Molecular mechanism and regulation in patients with Sjogren's syndrome

• Project/Area Number: 17K09966
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Tsukuba
• Principal Investigator: Sumida Takayuki 筑波大学, 医学医療系, 教授 (00183054)
• 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: シェーグレン症候群 / Th1細胞 / Treg細胞 / iPS細胞 / ムスカリン作動性アセチルコリン受容体3 / T細胞抗原受容体 / T細胞機能転換分子 / 膠原病学 / ムスカリン作働性アセチルコリン受容体3 / T細胞昨日転換分子 / ムスカリン作動性アセチルコリン受容体 / T細胞抗原病受容体

Outline of Final Research Achievements

M3R reactive Th1 cells play a crucial role in the generation of Sjogren’s syndrome(SS). In the present study, our object is to clarify the molecules which are able to change Th1 cells to Treg cells. We already generated several T-iPS cells from M3R reactive Th1 cells in patients with SS, induced DC cells from their T-iPS cells, and differentiated CD34+CD43+ progenitor stem cells form T-iPS cells in vitro. In future, we will differentiate CD34+CD43+ cells to Treg cells, and then elucidate the functional molecules which could change from Th1 cells to Treg cells. The candidate molecules should shed light on the new therapeutic approach to SS.

Academic Significance and Societal Importance of the Research Achievements

シェーグレン症候群(SS)は、ドライアイやドライマウスだけではなく全身の臓器病変を生じる自己免疫疾患である。全身の臓器病変に対する治療は、ステロイドや免疫抑制薬が主体であり、副作用として感染症、悪性腫瘍、生活習慣病、骨粗鬆症などを合併し、QOLの低下が起きてしまうことが問題となっている。本研究の意義は、SSの発症機序に基づいた治療戦略を開発するため、副作用のない疾患特異的な治療薬が創薬され患者さんのQOLの向上が期待されることである。

Research Products

• [Journal Article] Allergin-1 immunoreceptor suppresses house dust mite-induced allergic airway inflammation. (2020)
  • Author(s): Miki H, Tahara-Hanaoka S, Almeida MS, Hitomi K, Shibagaki S, Kanemaru K, Lin YH, Iwata K, Miyake S, Shibayama S, Sumida T, Shibuya K, Shibuya A
  • Journal Title: Journal of Immunology Volume: 204(4) Issue: 4 Pages: 753-762
  • DOI: 10.4049/jimmunol.1900180
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RORγt antagonist improves Sj?gren's syndrome‐like sialadenitis through downregulation of CD25 (2020)
  • Author(s): Ono Yuko、Tsuboi Hiroto、Moriyama Masafumi、Asashima Hiromitsu、Kudo Hanae、Takahashi Hiroyuki、Honda Fumika、Abe Saori、Kondo Yuya、Takahashi Satoru、Matsumoto Isao、Nakamura Seiji、Sumida Takayuki
  • Journal Title: Oral Diseases Volume: - Issue: 4 Pages: 766-777
  • DOI: 10.1111/odi.13255
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transgenic rice seeds expressing altered peptide ligands against the M3 muscarinic acetylcholine receptor suppress experimental sialadenitis-like Sjogren’s syndrome (2019)
  • Author(s): Kudo Hanae、Tsuboi Hiroto、Asashima Hiromitsu、Takahashi Hiroyuki、Ono Yuko、Abe Saori、Honda Fumika、Kondo Yuya、Wakasa Yuhya、Takaiwa Fumio、Takano Makoto、Matsui Minoru、Matsumoto Isao、Sumida Takayuki
  • Journal Title: Modern Rheumatology Volume: - Issue: 5 Pages: 1-10
  • DOI: 10.1080/14397595.2019.1664368
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis (2019)
  • Author(s): Izumi Kurata, Isao Matsumoto, Ayako Ohyama, Atsumu Osada, Hiroshi Ebe, Hoshimi Kawaguchi, Shunta Kaneko, Yuya Kondo, Hiroto Tsuboi, Azusa Tomioka, Hiroyuki Kaji, Takayuki Sumida
  • Journal Title: Annals of the Rheumatic Diseases Volume: 78 Issue: 11 Pages: 1488-1496
  • DOI: 10.1136/annrheumdis-2019-215195
  • Peer Reviewed
• [Journal Article] PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes (2019)
  • Author(s): Akizuki S, Ishigaki K, Kochi Y, Law SM, Matsuo K, Ohmura K, Suzuki A, Nakayama M, Iizuka Y, Koseki H, Ohara O, Hirata J, Kamatani Y, Matsuda F, Sumida T, Yamamoto K, Okada Y, Mimori T, Terao C.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 78 Issue: 4 Pages: 509-518
  • DOI: 10.1136/annrheumdis-2018-214116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease (2018)
  • Author(s): Segawa Seiji、Kondo Yuya、Nakai Yuji、Iizuka Akira、Kaneko Shunta、Yokosawa Masahiro、Furuyama Kotona、Tsuboi Hiroto、Goto Daisuke、Matsumoto Isao、Sumida Takayuki
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 12 Pages: 3534-3545
  • DOI: 10.4049/jimmunol.1800667
  • Peer Reviewed / Open Access
• [Journal Article] Clinical practice guideline for Sj?gren’s syndrome 2017 (2018)
  • Author(s): Sumida Takayuki、Azuma Naoto、Moriyama Masafumi、Takahashi Hiroyuki、Asashima Hiromitsu、Honda Fumika、Abe Saori、Ono Yuko、Hirota Tomoya、Hirata Shintaro、Tanaka Yoshiya、Shimizu Toshimasa、Nakamura Hideki、Kawakami Atsushi、Sano Hajime、Ogawa Yoko、Tsubota Kazuo、Ryo Koufuchi、Saito Ichiro、Tsuboi Hiroto
  • Journal Title: Modern Rheumatology Volume: 28 Issue: 3 Pages: 383-408
  • DOI: 10.1080/14397595.2018.1438093
  • Peer Reviewed / Open Access
• [Journal Article] Splicing variant ofWDFY4augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis (2018)
  • Author(s): Kochi Yuta et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 77 Issue: 4 Pages: 602-611
  • DOI: 10.1136/annrheumdis-2017-212149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis (2018)
  • Author(s): Kondo Yuya、Yokosawa Masahiro、Kaneko Shunta、Furuyama Kotona、Segawa Seiji、Tsuboi Hiroto、Matsumoto Isao、Sumida Takayuki
  • Journal Title: Arthritis Rheumatol Volume: in press Issue: 5 Pages: 653-661
  • DOI: 10.1002/art.40398
  • NAID: 120007134136
  • Peer Reviewed / Open Access
• [Journal Article] Functional Analysis of Dendritic Cells Generated from T-iPSCs from CD4+ T Cell Clones of Sj?gren's Syndrome (2017)
  • Author(s): Iizuka-Koga Mana、Asashima Hiromitsu、Ando Miki、Lai Chen-Yi、Mochizuki Shinji、Nakanishi Mahito、Nishimura Toshinobu、Tsuboi Hiroto、Hirota Tomoya、Takahashi Hiroyuki、Matsumoto Isao、Otsu Makoto、Sumida Takayuki
  • Journal Title: Stem Cell Reports Volume: 8 Issue: 5 Pages: 1155-1163
  • DOI: 10.1016/j.stemcr.2017.04.010
  • Peer Reviewed / Open Access
• [Presentation] 高橋広行、坪井洋人、瀬川誠司、浅島弘充、安部沙織、工藤華枝、小野由湖、本田文香、近藤裕也、松本功、大津真、住田孝之 (2019)
  • Author(s): シェーグレン症候群におけるM3R反応性Th1細胞由来T-iPS細胞を応用した治療戦略
  • Organizer: 第63回日本リウマチ学会総会・学術集会
• [Presentation] シェーグレン症候群におけるM3R反応性Th1細胞由来T-iPS細胞を応用した治療戦略 (2019)
  • Author(s): 高橋広行、坪井洋人、安部沙織、小野由湖、本田文香、安藤美樹、近藤裕也、松本功、大津真、住田孝之
  • Organizer: 第28回シェーグレン症候群学会学術集会
• [Presentation] Detection of circulating M3 muscarinic acetylcholine receptor reactive Th17 cells in patients with primary Sjogren's syndrome. (2019)
  • Author(s): Abe S, Tsuboi H, Kudo H, Ono Y, Honda F, Kurata I, Yagishita M, Takahashi H, Yokosawa M, Kondo Y, Matsumoto I, Sumida T.
  • Organizer: 第63回日本リウマチ学会総会・学術集会
• [Presentation] シェーグレン症候群患者末梢血中におけるM3ムスカリン作働性アセチルコリン受容体(M3R)反応性Th17細胞 (2019)
  • Author(s): 安部沙織、坪井洋人、本田文香、小野由湖、高橋広行、近藤裕也、松本功、住田孝之
  • Organizer: 第28回シェーグレン症候群学会学術集
• [Presentation] Detection and Clinical Significance of Circulating M3 Muscarinic Acetylcholine Receptor Reactive Th17 Cells in Patients with Primary Sjogren’s Syndrome. (2019)
  • Author(s): Abe S, Tsuboi H, Ono Y, Honda F, Kurata I, Yagishita M, Ohyama A, Takahashi H, Matsumoto A, Sumida T.
  • Organizer: The 2019 ACR/ARHP Annual Meeting in Atlanta
  • Int'l Joint Research
• [Presentation] A potential role of NR4A2 overexpression in CD4+ T cells in the pathogenesis of Sjogren's Syndrome. (2018)
  • Author(s): Takahashi H, Tsuboi H, Asashima H, Hirota T, Kondo Y, Matsumoto I, Sumida T.
  • Organizer: 14th International Symposium on Sjogren's Syndrome
  • Int'l Joint Research
• [Presentation] RORγt antagonis suppressed spontaneous sialadenitis in RORγt transgenic mice via inhibition of IL-17 production with increase of regulatory T cells. (2018)
  • Author(s): Ono Y, Tsuboi H, Moriyama M, Asashima H, Kudo H, Takahashi H, Kondo Y, Matsumoto I, Nakaramura S, Sumida T.
  • Organizer: 14th International Symposium on Sjogren's Syndrome
  • Int'l Joint Research
• [Presentation] Analysis of suppressive ability and its mechanisms of rice seeds expressing altered peptide ligands against M3 muscarinic acetylcholine receptor (M3R) induced sialadenitis. (2018)
  • Author(s): Kudo H, Tsuboi H, Asashima H, Takahashi H, Ono Y, Abe S, Kondo Y, Wakasa Y, Takaiwa F, Matsumoto I, Sumida T.
  • Organizer: 14th International Symposium on Sjogren's Syndrome
  • Int'l Joint Research
• [Presentation] シェーグレン症候群患者のCD4陽性T細胞におけるNR4A2発現亢進とTh17分化 (2018)
  • Author(s): 高橋広行、坪井洋人、浅島弘充、近藤裕也、松本功、住田孝之
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] M3ムスカリン作働性アセチルコリン受容体(M3R) 誘導性唾液腺炎に対するaltered peptide ligand (APL)発現米の抑制効果と 作用メカニズムの解析 (2018)
  • Author(s): 工藤華枝、坪井洋人、浅島弘充、髙橋広行、小野由湖、安部沙織、近藤裕也、若佐雄也、高岩文雄、松本功、住田孝之
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] シェーグレン症候群 vs IgG4関連疾患：似て非なる病 (2018)
  • Author(s): 住田孝之
  • Organizer: 第27回シェーグレン症候群学会
  • Invited
• [Presentation] The functional analysis of dendritic cells developed from T-iPS cells-derived from a single CD4+ T cell of Sjogren’s syndrome, (2017)
  • Author(s): Asashima H, Iizuka M, Ando M, Lai C-Y, Tsuboi H, Hirota T, Takahashi H, Matsumoto I, Otsu M, Sumida T.
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] The functional analysis of dendritic cells developed from T-iPS cells-derived from a single CD4+ T cell of Sjogren’s syndrome (2017)
  • Author(s): Asashima H, Iizuka M, Ando M, Lai C-Y, Tsuboi H, Hirota T, Takahashi H, Matsumoto I, Otsu M, Sumida T
  • Organizer: The 7th East Asian Group of Rheumatology
  • Int'l Joint Research
• [Presentation] シェーグレン症候群患者由来T-iPS細胞から誘導した樹状細胞の機能解析 (2017)
  • Author(s): 浅島弘充、飯塚麻菜、安藤美樹、頼貞儀、坪井洋人、高橋広行、松本功、大津真、住田孝之
  • Organizer: 第26回シェーグレン症候群学会学術集会
• [Book] シェーグレン症候群の診断と治療マニュアル (2018)
  • Author(s): 竹内勤、川上純、住田孝之
  • Total Pages: 268
  • Publisher: 診断と治療社
  • ISBN: 9784787823694