シェーグレン症候群発症の分子機構と制御

2011 年度 研究成果報告書

• 研究課題/領域番号: 21591260
• 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・アレルギー内科学
• 研究機関: 筑波大学
• 研究代表者: 住田 孝之 筑波大学, 医学医療系, 教授 (00183054)
• 研究期間 (年度): 2009 – 2011
• キーワード: 膠原病学

研究概要

シェーグレン症候群(SS)発症の分子機構を明らかにし、分子をターゲットとした新規治療戦略を開発する事を目的とした。本研究では、唾液分泌に重要な機能を有するムスカリン作働性アセチルコリン受容体3(M3R)を分子標的として、以下の研究成果を明らかにした。1)SSの約50%においてM3Rに対する自己抗体とT細胞が存在した。2)M3RのB細胞エピトープは複数あった。3)細胞外第二ドメインに対する抗M3R抗体は機能抑制する病因抗体であった。4)SS様の唾液腺炎(M3Rimmunized sialadnitis, MIS)を樹立した。5)MISの発症にはIFN-γおよびIL-17産生CD3+T細胞が必須である。6)MISの主要T細胞エピトープはM3R細胞外第一ドメインであり、単独免疫によりMISを誘導できた。

研究成果

• [雑誌論文] Association of UBE2L3 polymorphism with diffuse cutaneous systemic sclerosis in aJapanese population (2012)
  • 著者名/発表者名: Hasebe, N., Kawasaki, A., Ito, I., Kawamoto, M., Hasegawa, M., Fujimoto, M., Furukawa, H., Tohma, S., Sumida, T., Takehara, K., Sato, S., Kawaguchi, Y., and Tsuchiya, N
  • 雑誌名: Ann. Rheum. Dis 巻: (in press)
• [雑誌論文] Associationof PHRF1 polymorphism with the clinical phenotypes of, but not with susceptibility to, systemic lupus erythema tosus : An association study in a Japanese population (2012)
  • 著者名/発表者名: Kawasaki, A., Furukawa, H., Kondo, Y., Ito, S., Hayashi, T., Kusaoi, M., Matsumoto, I., Tohma, S., Takasaki, Y., Hashimoto, H., Sumida, T., and Tsuchiya, N
  • 雑誌名: Lupus 巻: (in press)
• [雑誌論文] monoclonal antibodies against the seconde xtracellular loop of human M3 muscarinic acetylcholine receptor (2012)
  • 著者名/発表者名: Tsuboi, H., Nakamura, Y., Iizuka, M., Matsuo, N., Matsumoto, I., and Sumida, T.
  • 雑誌名: Mod. Rheumatol 巻: (in press)
• [雑誌論文] Comprehensivediagnostic criteria (CDC criteria) forIgG4-related disease (IgG4-RD) (2012)
  • 著者名/発表者名: Umehara, H., Okazaki, K., Masaki, Y., Kawano, M., Yamamoto, M., Saeki, T., Kawa, S., Hamano, H., Kamisawa, T., Shimosegawa, T., Shimatsu, A., Nakamura, S., Ito, T., Notohara, K., Sumida, T., Tanaka, Y., Mimori, T., Chiba, T., Mishima, M., Hibi, T., Tsubouchi, H., Inui, K
  • 雑誌名: Mod. Rehumatol 巻: 22(1) ページ: 21-30
• [雑誌論文] Six-transmembrane epithelial antigen of prostate 4 (STEAP4) isexpressed on monocytes/neutrophils, and isregulated by TNF antagonist in patientswith rheumatoid arthritis (2012)
  • 著者名/発表者名: Tanaka, Y., Matsumoto, I., Iwanami, K., Inoue, A., Minami, R., Umeda, N., Kanamori, A., Ochiai, N., Miyazawa, K., Sugihara, M., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • 雑誌名: Clin. Exp.Rheumatol 巻: 30(1) ページ: 99-102
• [雑誌論文] The Research Program for Intractable Diseaseby Ministry of Health, Labor and Welfare Japan G4 team. A novel clinical entity, IgG4-related disease (IgG4RD) : generalconcept and details. (2012)
  • 著者名/発表者名: Umehara, H., Okazaki, K., Masaki, Y., Kawano, M., Yamamoto, M., Saeki, T., Matsui, S., Sumida, T., Mimori, T., Tanaka, Y., Tsubota, K., Yoshino, T., Kawa, S., Suzuki, R., Takegami, T., Tomosugi, N., Kurose, N., Ishigaki, H., Azumi, A., Kojima, M., Nakamura, S., Inoue, D
  • 雑誌名: Mod. Rheumatol 巻: 22(1) ページ: 1-14
• [雑誌論文] Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosisfactor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoidarthritis (2012)
  • 著者名/発表者名: Tanaka, Y., Matsumoto, I., Iwanami, K., Inoue, A., Umeda, N., Sugihara, M., Hayashi, T., Ito, S., and Sumida, T
  • 雑誌名: Mod. Rheumatol 巻: 22(1) ページ: 128-136
• [雑誌論文] Overexpression of T-bet gene regulatesmurine autoimmune arthritis (2012)
  • 著者名/発表者名: Kondo, Y., Matsumoto, I., Iizuka, M., Wakamatsu, E., Zhaojin, Y., Tsuboi, H., Sugihara, M., Hayashi, T., Goto, D., Ito, S., Takahashi, S., and Sumida, T
  • 雑誌名: ArthritisRheum 巻: 64 ページ: 162-172
• [雑誌論文] A genome-widesusceptibility locus for systemic lupuserythematosus in Japanese (2012)
  • 著者名/発表者名: Okada, Y., Shimane, K., Kochi, Y., Tahira, T., Suzuki, A., Higasa, K., Takahashi, A., Horita, T., Atsumi, T., Ishii, T., Okamoto, A., Fujio, K., Hirakata, M., Amano, H., Kondo, Y., Ito, S., Takada, K., Mimori, A., Saito, K., Kamachi, M., Kawaguchi, Y., IkIkari, K., Mohammed, W. O., Matsuda, K., Terao, C., Ohmura, K., Myouzen, K., Hosono, N., Tsunoda, T., Nishimoto, N., Mimori, T., Matsuda, F., Tanaka, Y., Sumida, T., Yamanaka, H., Takasaki, Y., Koike, T., Horiuchi, T., Hayashi, K., Kubo, M., Kamatani, N., Yamada, R., Nakumura, Y., and Yamamoto, K
  • 雑誌名: PLoS Genet 巻: 8(1)
• [雑誌論文] Cumulative association of eight susceptibility geneswith systemic lupus erythema tosus in a Japanese female population (2011)
  • 著者名/発表者名: Koga, M., Kawasaki, A., Ito, I., Furuya, T., Ohashi, J., Kyogoku, C., Matsushita, M., Oka, T., Ito, S., Hayashi, T., Matsumoto, I., Kusaoi, M., Takasaki, Y., Hashimoto, H., Sumida, T., and Tsuchiya, N
  • 雑誌名: J. HumanGen 巻: 56 ページ: 503-507
• [雑誌論文] TLR7 single-nucleotide polymorphisms in the 3'untranslated region and intron 2 independently contribute to systemic lupus erythema tosus in Japanese women : acase-control association study (2011)
  • 著者名/発表者名: Kawasaki, A., Furukawa, H., Kondo, Y., Ito, S., Hayashi, T., Kusaoi, M., Matsumoto, I., Tohma, S., Takasaki, Y., Hashimoto, H., Sumida, T., and Tsuchiya, N
  • 雑誌名: ArhritisReas.Ther 巻: 13(2) ページ: 41
• [雑誌論文] Activation of naturalkiller T cells by a-carba-GalCer (RCAI-56), a novel synthetic glycoipid ligand, suppresses murine collagen-inducedarhritis (2011)
  • 著者名/発表者名: Yoshiga, Y., Goto, D., Segawa, S., Hayashi, T., Matsumoto, I., Ito, S., Taniguchi, M., and Sumida, T
  • 雑誌名: Clin. Exp. Immunol 巻: 164(2) ページ: 236-247
• [雑誌論文] interleukin-18 plus interleukin-2-inducedinterstitial lung disease (2011)
  • 著者名/発表者名: Segawa, S., Goto, D., Yoshiga, Y., Horikoshi, M., Sugihara, M., Hayashi, T., Chino, Y., Matsumoto, I., Ito, S., and Sumida, T
  • 雑誌名: Am. J. Res. Cell.Mol. Biol 巻: 45(3) ページ: 659-666
• [雑誌論文] Comparative suppressive effects of tyrosine kinase inhibitors imatinib and nilotinib in models of autoimmune arthritis (2011)
  • 著者名/発表者名: Akashi, N., Matsumoto, I., Tanaka, Y., Inoue, A., Yamamoto, K., Umeda, N., Hayashi, T., Goto, D., Ito, S., Sekiguchi, K., and Sumida, T
  • 雑誌名: Mod. Rheumatol 巻: 21 ページ: 267-275
• [雑誌論文] Association of a functional polymorphism in the 3' untranslated region of SPl1 with systemic lupus erythematosus (2011)
  • 著者名/発表者名: Hikami, K., Kawasaki, A., Koga, M., Ito, S., Hayashi, T., Matsumoto, I., Tsutsumi, A., Kusaoi, M., Takasaki, Y., Hashimoto, H., Arinami, T., Sumida, T., and Tsuchiya, N
  • 雑誌名: Arthritis Rheum 巻: 63 ページ: 755-763
• [雑誌論文] Importnace of serine727 phosphorylated STAT1 in IFNγ-induced signaling and apoptosis of human salivary gland cells (2011)
  • 著者名/発表者名: Tsuboi, H., Wakamatsu, E., Iizuka, M., Nakamura, Y., Sugihara, M., Suzuki, T., Ogishima, H., Hayashi, T., Goto, D., Ito, S., Matsumoto, I., and Sumida, T
  • 雑誌名: Int. J. Rheum. Dis 巻: 14 ページ: 86-91
• [雑誌論文] Replication of association between FAM167A(C8orf13)-BLK region and rheumatoid arthritis in a Japanese polylation (2010)
  • 著者名/発表者名: Ito, I., Kawasaki, A., Ito, S., Kondo, S., Sugihara, M., Horikoshi, M., Hayashi, T., Goto, D., Matsumoto, I., Tsutsumi, A., Takasaki, Y., Hashimoto, H., Matsuta, K., Sumida, T., and Tsuchiya, N
  • 雑誌名: Ann. Rheum. Dis.(letter) 巻: 69 ページ: 936-937
• [雑誌論文] A patient with rheumatoid arthritis who had normal delivery with etanercept (2010)
  • 著者名/発表者名: Umeda, N., Ito, S., Hayashi, T., Goto, D., Matsumoto, I. and Sumida, T
  • 雑誌名: Intern. Med 巻: 49 ページ: 187-189
• [雑誌論文] Inhibition of TGF-b signaling attenuates IL-18 plusIL-2-induced interstitial lung disease (2010)
  • 著者名/発表者名: Segawa, S., Goto, D., Yoshiga, Y., Sugihara, M., Hayashi, T., Chino, Y., Matsumoto, I., Ito, S., Ito, S., and Sumida, T
  • 雑誌名: Clin. Exp. Immunol 巻: 160 ページ: 394-402
• [雑誌論文] Induction of Th1-biased cytokine production by a-carba-GalCer, a neoglycolipid ligand for natural killer T cells (2010)
  • 著者名/発表者名: Tashiro, T., Nakagawa, R., Inoue, S., Omori-Miyake, M., Chiba, T., FUjii, S-I, Shimizu, K., Mori, K., Yoshiga, Y., Sumida, T., Watarai, H. and Taniguchi, M
  • 雑誌名: Int. Immunol 巻: 22 ページ: 319-28
• [雑誌論文] Newlow-field extremity MRI, compactTscan : comparison with whole body 1.5 tesla conventional MRI (2010)
  • 著者名/発表者名: Suzuki, T., Ito, S., Hand, S., Kose, K., Okamaoto, Y., Minami, M., Sugihara, M., Horikoshi, M., Tsuboi, H., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T., Goto, D., Matsumoto, I., and Sumida, T.
  • 雑誌名: Mod. Rheumatol 巻: 20 ページ: 331-336
• [雑誌論文] Association of TNFAIP3 with susceptibility to systemic lupus erythematosus in a Japanese population. (2010)
  • 著者名/発表者名: Kawasaki, A., Ito, I., Ito, S., Hayashi, T., Goto, D., Matsumoto, I., Takasaki, Y., Hashimoto, H., Sumida, T., and Tsuchiya, N
  • 雑誌名: Biomed. Biotechnol 巻: 2010:207578
• [雑誌論文] Functional role of M3 muscarinic acetylcholine receptor (M3R) reactive T cells and anti-M3R autoantibodies in patients with Sjogren's syndrome (2010)
  • 著者名/発表者名: Sumida, T., Tsuboi, H., Iizuka, M., Nakamura, Y., and Matsumoto, I
  • 雑誌名: Autoimmunity Reviews 巻: 9 ページ: 915-617
• [雑誌論文] The effects of serum lactate dehydrogenase measurement and heparin dose adjustment on management of a pregnant patient with antiphospholipid syndrome (2010)
  • 著者名/発表者名: Ogishima, H., Ito, S., Tsutsumi, A., Sugihara, M., Goto, D., Matsumoto, I., Obata-Yasuoka, M., Hamada, H., Yoshikawa, H., Takahashi, H., Murashima, A., and Sumida, T
  • 雑誌名: Int. J. Rheu. Dis 巻: 13 ページ: 32-35
• [雑誌論文] New epitopes and funcion of anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjogren's syndrome (2010)
  • 著者名/発表者名: Tsuboi, H., Matumoto, I., Wakamatsu, E., Iizuka, M., Nakamura, Y., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • 雑誌名: Clin.Exp. Immunol 巻: 162 ページ: 53-61
• [雑誌論文] Elevated level of serum cystatin-C concentration is a useful predictor of myelosuppression induced by methotrexate for treatment of rheumatoid arthritis (2010)
  • 著者名/発表者名: Hayashi, T., Ito, S., Goto, D., Matsumoto, I., and Sumida, T
  • 雑誌名: Mod. Rheumatol
• [雑誌論文] Preostaglandin E2 stimulation of EP4 promotes Th1 differentiation and Th17 expansion and is critical for autoimmune disease (2010)
  • 著者名/発表者名: Chen, Q., Lamphier, M., Muramoto, K., Ding, Y., Ynag, H., Mackey, M., Li, W., Liu, D., Inoue, Y., Massaki, N., Patel, T., Groom, A., Reynolds, D., Perron, S., Shirota, H., Matsumoto, I., Sumida, T., Spyvee, M., Schiller, S., ZGusovsky, F., and Marc, K
  • 雑誌名: Br. J. Pharmacol 巻: 160 ページ: 292-310
• [雑誌論文] A comparison of low-field dedicated extremitymagnetic resonace imaging and articularultrasonography in patients withrheumatoid arthritis (2010)
  • 著者名/発表者名: Horikoshi, M., Suzuki, T., Sugihara, M., Kondo, Y., Tsuboi, H., Uehara, T., Hama, M., Takase, K., Ohno, S., Ishigatsubo, Y., Yoshida, Y., Sagawa, A., Ikeda, K., Ohta, T., Matsumoto, I., Ito, S., and Sumida, T.
  • 雑誌名: Mod. Rheumatol
• [雑誌論文] Difference in blood tacrolimus concentration between ACMIA and MEIA in samples with lowhaematocrit values (2010)
  • 著者名/発表者名: Doki, K., Homma, M., Hori, T., Tomita, T., Hasegawa, Y., Ito, S., Fukunaga, K., Kameko, M., Chiba, S., Sumida, T., Ohkohchi, N., and Kohda, Y
  • 雑誌名: J. Pharm. Pharmacol 巻: 62 ページ: 1185-1188
• [雑誌論文] Gender specific association of X-linked TLR7 with male systemic lypus erhythematosus (2010)
  • 著者名/発表者名: Shen, N., Fu, Q., Deng, Y., Qian, X., Zhao, J., Kaufman, K.M., Tang, Y., Chen, J-Y, Yang, W., Wong, M., Kawasaki, A., Tsuchiya, N., Sumida, T., Kawaguchi, Y., Yum C-Y, Takasaki, Y., Hashimoto, H., Harley, J.B., Guthridge, J.M., Grossman, J.M., Cantor, R.M., Song, Y.W., Bae, S, Cehn, S, Hahn, B.H., Lau, Y.L., and Tsao, B.P
  • 雑誌名: Proc. Natl. Acad. Sci. 巻: 43 ページ: 10715838
• [雑誌論文] Pathogenic role of immune response to M3 muscarinic acethylcholine receptor reactive in Sjogren's sndrome-like sialoadenitis (2010)
  • 著者名/発表者名: Iizuka, M., Wakamatsu, E., Matsumoto, I., Tsuboi, H., Nakamura, Y., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • 雑誌名: J. Autoimmunity 巻: 35 ページ: 383-389
• [雑誌論文] Muscarinic-3 acetylcholine receptor autoantibody in patients with systemic sclerosis : contribution to severe gastrointestinal tract dysmotility (2009)
  • 著者名/発表者名: Kawaguchi, Y., Wakamatsu, E., Matsumoto, I., Nishimagi, E., Kamatani, N., Satoh, T., Kuwana, M., Sumida, T., and Hara, M
  • 雑誌名: Ann. Rheum. Dis 巻: 68 ページ: 710-714
• [雑誌論文] Replication of theassociation between C8orf13-BLK regionand 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, R.R., Takasaki, Y., Hashimoto, H., Ohashi, J., Behrens, T.W., Sumida, T., and Tsuchiya, N
  • 雑誌名: Arthritis Rheum 巻: 60 ページ: 553-558
• [雑誌論文] B cells have crucial role asautoantibody producers in arthritis mediated by glucose-6-phospahte isomerase (2009)
  • 著者名/発表者名: Tanaka, Y., Matsumoto, I., Iwamami, K., Inoue, A., Goto, D., Ito, S., Tsutsumi, A., and Sumida, T
  • 雑誌名: Clin. Exp. Immunol 巻: 155 ページ: 285-294
• [雑誌論文] Mannose binding lectin gene polymorphism and the severity of chronic periodontitis. (2009)
  • 著者名/発表者名: Tsutsumi, A., Kobayashi, T., Ito, S., Goto, D., Matsumoto, I., Yoshie, H., and Sumida, T
  • 雑誌名: Jap. J. Clin. Immunol 巻: 32 ページ: 48-52
• [雑誌論文] Cytokine genepolymorphisms associated with rheumatoid arthritis and periodontitis in Japanes eadults (2009)
  • 著者名/発表者名: Kobayashi, T., Murasawa, A., Ito, S., Yamamoto, K., Komatsu, Y., Abe, A., Sumida, T., and Yoshie, H
  • 雑誌名: J. Periodontology 巻: 80 ページ: 792-799
• [雑誌論文] Efficacy of mizoribine pulse therapy inrheumatoid arthritis patients with reducedor insufficient response to infliximab (2009)
  • 著者名/発表者名: Horikoshi, M., Ito, S., Ishikawa, M., Umeda, N., Kondo, Y., Tsuboi, H., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T
  • 雑誌名: Mod. Rheumatol 巻: 19 ページ: 229-234
• [雑誌論文] A case ofatypical Cogan's syndrome with arortitis (2009)
  • 著者名/発表者名: Kondo, Y., Ito, S., Oi, Y., Satou, H., Tsuboi, H., Sugihara, M., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T
  • 雑誌名: Intern. Med. 巻: 49 ページ: 366-371
• [雑誌論文] A newlow-field extremity magnetic resonance imaging and proposed compact MRI score :evaluation of anti-tummor necrosis factor biologics on rheumatoid arthritis (2009)
  • 著者名/発表者名: Suzuki, T., Ito, S., Handa, S., Kose, K., Okamoto, Y., Minami, M., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T
  • 雑誌名: Mod.Rheumatol 巻: 19 ページ: 358-365
• [雑誌論文] Altered peptide ligands regulate type II collagen-induced arthritis in mice (2009)
  • 著者名/発表者名: Wakamatsu, E., Matsumoto, I., Yoshiga, Y., Iwanami, K., Tsuboi, H., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • 雑誌名: Mod. Rheumatol 巻: 19 ページ: 366-371
• [雑誌論文] The decrement of soluble CD1d proteinsaffects the function of NKT cells in patientswith rheumatoid arthritis (2009)
  • 著者名/発表者名: Segawa, S., Goto, D., Yoshiga, Y., Hayashi, T., Matsumoto, I., Ito, S., and Sumida, T.
  • 雑誌名: Int. J. Mol. Med 巻: 24 ページ: 481-486
• [雑誌論文] Role of tumor necrosis factor- & -inducedadipose-related protein in autoimmune arthritis (2009)
  • 著者名/発表者名: Inoue, A., Matsumoto, I., Tanaka, Y., Iwanami, K., Goto, D., Ito, S., and Sumida, T
  • 雑誌名: Arthrits Rheu. Ther 巻: 11 ページ: 118
• [雑誌論文] Analysis of cytokine balance in lupus nephritis by laser-microdissection (2009)
  • 著者名/発表者名: Wang, Y., Ito, S., Chino, Y., Goto, D., Matsumoto, I., Murata, H., Tsutsumi, A., Uchida, K., Usui, J., Yamagata, K., andSumida, T
  • 雑誌名: Clini. Exp. Immunol. 巻: 159 ページ: 1-10
• [雑誌論文] Altered peptide ligands inhibit glucose-6-phosphate isomerase (GPI)peptide-induced arthritis (2009)
  • 著者名/発表者名: Iwanami, K., Matsumoto, I., Tanaka, Y., Inoue, A., Minami, R., Hayashi, T., Goto, D., Ito, S., Nishimura, Y., and Sumida, T
  • 雑誌名: Arthritis Res. 巻: 11 ページ: 167
• [雑誌論文] 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., 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. 巻: 10 ページ: 113
• [雑誌論文] Arthrogeneic T cell epitope in glucose-6-phosphate isomerase(GPI)-induced arthritis (2008)
  • 著者名/発表者名: Inoue, A., Goto, D., Ito, S., Tsutsumi, A., and Sumida, T.
  • 雑誌名: Arthritis Res. 巻: 10 ページ: 130