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Study of connective tissue disease-associated interstitial lung disease (CTD-ILD) with single-cell RNA sequencing

Research Project

Project/Area Number 19K24000
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0904:Internal medicine of the bio-information integration and related fields
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Fujii Wataru  京都府立医科大学, 医学部附属病院, 専攻医 (60755643)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords膠原病関連間質性肺疾患 / シングルセルRNA-seq / 気管支肺胞洗浄液 / 肺胞マクロファージ / 関節リウマチ / シェーグレン症候群 / 全身性強皮症 / 膠原病関連肺疾患 / シングルセルRNAシークエンス / トランスクリプトーム / フローサイトメトリー
Outline of Research at the Start

関節リウマチ、多発性筋炎・皮膚筋炎、シェーグレン症候群、全身性強皮症などの膠原病ではしばしば難治性の間質性肺疾患を合併し膠原病関連間質性肺疾患と呼ばれるが、その分子病態は十分解明されておらず特異的治療法も確立されていない。近年発展した研究手法であるシングルセルRNAシークエンスは一細胞毎の全遺伝情報(トランスクリプトーム)を得ることで疾患における細胞集団の変化および各細胞の遺伝子発現変化を明らかにできる。本研究では膠原病関連間質性肺疾患患者の気管支肺胞洗浄液および血液検体のシングルセルRNAシークエンスを行うことで、各疾患の分子病態の解明および新たな治療標的の発見を目指す。

Outline of Final Research Achievements

We performed single-cell RNA-seq and ELISA for bronchoalveolar lavage fluid (BALF) and peripheral blood from 5 rheumatoid arthritis (RA), 4 dermatomyositis (DM), 2 systemic sclerosis (SSc), 4 Sjogren syndrome (SjS) and 7 idiopathic interstitial pneumonia (IIP) patients. We found neutrophils increased in BALF of RA patients, while lymphocytes increased in BALF of DM and SjS patients. The concentrations of IL-12p40 and CXCL10, both are associated with lymphocyte chemotaxis, were increased in BALF of DM and SJS patients. By using scRNA-seq, we found 14 different phenotypes of alveolar macrophages in CTD-ILD patients.
In conclusion, neutrophils increase in BALF of RA patients while lymphocytes increase in those of DM and SjS patients, possibly because of altered chemokine levels in BALF. Alveolar macrophages showed different phenotypes in CTD-ILD patients from those in IIP patients, indicating altered functions of these cells in CTD-ILD.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチ、シェーグレン症候群、多発性筋炎・皮膚筋炎、全身性強皮症などの膠原病ではしばしば難治性の間質性肺疾患を合併し膠原病関連間質性肺疾患(CTD-ILD)と呼ばれるが、その分子病態は十分解明されておらず特異的治療法も確立されていない。本研究によって、CTD-ILDにおける各基礎疾患毎の分子病態の特徴が明らかとなり、病態解明および間質性肺疾患の鑑別診断のための臨床応用が期待できる。
また今回確立した気管支肺胞洗浄液と血液検体の網羅的遺伝子解析による研究手法は、CTD-ILDのみならず種々の呼吸器・免疫疾患の病態解明に適用可能であり今後の難治性呼吸器・免疫疾患研究への応用が期待できる。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report

Research Products

(2 results)

All 2021 2020

All Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] Altered cellular phenotypes in bronchoalveolar lavage fluid of connective tissue disease-associated interstitial lung disease with single-cell RNA sequencing2021

    • Author(s)
      Wataru Fujii, Aki Sakashita, Aiko Hirano, Hideaki Sofue, Kazuki Fujioka, Makoto Wada, Masataka Kohno, Yutaka Kawahito
    • Organizer
      第65回日本リウマチ学会総会・学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Immune cell landscape of bronchoalveolar lavage fluid from connective tissue disease-associated interstitial pneumonia patients with single-cell RNA sequencing2020

    • Author(s)
      Wataru Fujii, Aiko Hirano, Aki Sakashita, Tatsuya Imabayashi, Yoshiko Kaneko, Taisuke Tsuji, Makoto Wada, Masataka Kohno, Noriya Hiraoka, Koichi Takayama, Yutaka Kawahito
    • Organizer
      22nd Asia-Pacific League of Associations for Rheumatology Virtual Congress
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research

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Published: 2019-09-03   Modified: 2022-01-27  

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