シェーグレン症候群発症の分子機構と制御

2011 Fiscal Year Annual Research Report

• Project/Area Number: 21591260
• Research Institution: University of Tsukuba
• Principal Investigator: 住田 孝之 筑波大学, 医学医療系, 教授 (00183054)
• Keywords: 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 / M3R / 自己免疫性唾液腺炎 / 抗原特異的制御

Research Abstract

シェーグレン症候群(SS)は原因不明の自己免疫疾患である。その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する。具体的には、唾液腺特異的に発現し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)を自己抗原候補として以下の研究成果を明らかにしてきた。
1.抗M3R抗体の機能解析
2種類のマウスモノクローナル抗M3R細胞外第二ドメイン抗体について、HSG唾液腺上皮細胞株を用いたin vitroで機能解析を行った。その結果、細胞内Ca influx濃度の有意な低下を誘導した。このことから、抗M3R細胞外第二ドメイン抗体が唾液分泌を抑制する病因抗体であることが明らかにされた。
2.M3R免疫唾液腺炎マウスにおけるM3R反応性T細胞解析
M3R免疫唾液腺炎(M3R immunized sialoadenitis,MIS)マウスにおいて、M3R反応性T細胞の機能解析を進めた。IFN-γKOxM3RKOマウスを用いたMISマウスにおいて、唾液腺発症が抑制されることからINF-γがMIS発症に関与していることが判明した。一方、IL-17KOxM3RKOマウスは現在作成中である。
3.MISマウスにおける抗原特異的治療法の確立
M3RのN領域、細胞外第一ドメイン、第二ドメイン、第三ドメインを構成する部位に対する合成ペプチドを作成し、M3R反応性T細胞のT細胞エピトープをin vitroで解析した。その結果、M3R細胞外第一ドメインが主要なT細胞エピトープであることが判明した。さらに、細胞外第一ドメイン単独でM3RKOマウスに免疫することによりMISの誘導に成功した。以上より、MIS発症におけるT細胞エピトープはM3R細胞外第一ドメインであることが判明した。現在、APLの選定を進めている。

Research Products

• [Journal Article] Association of UBE2L3 polymorphism with diffuse cutaneous systemic sclerosis in a Japanese 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., Tsuchiya, N.
  • Journal Title: Ann.Rheum.Dis. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Association of PHRF1 polymorphism with the clinical phenotypes of, but not with susceptibility to, systemic lupus erythematosus : 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., Tsuchiya, N.
  • Journal Title: Lupus Volume: (in press)
  • Peer Reviewed
• [Journal Article] Generation and functional analysis of monoclonal antibodies against the second extracellular loop of human M3 muscarinic acetylcholine receptor (2012)
  • Author(s): Tsuboi, H., Nakamura, Y., Iizuka, M., Matsuo, N., Matsumoto, I., Sumida, T.
  • Journal Title: Mod.Rheumatol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Comprehensive diagnostic criteria (CDC criteria) for IgG4-related disease (IgG4-RD), 2011 (2012)
  • Author(s): Umehara, H., Okazaki, K., Masaki, Y., Kawano, M., Yamamoto, M., Saeki, T., Matsui, S., Yoshino, T., Nakamura, S., 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 Pages: 21-30
  • Peer Reviewed
• [Journal Article] Six-transmembrane epithelial antigen of prostate 4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with 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., Sumida, T.
  • Journal Title: Clin.Exp.Rheumatol. Volume: 30 Pages: 99-102
  • Peer Reviewed
• [Journal Article] A novel clinical entity, IgG4-related disease (IgG4RD) : general concept 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., The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare Japan G4 team
  • Journal Title: Mod.Rheumatol. Volume: 22 Pages: 1-14
  • Peer Reviewed
• [Journal Article] Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis (2012)
  • Author(s): Tanaka, Y., Matsumoto, I., Iwanami, K., Inoue, A., Umeda, N., Sugihara, M., Hayashi, T., Ito, S., Sumida, T.
  • Journal Title: Mod.Rheumatol. Volume: 22 Pages: 128-36
  • Peer Reviewed
• [Journal Article] Overexpression of T-bet gene regulates murine 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., Sumida, T.
  • Journal Title: Arthritis Rheum. Volume: 64 Pages: 162-172
  • DOI: 10.1002/art.33335
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• [Journal Article] A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus erythematosus 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., Ikari, 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., Yamamoto, K.
  • Journal Title: PLoS Genet. Volume: 8
  • Peer Reviewed
• [Journal Article] Cumulative association of eight susceptibility genes with systemic lupus erythematosus 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., Tsuchiya, N.
  • Journal Title: J.Human Gen. Volume: 56 Pages: 503-507
  • DOI: 10.1038/jhg.2011.49
  • Peer Reviewed
• [Journal Article] TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women : a case-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., Tsuchiya, N.
  • Journal Title: Arhritis Reas.Ther. Volume: 13 Pages: R41
  • Peer Reviewed
• [Journal Article] Activation of natural killer T cells by α-carba-GalCer (RCAI-56), a novel synthetic glycoipid ligand, suppresses murine collagen-induced arhritis (2011)
  • Author(s): Yoshiga, Y., Goto, D., Segawa, S., Hayashi, T., Matsumoto, I., Ito, S., Taniguchi, M., Sumida, T.
  • Journal Title: Clin.Exp.Immunol. Volume: 164 Pages: 236-247
  • DOI: 10.1111/j.1365-2249.2011.04369.x
  • Peer Reviewed
• [Journal Article] Involvement of NK 1. 1-positive γδT cells in interleukin-18 plus interleukin-2-induced interstitial lung disease (2011)
  • Author(s): Segawa, S., Goto, D., Yoshiga, Y., Horikoshi, M., Sugihara, M., Hayashi, T., Chino, Y., Matsumoto, I., Ito, S., Sumida, T.
  • Journal Title: Am.J.Res.Cell.Mol.Biol. Volume: 45 Pages: 659-666
  • Peer Reviewed
• [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., Sumida, T.
  • Journal Title: Mod.Rheumatol. Volume: 21 Pages: 267-275
  • Peer Reviewed
• [Journal Article] Association of a functional polymorphism in the 3' untranslated region of SP11 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., Tsuchiya, N.
  • Journal Title: Arthritis Rheum. Volume: 63 Pages: 755-763
  • DOI: 10.1002/art.30188
  • Peer Reviewed
• [Journal Article] Importnace of serine727 phosphorylated STAT1 in IFN γ-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., Sumida, T.
  • Journal Title: Int.J.Rheum.Dis. Volume: 14 Pages: 86-91
  • DOI: 10.1111/j.1756-185X.2010.01575.x
  • Peer Reviewed