シェーグレン症候群発症の分子機構:M3Rに対する免疫応答解析

2008 年度 研究成果報告書

• 研究課題/領域番号: 19591151
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 膠原病・アレルギー・感染症内科学
• 研究機関: 筑波大学
• 研究代表者: 住田 孝之 筑波大学, 大学院・人間総合科学研究科, 教授 (00183054)
• 研究期間 (年度): 2007 – 2008
• キーワード: シェーグレン症候群 / T細胞 / 自己抗体 / T細胞エピトープ / アナログペプチド

研究概要

シェーグレン症候群(SS)の発症機序の解明、それに基づく抗原特異的治療の開発を目的として、ムスカリン作働性アセチルコリン受容体3(M3R)に対する免疫応答を明らかにすることを目的とした。その結果、SS患者末梢血中には多彩なB細胞エピトープに対する抗M3R抗体が存在し、唾液分泌に対する機能はM3R上のB細胞エピトープにより異なる事が明らかになった。さらに、M3Rペプチドを免疫することによりSSに類似した唾液腺炎を発症するモデルマウスの作成に成功した。

研究成果

• [雑誌論文] B cells play a crucial role as antigen-presenting cells and collaborate with inflammatory cytokines in glucose-6-phosphate isomerase-induced arthritis (2009)
  • 著者名/発表者名: Tanaka-Watanabe Y, Matsumoto I, Iwanami K, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 雑誌名: Clin. Exp. Immunol 155 ページ: 285-294
  • 査読あり
• [雑誌論文] Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population (2009)
  • 著者名/発表者名: Ito I, Kawasaki A, Ito S, Hayashi T, Goto D, Matsumoto I, Tsutsumi A, Hom G, Graham RR, Takasaki Y, Hashimoto H, Ohashi J, Behrens TW, Sumida T, Tsuchiya N.
  • 雑誌名: Arthritis Rheum 60 ページ: 553-8
  • 査読あり
• [雑誌論文] Arthritogenic T cell epitope in glucose-6-phosphate isomerase (GPI)-induced arthritis (2008)
  • 著者名/発表者名: Iwanami K, Matsumoto I, Tanaka Y, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 雑誌名: Arthritis Res Ther 10(Epub) ページ: R130
  • 査読あり
• [雑誌論文] Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population : a case-control association study of STAT1-STAT4 region (2008)
  • 著者名/発表者名: Arthritis Res TherKawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham R R, Hom G, Takasaki Y, Hashimoto H, Behrens T W, Sumida T and Tsuchiya N.
  • 雑誌名: Arthritis Res Ther 10(Epub) ページ: R113
  • 査読あり
• [雑誌論文] Muscarinic-3 acetylcholine receptor autoantibody in patients with systemic sclerosis : contribution to severe gastrointestinal tract dysmotility (2008)
  • 著者名/発表者名: Kawaguchi Y, Wakamatsu E, Matsumoto I, Nishimagi E, Kamatani N, Satoh T, Kuwana M, Sumida T, Hara M.
  • 雑誌名: Ann. Rheum. Dis. Sep1.Epub ページ: 1
• [雑誌論文] Therapeutic effects of antibodies to TNF alpha and IL-6 and CTLA-4 Ig in mice with glucose-6-phosphate isomerase-induced arthritis (2008)
  • 著者名/発表者名: Matsumoto I, Zhang H, Yasukochi T, Iwanami K, Tanaka Y, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 雑誌名: Arthritis Res Ther 10(Epub) ページ: R66
  • 査読あり
• [雑誌論文] Invariant NKT cells produce IL-17 through IL-23-dependent and-independent pathways with potential modulation of Th17 response in collagen-induced arthritis (2008)
  • 著者名/発表者名: Yoshiga Y, Goto D, Segawa S, Ohnishi Y, I. Yoshiga Y, Goto D, Segawa S, Ohnishi Y, I. Matsumoto I, Ito S, Tsutsumi A, Taniguchi M, Sumida T.
  • 雑誌名: Int. J. Mol. Med 22 ページ: 369-374
  • 査読あり
• [雑誌論文] Crucial role of IL-6/IL-17 cytokine axis in the induction of arthritis by glucose-6-phosphate-isomerase (2008)
  • 著者名/発表者名: Iwanami K, Matsumoto I, Watanabe Y, Mihara M, Ohsugi Y, Mamura M, Goto D, Ito S, Tsutsumi A, Kishimoto T, Sumida T.
  • 雑誌名: Arthritis Rheum 58 ページ: 754-763
  • 査読あり
• [雑誌論文] High prevalence of autoantibodies to muscarinic-3 acetylcholine receptor in patients with juvenile-onset Sjogren's syndrome (2008)
  • 著者名/発表者名: Nakamura Y, Wakamatsu E, Matsumoto I, Tomiita M, Kohno Y, Mori M, Yokota S, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 雑誌名: Ann. Rheum. Dis 67 ページ: 136-137
  • 査読あり
• [雑誌論文] Effects of infliximab therapy on gene expression levels of TNF-alpha, TTP, TIA-1 and Hu antigen R in patients with rheumatoid arthritis (2007)
  • 著者名/発表者名: Sugihara M, Tsutsumi A, Suzuki E, Wakamatsu E, Suzuki T, Ogishima H, Hayashi T, Chino Y, Ishii W, Mamura M, Goto D, Matsumoto I, Ito S, Sumida T.
  • 雑誌名: Arthritis Rheum 56 ページ: 2160-2169
  • 査読あり
• [雑誌論文] DNA microarray analysis of labial salivary glands of patients with Sjogren's syndrome (2007)
  • 著者名/発表者名: Wakamatsu E, Nakamura Y, Matsumoto I, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 雑誌名: Ann. Rheum. Dis 66 ページ: 844-845
  • 査読あり
• [学会発表] The Expression of MicroRNA-424 in Rheumatoid Arthritis (2008)
  • 著者名/発表者名: Yoshitaka T, Nakasa T, Inoue A, Okubo A, Takemoto F, Miyaki S, Nishida K, Ochi M, Ozaki T, Sumida T, Asahara H.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-28
• [学会発表] The Pathogenesis of Anti-M3 Muscarinic Acetylcholine Receptor Antibodies in Patients with Sjogren's Syndrome (2008)
  • 著者名/発表者名: Tsuboi H, Matsumoto I, Wakamatsu E, Iizuka M, Nakamura Y, Hayashi T, Goto D, Ito S, Sumida T.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-28
• [学会発表] Establishment Of New Murine Model For Sjogren'S Syndrome Using M3 Muscarinic Acethylcholine Receptor Knockout Mice (2008)
  • 著者名/発表者名: Wakamatsu E, Matsumoto I, Iizuka M, Tsuboi H, Nakamura Y, Hayashi T, Goto D, Ito S, Sumida T.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-28
• [学会発表] Overexpression Of TNFalpha-induced-adipose Related Protein (TIARP) In Joints With Autoimmune Arthritis Mediated By Glucose-6-phophate Isomerase (2008)
  • 著者名/発表者名: Inoue A, Matsumoto I, Iwanami K, Tanaka-Watanabe Y, Hayashi T, Goto D, Ito S, Sumida T.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-27
• [学会発表] Replication of the Association between C8orf13-BLK Region, Systemic Lupus Erythematosus in a Japanese Population (2008)
  • 著者名/発表者名: Ito I, Kawasaki A, Hayashi T, Matsumoto I, Ito S, Tsutsumi A, Ohashi J, Hom G, Graham R R, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-26
• [学会発表] Association of STAT4 polymorphisms with Systemic Lupus Erythematosus in a Japanese Population (2008)
  • 著者名/発表者名: Kawasaki A, Ito I, Hikami K, Hayashi T, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham R R, Hom G, Ohashi J, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-26
• [学会発表] Use of Laser Microdissection in the Analysis of Renal-infiltrating T cells in lupus nephritis (2008)
  • 著者名/発表者名: Wang Y, Ito S, Chino Y, Goto D, Matsumoto I, Hayashi T, Sumida T.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-26
• [学会発表] Muscarinic-3 Acetylcholine Receptor Autoantibody in Patients with Systemic Sclerosis (2008)
  • 著者名/発表者名: Kawaguchi Y, Nakamura Y, Matsumoto I, Ota Y, Nishimagi E, Kamatani N, Satoh T, Kuwana M, Sumida T, Hara M.
  • 学会等名: 2008 ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: San Francisco
  • 年月日: 2008-10-26
• [学会発表] Induction of experimental autoimmune sialoadenitis using organ-specific autoantigen knockout mice (2008)
  • 著者名/発表者名: Wakamatsu E, Matsumoto I, Iizuka M, Tsuboi H, Nakamura Y, Hayashi T, Goto D, Ito S, Sumida T.
  • 学会等名: APLAR2008
  • 発表場所: Yokohama
  • 年月日: 2008-09-26
• [学会発表] Evaluation of anti-TNF biologics on rheumatoid arthritis using the new low-field extremity MRI and scoring system (2008)
  • 著者名/発表者名: Suzuki T, Handa S, Kose K, Hayashi T, Goto D, Matsumoto I, Ito S, Sumida T.
  • 学会等名: APLAR2008
  • 発表場所: Yokohama
  • 年月日: 2008-09-26
• [学会発表] TNF alpha induces human six-transmembrane epitherial antigen of prostate 4 in rheumatoid synovium (2008)
  • 著者名/発表者名: Tanaka-Watanabe Y, Matsumoto I, Iwanami K, Inoue A, Minami R, Hayashi T, Goto D, Ito S, Sumida T.
  • 学会等名: APLAR2008
  • 発表場所: Yokohama
  • 年月日: 2008-09-24
• [学会発表] Functional gene polymorphisms in rheumatoid arthritis and periodontitis The 93rd (2007)
  • 著者名/発表者名: Kobayashi T, Ito S, Kuroda T, Yamamoto K, Sugita N, Narita I, Sumida T, Gejyo F, Yoshie H.
  • 学会等名: Annual Meeting of the American Academy of Periodontology
  • 発表場所: Washington DC
  • 年月日: 20071000
• [学会発表] Exploring the Role of TIARP(TNFαInduced Adipose Related Protein ) in Autoimmune Arthritis Mediated Driven by Glucose-6-phosphate Isomerase (2007)
  • 著者名/発表者名: Inoue A, Matsumoto I, Iwanami K, Tanaka-Watanabe Y, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-10
• [学会発表] A Novel Role For Natural Killer T Cells As Activators And Producers Of Interleukin-17 In The Pathogenesis Of Collagen-induced Arthritis (2007)
  • 著者名/発表者名: Yoshiga Y, Goto D, Segawa S, Matsumoto I, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-10
• [学会発表] The Function of CD1d Variants in Patients with Autoimmune Disease (2007)
  • 著者名/発表者名: Goto D, Yoshiga Y, Segawa S, Matsumoto I, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-09
• [学会発表] B Cell Have Crucial Role as Autoantibody Producers in Arthritis Mediates by Glucose-6-phosphate Isomerase (2007)
  • 著者名/発表者名: Tanaka-Watanabe Y, Matsumto I, Iwanami K, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-09
• [学会発表] Therapeutic Effects of Tnfα Antagonist, IL-6 Antagonist and Ctla-4 Ig in Glucose-6-phosphate Isomerase Induced Arthritis (2007)
  • 著者名/発表者名: Matsumoto I, Iwanami K, Tanaka Y, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-09
• [学会発表] Anti-glucose-6-phosphate Isomerase, Anti-cyclic Citrullinated Peptide Antibodies and HLA-DRB1 Genotypes in Japanese Patients with Early Rheumatoid Arthritis (2007)
  • 著者名/発表者名: Furuya T, Matsumoto I, Tsuchiya N, Hakoda M, Ichikawa N, Yago T, Nanke Y, Sumida T, Kamatani N, Kotake S.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-09
• [学会発表] New Murine Model for Sjogren's Syndrome Established by M3 Muscarinic Acethylcholine Receptor Immunization. (2007)
  • 著者名/発表者名: Wakamatsu E, Nakamura Y, Matsumoto I, Tsuboi H, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-09
• [学会発表] Expression of the Interleukin 17 Gene in Patients with Rheumatoid Arthritis (2007)
  • 著者名/発表者名: Kohno M, Tsutsumi A, Matsui H, Sugihara M, Mamura M, Suzuki T, Goto D, Matsumoto I, Ito S, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-08
• [学会発表] Tristetraprolin(TTP) Gene Polymorphisms in Patients with Rheumatoid Arthritis and Healthy Individuals (2007)
  • 著者名/発表者名: Suzuki T, Tsutsumi A, Sugihara M, Kohno M, Goto D, Matsumoto I, Ito S, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-08
• [学会発表] Analysis of T Cells Infiltrating in Kidneys of MRL/lpr Mouse by Laser-Microdissection Method (2007)
  • 著者名/発表者名: Wang Y, Ito S, Chino Y, Goto D, Matsumoto I, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-08
• [学会発表] Crucial Role of IL-6/IL-17 Axis in the Generation of GPI-induced Arthritis (2007)
  • 著者名/発表者名: Iwanami K, Matsumoto I, Watanabe-Tanaka Y, Inoue A, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: 2007ANNUAL SCIENTIFIC MEETING on the ACR
  • 発表場所: US
  • 年月日: 2007-11-08
• [学会発表] Essential role of immunoglobulin G in the development of arthritis immunized by glucose -6- phosphate isomerase, Annual European Congress of RHEUMATOLOGY (2007)
  • 著者名/発表者名: Watanabe Y, Matsumoto I, Iwanami K, Inoue A, Mamura M, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: EULAR 2007
  • 発表場所: Barcelona
  • 年月日: 2007-06-15
• [学会発表] Matsumoto I, Ito S, Sumida T. : Promoter region polymorphism of the tristetraprolin(TTP) gene in patients with rheumatoid arthritis Annual European Congress of RHEUMATOLOGY (2007)
  • 著者名/発表者名: Suzuki T, Tsutsumi A, Matsui M, Kouno M, Sugihara M, Mamura M, Goto D, Matsumoto I, Ito S, Sumida T.
  • 学会等名: EULAR 2007
  • 発表場所: Barcelona
  • 年月日: 2007-06-15
• [学会発表] NKT Cells are Novel Accelerator and Producer of IL-17 in the Pathogenesis of Collagen-induced Arthritis (2007)
  • 著者名/発表者名: Yoshiga Y., Goto D., Segawa S., Matsumoto I., Ito S., Tsutsumi A., Sumida T.
  • 学会等名: Focis2007
  • 発表場所: San diego
  • 年月日: 2007-06-09
• [学会発表] IL-6/T_H-17 axis plays a crucial role in the generation of GPI-induced arthritis (2007)
  • 著者名/発表者名: Iwanam K., Matsumoto I., Watanabe Y., Inoue A., Mamura M., Goto D., Ito S., Tsutsumi A., Sumida T.
  • 学会等名: Focis2007
  • 発表場所: San diego
  • 年月日: 2007-06-09
• [学会発表] Expression of the Interleukin 17 (IL-17) Gene in Patients with Rheumatoid Arthritis(RA) (2007)
  • 著者名/発表者名: Kohno M, Tsutsumi A, Sugihara M, Matsui H, Suzuki T, Mamura M, Goto D, Matsumoto I, Ito S, Sumida T.
  • 学会等名: The 2^<nd> East Asian Group of Rheumatology Meeting
  • 発表場所: Korea
  • 年月日: 2007-05-19
• [学会発表] Functional Analysis of Autoantibodies to Muscarinic M3 Acetylcholine Receptor in Patients with Sjogren's Syndrome (2007)
  • 著者名/発表者名: Nakamura Y, Wakamatsu E, Matsumoto I, Mamura M, Goto D, Ito S, Tsutsumi A, Sumida T.
  • 学会等名: The 2nd East Asian Group of Rheumatology Meeting
  • 発表場所: Korea
  • 年月日: 2007-05-19
• [学会発表] シェーグレン症候群の分子病態と治療戦略 (2007)
  • 著者名/発表者名: 住田孝之
  • 学会等名: 第104回日本内科学会講演会
  • 発表場所: 大阪
  • 年月日: 2007-04-03
• [図書] シェーグレン症候群とは、やさしいシェーグレン症候群の自己管理 (2008)
  • 著者名/発表者名: 住田孝之
  • 総ページ数: 10-14
  • 出版者: 医薬ジャーナル社(住田孝之)
• [図書] Sjogren症候群,今日の診断基準 (2007)
  • 著者名/発表者名: 住田孝之
  • 総ページ数: 646-648
  • 出版者: 南江堂(大田健、奈良信雄(編集))