粘膜免疫と自己識別

2011 年度 研究成果報告書

• 研究領域: 免疫系自己-形成・識別とその異常
• 研究課題/領域番号: 19059003
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 東京大学
• 研究代表者: 清野 宏 東京大学, 医科学研究所, 教授 (10271032)
• 研究分担者: シドニア ファガラサン 理化学研究所, 免疫アレルギーセンター科学総合研究センター, チームリーダー (00391970)
• 研究期間 (年度): 2007 – 2011
• キーワード: 共生細菌 / パイエル板 / Alcaligenes / フコシル化 / IgA / 孤立リンパ濾胞 / M細胞 / Tfh細胞

研究概要

我々の腸管内に共生している腸内細菌の中には、腸管リンパ組織内を生息場所としているものがあった。この細菌群の局在には宿主側の粘膜免疫機構が必要であり、その宿主-細菌間の共生機構の破綻は炎症性腸疾患を始めとする慢性炎症の発症に繋がる事が示唆された。また、粘膜免疫の恒常性維持には、腸内細菌、粘膜免疫担当細胞、上皮細胞の三者間相互作用によって厳密に制御されていることが明らかとなり、これらの相互作用の破綻は粘膜免疫のみにとどまらず、全身免疫系の異常にも繋がっている事が示唆された。

研究成果

• [雑誌論文] Impaired selection of IgA and intestinal dysbiosis associated with PD-1-deficiency (2013)
  • 著者名/発表者名: Maruya, M., Kawamoto, S., Kato, LM., and Fagarasan, S
  • 雑誌名: Gut Microbes 巻: 4(2) ページ: 65-71
• [雑誌論文] Nuclear transferred embryonic stem cells for analysis of B1 B-lymphocyte development (2013)
  • 著者名/発表者名: Takase, M., Iida, R., Maruya, M., Sakaue-Sawano, A., Miyawaki, A., Wakayama, T., Nishigami, S., Fagarasan, S. and Kanagawa O
  • 雑誌名: Int Immunol 巻: 25(3) ページ: 145-56
• [雑誌論文] The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut (2012)
  • 著者名/発表者名: Kawamoto, S., Tran, TH., Maruya, M., Suzuki, K., Doi, Y., Tsutsui, Y., Kato, LM., and Fagarasan, S
  • 雑誌名: Science. Apr 巻: 336(6080) ページ: 485-9
• [雑誌論文] The airway antigen sampling system: Respiratory M cells as an alternative gateway for inhaled antigens (2011)
  • 著者名/発表者名: Kim, D-Y., Sato, A., Fukuyama, S., Sagara, H, Nagatake, T., Kong, IG., Goda, K., Nochi, T., Kunisawa, J., Sato, S., Yokota, Y., Lee, CH., and Kiyono, H
  • 雑誌名: J. Immunol 巻: 186 ページ: 4253-4262
• [雑誌論文] Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells (2011)
  • 著者名/発表者名: Maruya M, Suzuki K, Fujimoto H, Miyajima M, Kanagawa O, Wakayama T, and Fagarasan, S
  • 雑誌名: Proc Natl Acad Sci U S A 巻: 108(2) ページ: 722-7
• [雑誌論文] Epithelial cell microRNAs in gut immunity (2011)
  • 著者名/発表者名: Goto, Y., and Kiyono, H
  • 雑誌名: Nat Immunol 巻: 12 ページ: 195-197
• [雑誌論文] Peaceful mutualism in the gut: revealing key commensal bacteria for the creation and maintenance of immunological homeostasis (2011)
  • 著者名/発表者名: Kunisawa, J., and Kiyono, H
  • 雑誌名: Cell Host Microbe 巻: 9 ページ: 83-84
• [雑誌論文] Distinct fucosylation of M cells and epithelial cells by Fut1 and Fut2, respectively, in response to intestinal environmental stress (2011)
  • 著者名/発表者名: Terahara, K., Nochi, T., Yoshida, M., Takahashi, Y., Goto, Y., Hatai, H., Kurokawa, S., Jang, H-M., Kweon, M-N, Domino, SE., Hiroi, T., Yuki, Y., Tsunetsugu-Yokota, Y., Kobayashi, K., and Kiyono, H
  • 雑誌名: Biochem. Biophys. Res. Commun 巻: 404 ページ: 822-828
• [雑誌論文] Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis (2010)
  • 著者名/発表者名: Fagarasan, S., Kawamoto, S., Kanagawa, O and Suzuki, K
  • 雑誌名: Annu Rev Immunol 巻: 28 ページ: 243-73
• [雑誌論文] The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut (2010)
  • 著者名/発表者名: Suzuki, K., Maruya, M., Kawamoto, S., Sitnik, K., Kitamura, H., Agace, WW and Fagarasan, S
  • 雑誌名: Immunity. Jul 巻: 33(1) ページ: 71-83
• [雑誌論文] Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines (2010)
  • 著者名/発表者名: Nochi, T., Yuki, Y., Takahashi, H., Sawada, SI., Mejima, M., Kohda, T., Harada, N., Kong, IG., Sato, A., Kataoka, N., Tokuhara, D., Kurokawa, S., Takahashi, Y., Tsukada, H., Kozaki, S., Akiyoshi, K., and Kiyono, H
  • 雑誌名: Nature Mater 巻: 9 ページ: 572-578
• [雑誌論文] Secretory IgA-mediated protection against V. cholerae and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine (2010)
  • 著者名/発表者名: Tokuhara, D., Yuki, Y., Nochi, T., Kodama, T., Mejima, M., Kurokawa, S., Takahashi, Y., Nanno, M., Nakanishi, U., Takaiwa, F., Honda, T., and Kiyono, H
  • 雑誌名: Proc. Natl. Acad. Sci. USA 巻: 107 ページ: 8794-8799
• [雑誌論文] Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis (2010)
  • 著者名/発表者名: Obata, T., Goto, Y., Kunisawa, J., Sato, S., Sakamoto, M., Setoyama, H., Matsuki, T., Nonaka, K., Shibata, N., Gohda, M., Kagiyama, Y., Nochi, T., Yuki, Y., Fukuyama, Y., Mukai, A., Shinzaki, S., Fujihashi, K., Sasakawa, C., Iijima, H., Goto, M., Umesaki, Y., Benno, Y., and Kiyono, H
  • 雑誌名: Proc. Natl. Acad. Sci. USA 巻: 107 ページ: 7419-7424
• [雑誌論文] Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis (2010)
  • 著者名/発表者名: Fagarasan, S. et al.
  • 雑誌名: Adv Immunol 巻: 107 ページ: xiii-xiv
• [雑誌論文] B cell-specific and stimulation-responsive enhancers derepress (2010)
  • 著者名/発表者名: Tran, TH., Nakata, M., Suzuki, K., Begum, NA., Shinkura, R., Fagarasan, S. and Honjo, T and Nagaoka H
  • 雑誌名: Aicda by overcoming the effects of silencers 巻: 11(2) ページ: 148-54
• [雑誌論文] Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches (2009)
  • 著者名/発表者名: Tsuji, M., Komatsu, N., Kawamoto, S., Suzuki, K., Kanagawa, O., Honjo, T., Hori, S and Fagarasan, S
  • 雑誌名: Science 巻: 13;323(5920) ページ: 1488-92
• [雑誌論文] Diverse regulatory pathways for IgA synthesis in the gut (2009)
  • 著者名/発表者名: Suzuki, K., and Fagarasan, S
  • 雑誌名: Mucosal Immunol 巻: 2(6) ページ: 468-71
• [雑誌論文] A Rice-based oral cholera vaccine induces macaque-specific systemic neutralizing Abs but does not influence pre-existing intestinal immunity (2009)
  • 著者名/発表者名: Nochi, T., Yuki,Y., Katakai, Y., Shibata, H., Tokuhara,D., Mejima, M., Kurokawa,S., Takahashi,Y., Nakanishi, U., Ono, F., Mimuro, H., Sasakawa, S., Takaiwa, F., Terao, K., and Kiyono, H
  • 雑誌名: J. Immunol 巻: 183 ページ: 6538-6544
• [雑誌論文] Expression of newly identified secretory CEACAM1(a) isoforms in the intestional epithelium (2009)
  • 著者名/発表者名: Terahara, K., Yoshida, M., Taguchi, F., Igarashi, O., Nochi, T., Gotoh, Y., Yamamoto, T., Tsunetsugu-Yokota, Y., Beauchemin, N., and Kiyono, H
  • 雑誌名: Biochem Biophys Res Commun 巻: 383 ページ: 340-346
• [雑誌論文] RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium (2009)
  • 著者名/発表者名: Knoop, KA., Kumar, N., Butler, BR., Sakthivel, SK., Taylor, RT., Nochi, T., Akiba, H., Yagita, H., Kiyono, H., and Williams, IR
  • 雑誌名: J. Immunol 巻: 183 ページ: 5738-5747
• [雑誌論文] Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response (2009)
  • 著者名/発表者名: Hase, K., Kawano, K., Nochi, T., Pontes, GS., Fukuda, S., Ebisawa, M., Kadokura, K., Tobe, T., Fujimura, Y., Kawano, S., Yabashi, A., Waguri, S., Nakato, G., Kimura, S., Murakami, T., Iimura, M., Hamura, K., Fukuoka, S., Lowe, AW., Itoh, K., Kiyono, H., and Ohno, H
  • 雑誌名: Nature 巻: 462 ページ: 226-230
• [雑誌論文] Mucosal immunosenescence : New developments and vaccines to control infectious diseases (2009)
  • 著者名/発表者名: Fujihashi, K. and Kiyono, H
  • 雑誌名: Trends Immunol 巻: 30 ページ: 334-343
• [雑誌論文] Id2-, RORγt-, and LTβR-independent lymphoid organogenesis in ocular immunity (2009)
  • 著者名/発表者名: Nagatake, T., Fukuyama, S, Kim. D-Y., Goda, K., Igarashi.O., Sato,S., Nochi, T., Sagara, H.,Yokota, Y., Jetten, AM., Kaisho, T., Akira, A., Mimuro, H., Sasakawa, C., Fukui, Y., Fujihashi, K., Akiyama, T., Inoue, J., Penninger, J.M., Kunisawa, J., and Kiyono, H
  • 雑誌名: J. Exp. Med 巻: 206 ページ: 2351-2364
• [雑誌論文] Peyer's patches are required for intestinal IgA responses to Salmonella (2008)
  • 著者名/発表者名: Hashizume, T., Togawa, A., Nochi, T., Igarashi, O., Kweon, MN., Kiyono, H. and Yamamoto, M
  • 雑誌名: Infect. Immun 巻: 76 ページ: 927-934
• [雑誌論文] Colonic patches direct the cross-talk between systemic compartments and large intestine independently of innate immunity (2008)
  • 著者名/発表者名: Chang, SY., Cha, HR., Uematsu, S., Akira, S., Igarashi, O., Kiyono, H., and Kweon, M-N
  • 雑誌名: J. Immunol 巻: 180 ページ: 1609-18
• [雑誌論文] Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5 (2008)
  • 著者名/発表者名: Uematsu, S., Fujimoto, K., Jang, MH., Yang, BG., Jung, YJ., Nishiyama, M., Sato, S., Tsujimura, T., Yamamoto, M., Yokota, Y., Kiyono, H., Miyasaka, M., Ishii, KJ., and Akira, S
  • 雑誌名: Nature Immunol 巻: 9 ページ: 769-776
• [雑誌論文] Comprehensive gene expression analysis among Peyer's patch M cells, villous M cells and intestinal epithelial cells by DNA microarray analysis (2008)
  • 著者名/発表者名: Terahara, K., Yoshida, M., Igarashi, O., Nochi, T., Pontes, GS., Hase, K., Ohno, H., Kurokawa, S., Mejima, M., Takayama, N., Yuki, Y., Lowe, AW. and Kiyono, H
  • 雑誌名: J. Immunol 巻: 180 ページ: 7840-7846
• [雑誌論文] The mucosa: at the frontlines of immunity (2008)
  • 著者名/発表者名: Fehervari1, Z., and Kiyono, H
  • 雑誌名: Trends Immunol 巻: 29 ページ: 503-504
• [学会発表] PD-1 Defeciency Skews the Gut Microbiota by altering the IgA Selection in Gut (2012)
  • 著者名/発表者名: Fagarasan, S
  • 学会等名: The 2012 Spring Conference of the Korean Association of Immunologists
  • 発表場所: Seoul, Korea
  • 年月日: 20120400
• [学会発表] Mucosal Decisions of Mutualisum and Elimination for Surface barrier system (2012)
  • 著者名/発表者名: Invited Speaker
  • 学会等名: The 6^<th> Annual International Symposium in Institute of Dermatological Science(IDS)
  • 発表場所: Seoul, Korea
  • 年月日: 20120200
• [学会発表] The Mucosal Gateway System for Antigen-sampling and Homestatic Niche (2011)
  • 著者名/発表者名: Invited Speaker
  • 学会等名: The 15^<th> International Congress of Mucosal Immunology
  • 発表場所: Paris, France
  • 年月日: 20110700
• [学会発表] Intra-Tissue Habitation of Commensal Bacteria in Peyer's patches for Gut Immunity (2010)
  • 著者名/発表者名: Invited Speaker
  • 学会等名: The 8^<th> German-Japanease International Symposium, Regulation of Immune Response and Diseases
  • 発表場所: Cuxhahen, Germany
  • 年月日: 20100900
• [学会発表] Mucosal Decision of Immunity and Tolerance (2010)
  • 著者名/発表者名: Invited Speaker
  • 学会等名: The 83^<rd> Annunal Meeting of Japanese Society for Bacteriology
  • 発表場所: Yokohama, Japan
  • 年月日: 20100300
• [学会発表] T-dependent and T-independent IgA responses in the gut (2009)
  • 学会等名: Annual Meeting of The Japanese Society for Immunology
  • 発表場所: Osaka
  • 年月日: 20091200
• [学会発表] Session 1"Id2, RORγt, and LTβR independent initiation of TALT genesis in ocular immunity."and Session 2" Indigenous Opportunistic Bacteria Inhabit Mammalian Gut-associated Lymphoid Tissues for Gut Immunity" (2009)
  • 学会等名: Trudeau Institute Mucosal Immunology Workshop
  • 発表場所: New York, USA
  • 年月日: 20091000
• [学会発表] T-dependent and T-independent IgA responses in the gut (2009)
  • 学会等名: Microanatomy of the Immune Responses in Health and Disease
  • 発表場所: University of Birmingham, UK
  • 年月日: 20090900
• [学会発表] Development of Intestinal Symbiosis by the Mucosal Immune System (2009)
  • 著者名/発表者名: Invited Speaker
  • 学会等名: The 63^<th> Japanese Society for Bacteriology Tohoku District Research Conference
  • 発表場所: Morioka, Japan
  • 年月日: 20090800
• [学会発表] The Mucosal Immune System for the Creation of Gut Symbiosis (2009)
  • 学会等名: The 91^<st> Japanese Association of Gastroenteology, Chugoku Division Meeting
  • 発表場所: Okayama, Japan
  • 年月日: 20090600
• [学会発表] Mucosal Decision of Immunity and Tolerance for Creation of Symbiosis (2009)
  • 著者名/発表者名: Invited Speaker
  • 学会等名: The 6^<th> Extraordinary International Symposium on Recent Advances in Otitis Media
  • 発表場所: Seoul, Korea
  • 年月日: 20090500
• [図書] 臨床粘膜免疫学
  • 著者名/発表者名: 清野宏
  • 出版者: (株)シナジー