Molecular mechanism and regulation of Sjogrens syndrome

• Project/Area Number: 24591439
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: University of Tsukuba
• Principal Investigator: SUMIDA Takayuki 筑波大学, 医学医療系, 教授 (00183054)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自己抗原 / 自己反応性T細胞 / 自己免疫性唾液腺炎 / ムスカリン作動性アセチルコリン受容体 / T細胞エピトープ / IFN-γ / IL-17 / RORγt / 自己免疫生唾液腺炎 / ムスカリン作働性アセチルコリン受容体

Outline of Final Research Achievements

To clarify the role of M3R immune response in the generation of Sjogren’s syndrome (SS), we established M3R induced sialadenitis (MIS) mouse model and examined whether M3R reactive T cells trigger the autoimmune sialadenitis or not. In the present study, we obtained evidence that M3R reactive Th1 and Th17 cells were associated with the generation of MIS, the major T cell epitopes of M3R were N1 and the first extra-cellular domain, and one of analogue ligand peptide (APL) coding N1 region could inhibit the induction of sialadenitis significantly. These observations should shed light on the antigen-specific therapy in SS near future.

Research Products

• [Journal Article] M3 muscarinic acetylcholine receptor reactive IL-17 producing T cells promotes development of Sjogren's syndrome like sialadenitis. (2015)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Hirota T, Kondo Y, Matsui M, Matsumoto I, Sumida T.
  • Journal Title: Mod Rheumatol. Volume: 25 Issue: 1 Pages: 158-60
  • DOI: 10.3109/14397595.2014.884683
  • Peer Reviewed
• [Journal Article] The regulation of antigen-specific CD4+ T cells suppresses Sjogren's syndrome-like M3R induced autoimmune sialadenitis in vivo. (2015)
  • Author(s): Asashima H, Tsuboi H, Iizuka M, Hirota T, Kondo Y, Matsumoto I, Sumida T.
  • Journal Title: Arthritis Rheum. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The role of M3 muscarinic acetylcholine receptor reactive T cells in Sjogren's syndrome: a critical review. (2014)
  • Author(s): Sumida T, Tsuboi H, Iizuka M, Hirota T, Asashima H, Matsumoto I.
  • Journal Title: J Autoimmun. Volume: 51 Pages: 44-50
  • DOI: 10.1016/j.jaut.2013.12.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The role of M3 muscarinic acetylcholine receptor reactive T cells in Sjogren's syndrome: A critical review. (2014)
  • Author(s): Sumida T, Tsuboi H, Iizuka M, Hirota T, Asashima H, Matsumoto I.
  • Journal Title: J Autoimmun Volume: in press
  • Peer Reviewed
• [Journal Article] M3 muscarinic acetylcholine receptor reactive IL-17- producing T cells promotes development of Sjogren's syndrome like sialadenitis. (2014)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Hirota T, Kondo Y, Matsui M, Matsumoto I, Sumida T.
  • Journal Title: Mod Rheumatol Volume: in press
  • Peer Reviewed
• [Journal Article] The crucial roles of IFN-g in the development of M3 muscarinic acetylcholine receptor induced Sjogren's syndrome-like sialadenitis. (2013)
  • Author(s): Iizuka M, Tsuboi H, Matsuo N, Kondo Y, Asashima H, Matsui M, Matsumoto I, Sumida T.
  • Journal Title: Mod Rheumatol Volume: 23(3) Pages: 614-616
  • Peer Reviewed
• [Journal Article] Overexpression of T-bet gene regulates murine autoimmune arthritis (2012)
  • Author(s): Kondo Y, Iizuka M, Wakamatsu E, Yao Z, TaharTsuboi H, Sugihara M, Hayashi T, Yoh K, Takahashi S, Matsumoto I, Sumida T.
  • Journal Title: Arthritis Rheum. Volume: 64(1) Pages: 162-172
  • Peer Reviewed
• [Journal Article] Analysis of IgG4 class switch-related molecules in IgG4-related disease. (2012)
  • Author(s): Tsuboi H, Matsuo N, Iizuka M, Tsuzuki S, Kondo Y, Tanaka A, Moriyama M, Matsumoto I, Nakamura S, Sumida T.
  • Journal Title: Arthritis Res.Ther. Volume: 14(4)
  • NAID: 120007137060
  • Peer Reviewed
• [Journal Article] Murine tumor necrosis factor α-induced adipose-related protein (tumor necrosis factor α-induced protein 9) deficiency leads to arthritis via interleukin-6 overproduction with enhanced NF-κB, STAT-3 signaling, and dysregulated apoptosis of macrophages. (2012)
  • Author(s): Inoue A, Matsumoto I, Tanaka Y, Umeda N, Tanaka Y, Mihara M, Takahashi S, Sumida T.
  • Journal Title: Arthritis Rheum. Volume: 64(12) Pages: 3877-3885
  • Peer Reviewed
• [Journal Article] Pathogenic role of anti-M3muscarinic acetylcholine receptor immune response in Sjögren’s syndrome. (2012)
  • Author(s): Sumida T, Iizuka M, Asashima H, Tsuboi H, Matsumoto I.
  • Journal Title: Presse Med. Volume: 41
  • Peer Reviewed
• [Journal Article] Activation of invariant NKT cells with glycolipid ligand α-galactosylceramide ameliorates glucose-6-phosphate isomerase peptide-induced arthritis. (2012)
  • Author(s): Horikoshi M, Goto D, Segawa S, Yoshiga Y, Iwanami K, Inoue A, Tanaka Y, Matsumoto I, Sumida T.
  • Journal Title: PLoS One Volume: 7(12)
  • NAID: 120007137100
  • Peer Reviewed
• [Presentation] The suppressive ability of altered peptide ligands to M3R reactive T cells in M3R induced autoimmune sialadenitis. (2014)
  • Author(s): Asashima H, Tsuboi H, Takahashi H, Hagiya C, Hirota T, Iizuka M, Kondo Y, Matsumoto I, Sumida T.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10
• [Presentation] Enforced RORγt expression in T cells induced spontaneous development. (2014)
  • Author(s): Iizuka M, Tsuboi H, Asashima H,Hirota T, Takahashi H, Kondo Y, Takahashi S, Matsumoto I, Sumida T.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10
• [Presentation] APL投与によるM3R誘導自己免疫性唾液腺炎の抗原特異的制御 (2014)
  • Author(s): 浅島弘充、坪井洋人、飯塚麻菜、高橋広行、萩谷千裕、近藤裕也、松本功、住田孝之
  • Organizer: 第23回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-13
• [Presentation] 唾液腺炎発症におけるTh17マスター転写因子RORγtの機能解析 (2014)
  • Author(s): 飯塚麻菜、坪井洋人、浅島弘充、廣田智哉、近藤裕也、高橋智、松本功、住田孝之
  • Organizer: 第23回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-12
• [Presentation] The suppressive ability of altered peptide ligands to M3R induced antoimmune sialoadenitis in vivo. (2014)
  • Author(s): Asashima H, Tsuboi H, Iizuka M, Hagiya C, Hirota T, Kondo Y, Matsumoto I, Sumida T.
  • Organizer: The EULAR Annual European Congress of Rheumatology
  • Place of Presentation: paris
  • Year and Date: 2014-06-12
• [Presentation] RORgt inhibit the expression of Foxp3 in CD4+CD25+ T cells in spontaneous development Sjogren’s syndrome like sialadenitis (2014)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Hirota T, Kondo Y, Takahashi S, Matsumoto I, Sumida T.
  • Organizer: 第58回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-25
• [Presentation] シェーグレン症候群様唾液腺炎発症モデルマウスにおけるRORγtの病因的役割 (2013)
  • Author(s): 飯塚麻菜、坪井洋人、浅島弘充、近藤裕也、高橋智、松本功、住田孝之
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都府）
• [Presentation] M3R誘導自己免疫性唾液腺炎モデルマウスにおけるM3R反応性T細胞のエピトープ解析 (2013)
  • Author(s): 浅島弘充、坪井洋人、松尾直美、飯塚麻菜、近藤裕也、松本功、住田孝之
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都府）
• [Presentation] Analysis of molecular mechanism in IgG4-related disease: Comparison with Sjogren’s syndrome. (2013)
  • Author(s): Tsuboi H, Nakai Y, Iizuka M, Asashima H, Kondo Y, Tanaka A, Moriyama M, Matsumoto I, Yoshihara T, Nakamura S, Abe K, Sumida T.
  • Organizer: The EULAR Annual European Congress of Rheumatology 2013
  • Place of Presentation: IFEMA（Madrid）Spain
• [Presentation] RORγt transgenic mice developed spontaneous sialadenitis like Sjogren’s syndrome. (2013)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Kondo Y, Takahashi S, Matsumoto I, Sumida T.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: MiCo（Milano）Italy
• [Presentation] Pathological role of M3 muscarinic acethylcholine receptor reactive immune response in development of autoimmune sialadenitis murine model like Sjogren's syndrome. (2013)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Hirota T, Kondo Y, Matsumoto I, Sumida T.
  • Organizer: 12th International Sjogren’s Syndrome Synposium
  • Place of Presentation: Kyoto Hotel Okura（Kyoto）Japan
• [Presentation] Clinical significance of anti-M3 muscarinic acetylcholine receptor antibodies in patients with primary biliary cirrhosis. (2013)
  • Author(s): Tsuboi H, Ohira H, Asashima H, Tsuzuki S, Iizuka M, Kondo Y, Matsumoto I, Sumida T.
  • Organizer: 12th International Sjogren’s Syndrome Synposium
  • Place of Presentation: Kyoto Hotel Okura（Kyoto）Japan
• [Presentation] Pathogenesis of spontaneous sialadenitis in orphan nuclear receptor RORgt transgenic mice (2012)
  • Author(s): Iizuka M, Tsuboi H, Kondo Y, Takahiashi S, Matsumoto I, Sumida T.
  • Organizer: 56回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
• [Presentation] シェーグレン症候群 VS IgG4関連疾患 (2012)
  • Author(s): 住田 孝之
  • Organizer: 日本内科学会生涯教育講演会（招待講演）
  • Place of Presentation: 東京国際 フォーラム（東京）
• [Presentation] 自己免疫疾患の発症機序と抗原特異的制御 (2012)
  • Author(s): 住田 孝之、坪井 洋人、飯塚 麻菜、近藤 裕也、松本 功
  • Organizer: 第40回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（東京）
• [Presentation] Spontaneous sialadenitis like Sjögren’s syndrome in orphan nuclear receptor gt (RORgt) transgenic mice. (2012)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Kondo Y, Takahashi S, Matsumoto I, Sumida T.
  • Organizer: 2012 ANNUAL SCIENTIFIC MEETING on the College of Rheumatology
  • Place of Presentation: ワシントンD.C.
• [Presentation] A crucial role of orphan nuclear receptor gt (RORgt) overexpressed CD4+ T cells in sialadenitis like Sjögren’s syndrome. (2012)
  • Author(s): Iizuka M, Tsuboi H, Asashima H, Koundo Y, Takahashi S, Matsumoto I, Sumida T.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Book] シェーグレン症候群の診断と治療マニュアル改訂第2版 (2014)
  • Author(s): 住田 孝之
  • Total Pages: 280
  • Publisher: 診断と治療社
• [Book] EXPERT 膠原病・リウマチ改訂第3版 (2013)
  • Author(s): 住田 孝之
  • Total Pages: 432
  • Publisher: 診断と治療社
• [Remarks] 筑波大学 膠原病リウマチアレルギー内科
  • URL: http://www.md.tsukuba.ac.jp/clinical-med/rheumatology/
• [Remarks] 筑波大学膠原病内科
  • URL: http://www.md.tsukuba.ac.jp/clinical-med/rheumatology/