Establishment of an innovative morphological and functional evaluation method in patients with systemic sclerosis

• Project/Area Number: 17K16218
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Kubo Satoshi 産業医科大学, 医学部, 助教 (70461548)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 強皮症 / 爪郭部毛細血管顕微鏡 / 免疫フェノタイプ / 肺動脈性肺高血圧症 / 間質性肺疾患 / 肺動脈性高血圧症 / リンパ球 / 臨床 / 免疫

Outline of Final Research Achievements

Peripheral blood mononuclear cells obtained from 150 SSc patients were used for comprehensive flow cytometric analysis. Hierarchical cluster analysis stratified SSc patients into three groups: patients with few immune abnormalities, high proportions of activated T and Treg cells, and patients with high proportions of Tfh and plasmablasts (Tfh-dominant group). Microvascular abnormalities, especially the “late” nailfold videocapillaroscopy (NVC) pattern, correlated with internal organ involvement. Among the groups stratified according to immune cell phenotype, the progression to the “late” NVC pattern was more frequent in the Tfh-dominant group.
In conclusion, our study confirmed the presence of immunophenotypic abnormalities in SSc. Immunological abnormalities were not uniform but rather limited to subpopulations, particularly the Tfh-dominant group, where they were highly associated with microvascular abnormalities and organ involvement.

Academic Significance and Societal Importance of the Research Achievements

本研究により強皮症の免疫フェノタイプ異常と強皮症患者の細分化が示された。免疫学的異常は強皮症患者で均一ではなく、免疫フェノタイプの相違により細分化することにより、爪郭部毛細血管顕微鏡で検出した血管障害の進行や臓器障害の併発に関連するサブグループが存在することが明らかになり、そのサブグループが濾胞性T細胞が優位な免疫フェノタイプを有することが示された。このような試みによるエビデンスの蓄積は、強皮症の病態解明のみならず治療への応用、precision medicineの実現が期待される。

Research Products

• [Journal Article] Correlation between serological biomarkers of extracellular matrix turnover and lung fibrosis and pulmonary artery hypertension in patients with systemic sclerosis (2020)
  • Author(s): Kubo Satoshi、Siebuhr Anne Sofie、Bay‐Jensen Anne‐C.、Juhl Pernille、Karsdal Morten A.、Satoh Yurie、Todoroki Yasuyuki、Nakano Kazuhisa、Nakayamada Shingo、Tanaka Yoshiya
  • Journal Title: International Journal of Rheumatic Diseases Volume: Epub Issue: 4 Pages: 532-539
  • DOI: 10.1111/1756-185x.13804
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fast track algorithm: How to differentiate a “scleroderma pattern” from a “non-scleroderma pattern” (2019)
  • Author(s): Smith Vanessa、Vanhaecke Amber、Herrick Ariane L、Distler Oliver、Guerra Miguel G、Denton Christopher P、Deschepper Ellen、Foeldvari Ivan、Gutierrez Marwin、Hachulla Eric、Ingegnoli Francesca、Kubo Satoshi、Muller-Ladner Ulf、Riccieri Valeria、Sulli Alberto、van Laar Jaap M、Vonk Madelon C、Walker Ulrich A、et al
  • Journal Title: Autoimmunity Reviews Volume: 18 Issue: 11 Pages: 102394-102394
  • DOI: 10.1016/j.autrev.2019.102394
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinctive association of peripheral immune cell phenotypes with capillaroscopic microvascular patterns in systemic sclerosis. (2019)
  • Author(s): Kubo S, Nakayamada S, Miyazaki Y, Yoshikawa M, Yoshinari H, Satoh Y, Todoroki Y, Nakano K, Satoh M, Smith V, Cutolo M, Tanaka Y
  • Journal Title: Rheumatology Volume: 58 Issue: 12 Pages: 2273-2283
  • DOI: 10.1093/rheumatology/kez244
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The role of nailfold videocapillaroscopy in patients with systemic sclerosis (2018)
  • Author(s): Kubo Satoshi、Smith Vanessa、Cutolo Maurizio、Tanaka Yoshiya
  • Journal Title: Immunological Medicine Volume: 41 Issue: 3 Pages: 113-119
  • DOI: 10.1080/25785826.2018.1531189
  • Peer Reviewed
• [Journal Article] Scleroderma in an ice-cream shop worker (2018)
  • Author(s): Kubo Satoshi、Tanaka Yoshiya
  • Journal Title: Rheumatology Volume: Epub Issue: 6 Pages: 1120-1121
  • DOI: 10.1093/rheumatology/key400
  • Peer Reviewed
• [Journal Article] Significance of nailfold videocapillaroscopy in patients with idiopathic inflammatory myopathies (2018)
  • Author(s): Kubo Satoshi、Todoroki Yasuyuki、Nakayamada Shingo、Nakano Kazuhisa、Satoh Minoru、Nawata Aya、Satoh Yurie、Miyagawa Ippei、Saito Kazuyoshi、Smith Vanessa、Cutolo Maurizio、Tanaka Yoshiya
  • Journal Title: Rheumatology Volume: 58 Issue: 1 Pages: 120-130
  • DOI: 10.1093/rheumatology/key257
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Correlation of T follicular helper cells and plasmablasts with the development of organ involvement in patients with IgG4-related disease (2017)
  • Author(s): Kubo Satoshi、Nakayamada Shingo、Zhao Jidong、Yoshikawa Maiko、Miyazaki Yusuke、Nawata Aya、Hirata Shintaro、Nakano Kazuhisa、Saito Kazuyoshi、Tanaka Yoshiya
  • Journal Title: Rheumatology (Oxford) Volume: 57 Issue: 3 Pages: 514-524
  • DOI: 10.1093/rheumatology/kex455
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Peripheral Immunophenotyping Identifies Three Subgroups Based on T Cell Heterogeneity in Lupus Patients. (2017)
  • Author(s): Kubo S, Nakayamada S, Yoshikawa M, Miyazaki Y, Sakata K, Nakano K, Hanami K, Iwata S, Miyagawa I, Saito K, Tanaka Y.
  • Journal Title: Arthritis Rheumatol. Volume: 69(10) Issue: 10 Pages: 2029-2037
  • DOI: 10.1002/art.40180
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 強皮症患者は末梢血免疫フェノタイプにより3つの亜群に分かれ、微小血管障害の進行と関連する (2018)
  • Author(s): 久保智史、中山田真吾、中野和久、岩田慈、花見健太郎、福與俊介、宮川一平、宮崎祐介、河邊明男、吉成紘子、佐藤友梨恵、轟泰幸、佐藤実、田中良哉
  • Organizer: 第46回日本臨床免疫学会総会
• [Presentation] The association between immunophenotype of peripheral blood and nailfold microvascular changes in patients with systemic sclerosis (SSc). (2018)
  • Author(s): Satoshi Kubo, Shingo Nakayamada, Kazuhisa Nakano, Maiko Yoshikawa, Yusuke Miyazaki, Hiroko Yoshinari, Yasutaro Tamaki, Shigeru Iwata, Kentaro Hanami, Shunsuke Fukuyo, Ippei Miyagawa, Yoshiya Tanaka.
  • Organizer: 第62回日本リウマチ学会
• [Presentation] The association between immunophenotype of peripheral blood and nailfold microvascular changes in patients with systemic sclerosis (SSc) (2018)
  • Author(s): Satoshi Kubo, Shingo Nakayamada, Kazuhisa Nakano, Maiko Yoshikawa, Yusuke Miyazaki, Hiroko Yoshinari, Yasutaro Tamaki, Shigeru Iwata, Kentaro Hanami, Shunsuke Fukuyo, Ippei Miyagawa, Yoshiya Tanaka
  • Organizer: 第62回日本リウマチ学会
• [Presentation] The immunophenotyping of peripheral blood associates with nailfold microvascular changes in patients with systemic sclerosis (2017)
  • Author(s): Satoshi Kubo, Shingo Nakayamada, Maiko Yoshikawa, Yusuke Miyazaki, Hiroko Yoshinari, Yurie Satoh, Yasuyuki Todoroki, Kazuhisa Nakano, Shigeru Iwata, Kentaro Hanami, Shunsuke Fukuyo, Ippei Miyagawa, Minoru Satoh and Yoshiya Tanaka
  • Organizer: 2017アメリカリウマチ学会
  • Int'l Joint Research