 6; K. Kawahata: None; Y. Kamata: AstraZeneca, 6, Boehringer Ingelheim, 6, Eisai, 6, GlaxoSmithKline, 6, Nippon Shinyaku, 6, Taisho Pharmaceutical, 6; K. Sato: AbbVie, 6, Asahi Kasei, 5, 6, Astellas, 6, AstraZeneca, 6, Ayumi Pharmaceutical, 6, Boehringer Ingelheim, 5, 6, Chugai Pharmaceutical, 5, Eisai, 6, Gilead Sciences, 6, GlaxoSmithKline, 6, Janssen, 6, Kissei Pharmaceutical, 6, Kyowa Kirin, 5, 6, Lilly, 6, Nippon Kayaku, 6, Novartis, 6, Ono Pharmaceutical, 6, Sanofi, 6, Taisho, 6, Takeda, 6, Tanabe Mitsubishi, 6; Y. Tanaka: AbbVie, 6, Asahi-kasei, 6, Astellas, 6, AstraZeneca, 6, Boehringer Ingelheim, 5, 6, Chugai, 5, 6, Daiichi Sankyo, 6, Eisai, 6, Gilead, 6, GSK, 6, Lilly, 6, Pfizer, 6, Taisho, 5, 6, UCB, 6; A. Suzuki: None; K. Yamamoto: Chugai Pharmaceutical Co.,LTD., 6, Sun Pharma Japan Limited, 6; T. Okamura: Chugai Pharmaceutical, 12, TO belonged to the Social Cooperation Program, Department of functional genomics and immunological diseases, supported by this company., Science Japan, 6; K. Fujio: AbbVie/Abbott, 5, 6, Alexion, 6, Asahi Kasei Pharma, 1, 2, 5, 6, AstraZeneca, 5, 6, Bristol-Myers Squibb(BMS), 5, 6, Chugai Pharmaceutical, 5, 6, Daiichi-Sankyo, 6, Eisai, 5, 6, Eli Lilly, 6, Gilead, 6, GlaxoSmithKlein(GSK), 6, Mitsubishi Tanabe Pharma, 6, Novartis, 6, Pfizer, 6, Taisho Pharmaceutical, 5, 6, Tsumura, 5.

To cite this abstract in AMA style:

Izuka S, Komai T, Yuuki H, Ueda I, Fujimoto M, Fukui H, Takeshita M, Umezawa N, Yasuda S, Yasuda M, Fujieda Y, Atsumi T, Iwasaki T, Morinobu A, Kondo Y, Matsumoto I, Kawamoto T, Matsushita M, Tamura N, Iwamoto T, Nakajima H, Yoshida K, Isozaki T, Yajima N, Sakurai K, Kawahata K, Kamata Y, Sato K, Tanaka Y, Suzuki A, Yamamoto K, Okamura T, Fujio K. Comprehensive Single-cell Profiling of Diverse Circulating Immune Cells in Idiopathic Inflammatory Myopathies Identifies a Novel Pathogenic Subset of Monocytes [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/comprehensive-single-cell-profiling-of-diverse-circulating-immune-cells-in-idiopathic-inflammatory-myopathies-identifies-a-novel-pathogenic-subset-of-monocytes/. Accessed .

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