Identification of circulating monocyte subset contributing to pathogenesis of systemic sclerosis

• Project/Area Number: 17K09989
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Nippon Medical School
• Principal Investigator: Kuwana Masataka 日本医科大学, 大学院医学研究科, 大学院教授 (50245479)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 強皮症 / 単球 / I型インターフェロン / 線維芽細胞 / 間質性肺疾患 / 膠原病 / 線維化

Outline of Final Research Achievements

Systemic sclerosis (SSc) is one of the intractable diseases and is characterized by irreversible fibrosis and vascular lesions. Peripheral blood monocytes with a unique phenotype have been identified as a central mechanism that induces all SSc lesions. In this study, we identified a series of type I interferon-inducible genes as genes upregulated in SSc monocytes using a comprehensive RNA sequencing with a next-generation sequencer. This indicates that SSc monocytes with a unique phenotype that promotes fibrosis may be induced by type I interferon.

Academic Significance and Societal Importance of the Research Achievements

I型インターフェロンが強皮症（SSc）の病態の上流に位置することが明らかにされたことは、I型インターフェロンが早期診断に役立つ臨床検査として活用できるだけで無く、現状で根治的治療法のない難治性病態に対してI型インターフェロンを標的とした新たな治療の開発にもつながる。

Research Products

• [Journal Article] Endothelial cells and endothelial progenitor cells in the pathogenesis of systemic sclerosis (2020)
  • Author(s): Ota Yuko、Kuwana Masataka
  • Journal Title: European Journal of Rheumatology Volume: 7 Issue: -3 Pages: 139-146
  • DOI: 10.5152/eurjrheum.2019.19158
  • Peer Reviewed
• [Journal Article] Progression of Interstitial Lung Disease in Systemic Sclerosis: The Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18 (2019)
  • Author(s): Volkmann Elizabeth R.、Tashkin Donald P.、Kuwana Masataka、et al
  • Journal Title: Arthritis & Rheumatology Volume: 71 Issue: 12 Pages: 2059-2067
  • DOI: 10.1002/art.41020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Performance of candidate serum biomarkers for systemic sclerosis-interstitial lung disease (2019)
  • Author(s): Elhai M, Hoffmann-Vold AM, Pezet S, Cauvet A, Leblond A, Avouac J, Kuwana M, Molberg ø248; 248; 248;216;216;, and Allanore Y
  • Journal Title: Arthritis Rheumatol Volume: 0 Issue: 6 Pages: 0-0
  • DOI: 10.1002/art.40815
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fos-related antigen-1 transgenic mouse as a model for systemic sclerosis: A potential role of M2 polarization (2019)
  • Author(s): Yasuoka H, Yuen Yu Angela Tam, Okazaki Y, Tamura Y, Matsuo K, Carol Feghali-Bostwick, Takeuchi T, Kuwana M
  • Journal Title: J Scleroderma Relat Disord Volume: 4(2) Issue: 2 Pages: 137-148
  • DOI: 10.1177/2397198319838140
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Add-on tocilizumab versus conventional treatment for systemic sclerosis, and cytokine analysis to identify endotype to tocilizumab therapy (2019)
  • Author(s): Shima Y, Kawaguchi Y, and Kuwana M
  • Journal Title: Mod. Rheumatol Volume: 29 Issue: 1 Pages: 134-139
  • DOI: 10.1080/14397595.2018.1452178
  • Peer Reviewed
• [Journal Article] Fra-1 transgenic mouse as a model for systemic sclerosis: a potential role of M2 polarization (2019)
  • Author(s): Yasuoka H, Tam YY, Okazaki Y, Tamura Y, Matsuo K, Feghali-Bostwick C, Takeuchi T, and Kuwana M
  • Journal Title: J. Scleroderma Relat. Disord Volume: 0 Pages: 0-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] KL-6 but not CCL-18 is a predictor of early progression in systemic sclerosis-related interstitial lung disease (2018)
  • Author(s): Salazar GA, Kuwana M, Wu M, Estrada-Y-Martin RM, Ying J, Charles J, Mayes MD, and Assassi S
  • Journal Title: J. Rheumatol Volume: 45 Issue: 8 Pages: 1153-1158
  • DOI: 10.3899/jrheum.170518
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] KL-6 but not CCL-18 is a predictor of early progression in systemic sclerosis related interstitial lung disease (2018)
  • Author(s): 335.Salazar GA, Kuwana M, Wu M, Estrada-Y-Martin R, Ying J, Charles J, Mayes MD and Assassi S
  • Journal Title: J. Rheumatol Volume: In press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities (2017)
  • Author(s): Varga J, Trojanowska M, and Kuwana M
  • Journal Title: J. Scleroderma Relat. Disord Volume: 2 Issue: 3 Pages: 137-152
  • DOI: 10.5301/jsrd.5000249
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Are we on the verge of cracking the nut in systemic sclerosis? (2019)
  • Author(s): Kuwana M
  • Organizer: 21st Asia Pacific League of Associations for Rheumatology Congress
  • Int'l Joint Research / Invited
• [Presentation] Utility of risk stratification in predicting outcomes of initial monotherapy versus combination therapy in pulmonary arterial hypertension associated with connective tissue disease: a post-hoc analysis of the AMBITION study (2019)
  • Author(s): Kuwana M, Blair C, Langley J, Takahashi T, Coghlan G
  • Organizer: EULAR2019
  • Int'l Joint Research
• [Presentation] Current problems and future direction of management of systemic sclerosis (2019)
  • Author(s): Kuwana M
  • Organizer: 第63回日本リウマチ学会総会・学術集会
  • Invited
• [Presentation] 強皮症の病態関連遺伝子 (2019)
  • Author(s): 桑名正隆
  • Organizer: 第40回日本炎症・再生医学会
  • Invited
• [Presentation] Interstitial lung disease associated with systemic sclerosis: current and future approach to the management (2018)
  • Author(s): Kuwana M
  • Organizer: 20th Asia Pacific League of Associations for Rheumatology Congress
  • Int'l Joint Research / Invited
• [Presentation] Management of systemic sclerosis: current status and future directions (2018)
  • Author(s): Kuwana M
  • Organizer: The 38th Korean College of Rheumatology Annual Scientific Symposium
  • Int'l Joint Research / Invited
• [Presentation] Biomarker in SSc-associated interstitial lung disease (2018)
  • Author(s): Kuwana M
  • Organizer: The 9th Symposium of International Network of Scleroderma Clinical Care and Research
  • Int'l Joint Research / Invited
• [Presentation] 全身性強皮症 (2018)
  • Author(s): 桑名 正隆
  • Organizer: 第39回日本炎症・再生医学会
  • Invited
• [Presentation] New Autoantibodies, organ involvement and disease progression (2018)
  • Author(s): Kuwana M
  • Organizer: 5th Systemic Sclerosis World Congress
  • Int'l Joint Research / Invited