Establishment of iPS cell-based strategy for elucidating the pathogenesis of autoimmune diseases and discovery of therapeutic targets

• Project/Area Number: 20K08800
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: The University of Tokyo
• Principal Investigator: Shoda Hirofumi 東京大学, 医学部附属病院, 准教授 (20529036)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 全身性エリテマトーデス / iPS細胞 / インターフェロン / 疾患感受性遺伝子変異 / フラグメント分子軌道法 / 樹状細胞 / rare variant / 創薬

Outline of Research at the Start

SLEの遺伝的要因が免疫細胞における遺伝子発現、生物学的機能、疾患病態へ及ぼす影響及びその作用機序について疾患特異的iPS細胞を用いた解析手法を確立し、病態解明、新規創薬標的同定、及び創薬の推進を目的とする。SLEにおけるrare variantsの候補を同定し、新規同定されたrare variantsについて、ゲノム編集で変異を導入・修正したiPS細胞を用いて解析する。またiPS細胞を用いた新規創薬スクリーニングを行う。遺伝学的研究と疾患特異的iPS細胞研究を組み合わせた本研究の手法により、SLE病態を解明し、創薬を推進することができると考える。

Outline of Final Research Achievements

The aim of this study is to elucidate the pathogenesis of autoimmune diseases and to establish basic technologies and strategies for drug discovery by applying iPS cells. Using iPS cells established from systemic lupus erythematosus (SLE) patients, we performed functional analysis of newly identified rare variants of OASL gene. In particular, we created wild type and mutated iPS cell strains by genome editing. OASL variants were found to enhance the type I interferon (IFN) response to dsRNA stimulation in dendritic cells, suggesting a contribution to SLE pathogenesis. This study is expected to establish a technical fundation for studying the involvement of rare variants in autoimmune diseases and lead to future drug discovery research.

Academic Significance and Societal Importance of the Research Achievements

iPS細胞を活用した自己免疫疾患研究および創薬研究の技術的基盤の開発が本研究の最も重要な意義である。SLEに関連するOASL遺伝子変異の新規同定は、SLE病態の解明および新規創薬標的として、臨床応用につながる可能性がある。またOASL遺伝子変異はSLE患者においてOdds ratio 8と高頻度で認められたが、これは従来のSNPにおけるリスクよりかなり高い寄与が関与される。この結果は、特定の患者における自己免疫疾患の遺伝的メカニズムにおいてrare variantはより強く関与している可能性を示唆し、自己免疫性疾患を遺伝学的に理解するうえで重要な知見の可能性がある。

Research Products

• [Journal Article] Distinct transcriptome architectures underlying lupus establishment and exacerbation (2022)
  • Author(s): Nakano Masahiro et al.
  • Journal Title: Cell Volume: 185 Issue: 18 Pages: 3375-3389.e21
  • DOI: 10.1016/j.cell.2022.07.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum extracellular traps associate with the activation of myeloid cells in SLE patients with the low level of anti-DNA antibodies (2022)
  • Author(s): Hanata Norio、Ota Mineto、Tsuchida Yumi、Nagafuchi Yasuo、Okamura Tomohisa、Shoda Hirofumi、Fujio Keishi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-23076-1
• [Journal Article] Autotaxin is a potential link between genetic risk factors and immunological disturbances of plasmacytoid dendritic cells in systematic lupus erythematosus (2022)
  • Author(s): Tsuchida Yumi、Shoda Hirofumi、Nakano Masahiro、Ota Mineto、Okamura Tomohisa、Yamamoto Kazuhiko、Kurano Makoto、Yatomi Yutaka、Fujio Keishi、Sawada Tetsuji
  • Journal Title: Lupus Volume: 31 Issue: 13 Pages: 1578-1585
  • DOI: 10.1177/09612033221128494
  • Peer Reviewed
• [Journal Article] Dysregulation of the gene signature of effector regulatory T cells in the early phase of systemic sclerosis (2022)
  • Author(s): Kobayashi Satomi、Nagafuchi Yasuo、Okubo Mai、Sugimori Yusuke、Hatano Hiroaki、Yamada Saeko、Nakano Masahiro、Yoshida Ryochi、Takeshima Yusuke、Ota Mineto、Tsuchida Yumi、Iwasaki Yukiko、Setoguchi Keigo、Kubo Kanae、Okamura Tomohisa、Yamamoto Kazuhiko、Shoda Hirofumi、Fujio Keishi
  • Journal Title: Rheumatology Volume: Online ahead of print Issue: 10 Pages: 4163-4174
  • DOI: 10.1093/rheumatology/keac031
  • Peer Reviewed
• [Journal Article] Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci (2022)
  • Author(s): Yamaguchi Kensuke、Ishigaki Kazuyoshi、Suzuki Akari、Tsuchida Yumi、Tsuchiya Haruka、Sumitomo Shuji、Nagafuchi Yasuo、Miya Fuyuki、Tsunoda Tatsuhiko、Shoda Hirofumi、Fujio Keishi、Yamamoto Kazuhiko、Kochi Yuta
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 4659-4659
  • DOI: 10.1038/s41467-022-32358-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Control of naive and effector CD4 T cell receptor repertoires by rheumatoid-arthritis-risk HLA alleles (2022)
  • Author(s): Nagafuchi Yasuo、Ota Mineto、Hatano Hiroaki、Inoue Mariko、Kobayashi Satomi、Okubo Mai、Sugimori Yusuke、Nakano Masahiro、Yamada Saeko、Yoshida Ryochi、Tsuchida Yumi、Iwasaki Yukiko、Shoda Hirofumi、Okada Yukinori、Yamamoto Kazuhiko、Ishigaki Kazuyoshi、Okamura Tomohisa、Fujio Keishi
  • Journal Title: Journal of Autoimmunity Volume: 133 Pages: 102907-102907
  • DOI: 10.1016/j.jaut.2022.102907
  • Peer Reviewed
• [Journal Article] Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases (2021)
  • Author(s): Ota M, Nagafuchi Y, Hatano H, Ishigaki K, Terao C, Takeshima Y, Yanaoka H, Kobayashi S, Okubo M, Shirai H, Sugimori Y, Maeda J, Nakano M, Yamada S, Yoshida R, Tsuchiya H, Tsuchida Y, Iwasaki Y, Sumitomo S, Shoda H, Kochi Y, Okada Y, Yamamoto K, Okamura T, Fujio K, et al.
  • Journal Title: Cell Volume: 184 Issue: 11 Pages: 1-16
  • DOI: 10.1016/j.cell.2021.03.056
  • Peer Reviewed
• [Journal Article] Identifying the most influential gene expression profile in distinguishing ANCA-associated vasculitis from healthy controls. (2021)
  • Author(s): Yanaoka H, Nagafuchi Y, Hanata N, Takeshima Y, Ota M, Suwa Y, Shirai H, Sugimori Y, Okubo M, Kobayashi S, Hatano H, Yamada S, Tsuchida Y, Iwasaki Y, Sumitomo S, Shoda H, Okada M, Okamura T, Yamamoto K, Fujio K.
  • Journal Title: J Autoimmun. Volume: 119 Pages: 102617-102617
  • DOI: 10.1016/j.jaut.2021.102617
  • Peer Reviewed
• [Journal Article] Serum Amphiregulin and Heparin-Binding Epidermal Growth Factor as Biomarkers in Patients with Idiopathic Inflammatory Myopathy (2021)
  • Author(s): Hanata Norio、Nagafuchi Yasuo、Sugimori Yusuke、Kobayashi Satomi、Tsuchida Yumi、Iwasaki Yukiko、Shoda Hirofumi、Fujio Keishi
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 16 Pages: 3730-3730
  • DOI: 10.3390/jcm10163730
  • Peer Reviewed / Open Access
• [Journal Article] Integrated bulk and single-cell RNA-sequencing identified disease-relevant monocytes and a gene network module underlying systemic sclerosis. (2021)
  • Author(s): Kobayashi S, Nagafuchi Y, Okubo M, Sugimori Y, Shirai H, Hatano H, Junko M, Yanaoka H, Takeshima Y, Ota M, Iwasaki Y, Sumitomo S, Okamura T, Yamamoto K, Shoda H, Fujio K.
  • Journal Title: J Autoimmun Volume: 116 Pages: 102547-102547
  • DOI: 10.1016/j.jaut.2020.102547
  • Peer Reviewed / Open Access
• [Journal Article] Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: a case-control study. (2021)
  • Author(s): Shimizu T, Nagafuchi Y, Harada H, Tsuchida Y, Tsuchiya H, Hanata N, Tateishi S, Kanda H, Sumitomo S, Shoda H, Yamamoto K, Fujio K.
  • Journal Title: Mod Rheumatol. Volume: 31 Issue: 1 Pages: 127-132
  • DOI: 10.1080/14397595.2020.1719596
  • Peer Reviewed
• [Journal Article] Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and Exacerbates the TLR7 Agonist-Induced Lupus Mice (2020)
  • Author(s): Norio Hanata, Hirofumi Shoda, Hiroaki Hatano, Yasuo Nagafuchi, Toshihiko Komai, Tomohisa Okamura, Akari Suzuki, I Ketut Gunarta, Katsuji Yoshioka, Kazuhiko Yamamoto, Keishi Fujio
  • Journal Title: Frontiers in immunology Volume: 11 Pages: 1095-1095
  • DOI: 10.3389/fimmu.2020.01095
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elevation of cytomegalovirus antigenemia predicts serious infection and death in patients receiving immunosuppressive therapies for autoimmune diseases. (2020)
  • Author(s): Yoshihara R, Komai T, Shoda H, Fujio K.
  • Journal Title: Int J Rheum Dis. Volume: 23 Issue: 11 Pages: 1534-1540
  • DOI: 10.1111/1756-185x.13990
  • Peer Reviewed
• [Presentation] 膠原病の機能ゲノム学 (2022)
  • Author(s): 庄田 宏文
  • Organizer: 第86回日本皮膚科会学会東部支部学術集会
  • Invited
• [Presentation] 疾患特異的iPS細胞による臨床免疫研究 (2021)
  • Author(s): 庄田宏文
  • Organizer: 第65回日本リウマチ学会
  • Invited
• [Presentation] SLE患者由来iPS細胞を用いたrare variantsの探索と免疫学的機序の解明 (2021)
  • Author(s): 夏本文輝、庄田宏文
  • Organizer: 第49回日本臨床免疫学会
• [Presentation] Functional analysis of rare variants associated with SLE using patients derived iPS cells (2021)
  • Author(s): Bunki Natsumoto, Hirofumi Shoda, Yasuo Nagafuchi, Makoto Otsu, Kazuhiko Yamamoto, Hideki Taniguchi, Keishi Fujio
  • Organizer: 第50回日本免疫学会
• [Presentation] 疾患特異的iPS細胞による全身性エリテマトーデス研究 (2020)
  • Author(s): 庄田宏文
  • Organizer: 第48回日本臨床免疫学会総会
  • Invited
• [Presentation] Identification and functional analysis of SLE rare variants using patients-derived iPS cells (2020)
  • Author(s): 夏本文輝、庄田宏文、藤尾圭志
  • Organizer: 第64回日本リウマチ学会学術集会