Molecular mechanism and regulation in Sjogren's syndrome

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591260
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• 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): 2009 – 2011
• Keywords: 膠原病学

Research Abstract

Sjogren's syndrome (SS) is one of autoimmune diseases. The purpose of this study is to clarify the molecular mechanism in the pathogenesis of SS and establish the new therapeutic strategy against target molecule. In this research, we focused on Muscarinic acetylcholine receptor 3 (M3R), because this receptor is a functional molecule to produce saliva from salivary glands. Our results are followings. 1) There were anti-M3R autoantibodies and M3R reactive T cells in about 50% of patients with SS. 2) The B cell epitopes were on N region, the first, the second, and the third extra-cellular domains of M3R molecules. 3) Antibodies against the second extracellular domain of M3R were the pathogenic autoantibody to suppress the saliva production. 4) We established M3R immunized sialadenitis (MIS) mouse model using M3RKO mouse and Rag-1KO mouse. 5) IFN-γand/or IL-17 producing M3R reactive T cells were necessary to generate MIS. 6) The dominant T cell epitope of M3R was the first extracellular domain to induce MIS. Now we are selecting APL of T cell epitope and near future try to control MIS and SS via antigen-specific therapeutic strategy.

Research Products

• [Journal Article] Association of UBE2L3 polymorphism with diffuse cutaneous systemic sclerosis in aJapanese population (2012)
  • Author(s): 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
  • Journal Title: Ann. Rheum. Dis Volume: (in press)
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Lupus Volume: (in press)
• [Journal Article] monoclonal antibodies against the seconde xtracellular loop of human M3 muscarinic acetylcholine receptor (2012)
  • Author(s): Tsuboi, H., Nakamura, Y., Iizuka, M., Matsuo, N., Matsumoto, I., and Sumida, T.
  • Journal Title: Mod. Rheumatol Volume: (in press)
• [Journal Article] Comprehensivediagnostic criteria (CDC criteria) forIgG4-related disease (IgG4-RD) (2012)
  • Author(s): 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
  • Journal Title: Mod. Rehumatol Volume: 22(1) Pages: 21-30
• [Journal Article] Six-transmembrane epithelial antigen of prostate 4 (STEAP4) isexpressed on monocytes/neutrophils, and isregulated by TNF antagonist in patientswith rheumatoid arthritis (2012)
  • Author(s): 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
  • Journal Title: Clin. Exp.Rheumatol Volume: 30(1) Pages: 99-102
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Mod. Rheumatol Volume: 22(1) Pages: 1-14
• [Journal Article] 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)
  • Author(s): Tanaka, Y., Matsumoto, I., Iwanami, K., Inoue, A., Umeda, N., Sugihara, M., Hayashi, T., Ito, S., and Sumida, T
  • Journal Title: Mod. Rheumatol Volume: 22(1) Pages: 128-136
• [Journal Article] Overexpression of T-bet gene regulatesmurine autoimmune arthritis (2012)
  • Author(s): 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
  • Journal Title: ArthritisRheum Volume: 64 Pages: 162-172
• [Journal Article] A genome-widesusceptibility locus for systemic lupuserythematosus in Japanese (2012)
  • Author(s): 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
  • Journal Title: PLoS Genet Volume: 8(1)
• [Journal Article] Cumulative association of eight susceptibility geneswith systemic lupus erythema tosus in a Japanese female population (2011)
  • Author(s): 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
  • Journal Title: J. HumanGen Volume: 56 Pages: 503-507
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: ArhritisReas.Ther Volume: 13(2) Pages: 41
• [Journal Article] Activation of naturalkiller T cells by a-carba-GalCer (RCAI-56), a novel synthetic glycoipid ligand, suppresses murine collagen-inducedarhritis (2011)
  • Author(s): Yoshiga, Y., Goto, D., Segawa, S., Hayashi, T., Matsumoto, I., Ito, S., Taniguchi, M., and Sumida, T
  • Journal Title: Clin. Exp. Immunol Volume: 164(2) Pages: 236-247
• [Journal Article] interleukin-18 plus interleukin-2-inducedinterstitial lung disease (2011)
  • Author(s): Segawa, S., Goto, D., Yoshiga, Y., Horikoshi, M., Sugihara, M., Hayashi, T., Chino, Y., Matsumoto, I., Ito, S., and Sumida, T
  • Journal Title: Am. J. Res. Cell.Mol. Biol Volume: 45(3) Pages: 659-666
• [Journal Article] Comparative suppressive effects of tyrosine kinase inhibitors imatinib and nilotinib in models of autoimmune arthritis (2011)
  • Author(s): Akashi, N., Matsumoto, I., Tanaka, Y., Inoue, A., Yamamoto, K., Umeda, N., Hayashi, T., Goto, D., Ito, S., Sekiguchi, K., and Sumida, T
  • Journal Title: Mod. Rheumatol Volume: 21 Pages: 267-275
• [Journal Article] Association of a functional polymorphism in the 3' untranslated region of SPl1 with systemic lupus erythematosus (2011)
  • Author(s): 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
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 755-763
• [Journal Article] Importnace of serine727 phosphorylated STAT1 in IFNγ-induced signaling and apoptosis of human salivary gland cells (2011)
  • Author(s): 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
  • Journal Title: Int. J. Rheum. Dis Volume: 14 Pages: 86-91
• [Journal Article] Replication of association between FAM167A(C8orf13)-BLK region and rheumatoid arthritis in a Japanese polylation (2010)
  • Author(s): 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
  • Journal Title: Ann. Rheum. Dis.(letter) Volume: 69 Pages: 936-937
• [Journal Article] A patient with rheumatoid arthritis who had normal delivery with etanercept (2010)
  • Author(s): Umeda, N., Ito, S., Hayashi, T., Goto, D., Matsumoto, I. and Sumida, T
  • Journal Title: Intern. Med Volume: 49 Pages: 187-189
• [Journal Article] Inhibition of TGF-b signaling attenuates IL-18 plusIL-2-induced interstitial lung disease (2010)
  • Author(s): Segawa, S., Goto, D., Yoshiga, Y., Sugihara, M., Hayashi, T., Chino, Y., Matsumoto, I., Ito, S., Ito, S., and Sumida, T
  • Journal Title: Clin. Exp. Immunol Volume: 160 Pages: 394-402
• [Journal Article] Induction of Th1-biased cytokine production by a-carba-GalCer, a neoglycolipid ligand for natural killer T cells (2010)
  • Author(s): 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
  • Journal Title: Int. Immunol Volume: 22 Pages: 319-28
• [Journal Article] Newlow-field extremity MRI, compactTscan : comparison with whole body 1.5 tesla conventional MRI (2010)
  • Author(s): 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.
  • Journal Title: Mod. Rheumatol Volume: 20 Pages: 331-336
• [Journal Article] Association of TNFAIP3 with susceptibility to systemic lupus erythematosus in a Japanese population. (2010)
  • Author(s): Kawasaki, A., Ito, I., Ito, S., Hayashi, T., Goto, D., Matsumoto, I., Takasaki, Y., Hashimoto, H., Sumida, T., and Tsuchiya, N
  • Journal Title: Biomed. Biotechnol Volume: 2010:207578
• [Journal Article] Functional role of M3 muscarinic acetylcholine receptor (M3R) reactive T cells and anti-M3R autoantibodies in patients with Sjogren's syndrome (2010)
  • Author(s): Sumida, T., Tsuboi, H., Iizuka, M., Nakamura, Y., and Matsumoto, I
  • Journal Title: Autoimmunity Reviews Volume: 9 Pages: 915-617
• [Journal Article] The effects of serum lactate dehydrogenase measurement and heparin dose adjustment on management of a pregnant patient with antiphospholipid syndrome (2010)
  • Author(s): 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
  • Journal Title: Int. J. Rheu. Dis Volume: 13 Pages: 32-35
• [Journal Article] New epitopes and funcion of anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjogren's syndrome (2010)
  • Author(s): Tsuboi, H., Matumoto, I., Wakamatsu, E., Iizuka, M., Nakamura, Y., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • Journal Title: Clin.Exp. Immunol Volume: 162 Pages: 53-61
• [Journal Article] Elevated level of serum cystatin-C concentration is a useful predictor of myelosuppression induced by methotrexate for treatment of rheumatoid arthritis (2010)
  • Author(s): Hayashi, T., Ito, S., Goto, D., Matsumoto, I., and Sumida, T
  • Journal Title: Mod. Rheumatol
• [Journal Article] Preostaglandin E2 stimulation of EP4 promotes Th1 differentiation and Th17 expansion and is critical for autoimmune disease (2010)
  • Author(s): 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
  • Journal Title: Br. J. Pharmacol Volume: 160 Pages: 292-310
• [Journal Article] A comparison of low-field dedicated extremitymagnetic resonace imaging and articularultrasonography in patients withrheumatoid arthritis (2010)
  • Author(s): 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.
  • Journal Title: Mod. Rheumatol
• [Journal Article] Difference in blood tacrolimus concentration between ACMIA and MEIA in samples with lowhaematocrit values (2010)
  • Author(s): 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
  • Journal Title: J. Pharm. Pharmacol Volume: 62 Pages: 1185-1188
• [Journal Article] Gender specific association of X-linked TLR7 with male systemic lypus erhythematosus (2010)
  • Author(s): 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
  • Journal Title: Proc. Natl. Acad. Sci. Volume: 43 Pages: 10715838
• [Journal Article] Pathogenic role of immune response to M3 muscarinic acethylcholine receptor reactive in Sjogren's sndrome-like sialoadenitis (2010)
  • Author(s): Iizuka, M., Wakamatsu, E., Matsumoto, I., Tsuboi, H., Nakamura, Y., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • Journal Title: J. Autoimmunity Volume: 35 Pages: 383-389
• [Journal Article] Muscarinic-3 acetylcholine receptor autoantibody in patients with systemic sclerosis : contribution to severe gastrointestinal tract dysmotility (2009)
  • Author(s): Kawaguchi, Y., Wakamatsu, E., Matsumoto, I., Nishimagi, E., Kamatani, N., Satoh, T., Kuwana, M., Sumida, T., and Hara, M
  • Journal Title: Ann. Rheum. Dis Volume: 68 Pages: 710-714
• [Journal Article] Replication of theassociation between C8orf13-BLK regionand systemic lupus erythematosus in a Japanese population (2009)
  • Author(s): 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
  • Journal Title: Arthritis Rheum Volume: 60 Pages: 553-558
• [Journal Article] B cells have crucial role asautoantibody producers in arthritis mediated by glucose-6-phospahte isomerase (2009)
  • Author(s): Tanaka, Y., Matsumoto, I., Iwamami, K., Inoue, A., Goto, D., Ito, S., Tsutsumi, A., and Sumida, T
  • Journal Title: Clin. Exp. Immunol Volume: 155 Pages: 285-294
• [Journal Article] Mannose binding lectin gene polymorphism and the severity of chronic periodontitis. (2009)
  • Author(s): Tsutsumi, A., Kobayashi, T., Ito, S., Goto, D., Matsumoto, I., Yoshie, H., and Sumida, T
  • Journal Title: Jap. J. Clin. Immunol Volume: 32 Pages: 48-52
• [Journal Article] Cytokine genepolymorphisms associated with rheumatoid arthritis and periodontitis in Japanes eadults (2009)
  • Author(s): Kobayashi, T., Murasawa, A., Ito, S., Yamamoto, K., Komatsu, Y., Abe, A., Sumida, T., and Yoshie, H
  • Journal Title: J. Periodontology Volume: 80 Pages: 792-799
• [Journal Article] Efficacy of mizoribine pulse therapy inrheumatoid arthritis patients with reducedor insufficient response to infliximab (2009)
  • Author(s): Horikoshi, M., Ito, S., Ishikawa, M., Umeda, N., Kondo, Y., Tsuboi, H., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T
  • Journal Title: Mod. Rheumatol Volume: 19 Pages: 229-234
• [Journal Article] A case ofatypical Cogan's syndrome with arortitis (2009)
  • Author(s): Kondo, Y., Ito, S., Oi, Y., Satou, H., Tsuboi, H., Sugihara, M., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T
  • Journal Title: Intern. Med. Volume: 49 Pages: 366-371
• [Journal Article] A newlow-field extremity magnetic resonance imaging and proposed compact MRI score :evaluation of anti-tummor necrosis factor biologics on rheumatoid arthritis (2009)
  • Author(s): Suzuki, T., Ito, S., Handa, S., Kose, K., Okamoto, Y., Minami, M., Hayashi, T., Goto, D., Matsumoto, I., and Sumida, T
  • Journal Title: Mod.Rheumatol Volume: 19 Pages: 358-365
• [Journal Article] Altered peptide ligands regulate type II collagen-induced arthritis in mice (2009)
  • Author(s): Wakamatsu, E., Matsumoto, I., Yoshiga, Y., Iwanami, K., Tsuboi, H., Hayashi, T., Goto, D., Ito, S., and Sumida, T
  • Journal Title: Mod. Rheumatol Volume: 19 Pages: 366-371
• [Journal Article] The decrement of soluble CD1d proteinsaffects the function of NKT cells in patientswith rheumatoid arthritis (2009)
  • Author(s): Segawa, S., Goto, D., Yoshiga, Y., Hayashi, T., Matsumoto, I., Ito, S., and Sumida, T.
  • Journal Title: Int. J. Mol. Med Volume: 24 Pages: 481-486
• [Journal Article] Role of tumor necrosis factor- & -inducedadipose-related protein in autoimmune arthritis (2009)
  • Author(s): Inoue, A., Matsumoto, I., Tanaka, Y., Iwanami, K., Goto, D., Ito, S., and Sumida, T
  • Journal Title: Arthrits Rheu. Ther Volume: 11 Pages: 118
• [Journal Article] Analysis of cytokine balance in lupus nephritis by laser-microdissection (2009)
  • Author(s): Wang, Y., Ito, S., Chino, Y., Goto, D., Matsumoto, I., Murata, H., Tsutsumi, A., Uchida, K., Usui, J., Yamagata, K., andSumida, T
  • Journal Title: Clini. Exp. Immunol. Volume: 159 Pages: 1-10
• [Journal Article] Altered peptide ligands inhibit glucose-6-phosphate isomerase (GPI)peptide-induced arthritis (2009)
  • Author(s): Iwanami, K., Matsumoto, I., Tanaka, Y., Inoue, A., Minami, R., Hayashi, T., Goto, D., Ito, S., Nishimura, Y., and Sumida, T
  • Journal Title: Arthritis Res. Volume: 11 Pages: 167
• [Journal Article] Association of STAT4 polymorphisms with systemic lupus erythematosus in a Japanese population (2008)
  • Author(s): 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
  • Journal Title: Arthritis Res. Volume: 10 Pages: 113
• [Journal Article] Arthrogeneic T cell epitope in glucose-6-phosphate isomerase(GPI)-induced arthritis (2008)
  • Author(s): Inoue, A., Goto, D., Ito, S., Tsutsumi, A., and Sumida, T.
  • Journal Title: Arthritis Res. Volume: 10 Pages: 130