Elucidation of T-independent IgA class switch machinery

• Project/Area Number: 17H04089
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Keio University
• Principal Investigator: Hase Koji 慶應義塾大学, 薬学部(芝共立), 教授 (20359714)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: IgA抗体 / 腸内細菌 / 酪酸 / IgA / 粘膜免疫 / 短鎖脂肪酸 / 腸管免疫 / 免疫学 / 細胞・組織 / 細菌

Outline of Final Research Achievements

Secretory immunoglobulin A, the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensal-bacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon.

Academic Significance and Societal Importance of the Research Achievements

近年、腸内共生バランス失調（ディスバイオーシス）が炎症性腸疾患、自己免疫性疾患、動脈硬化、がん、糖尿病、肝硬変などの発症と関連するとの報告が相次いでいる。分泌型IgAは腸内細菌のバランス制御にも関わっており、分泌型IgAの質と量を適切に保つことは、ディスバイオーシスの防止に重要である。よって、本研究で行った分泌型IgA抗体の産生機構の解明は、腸内環境の改善を標的とした新たな医療の発展に繋がるものと期待できる。

Research Products

• [Int'l Joint Research] Max-Plank-Institute(ドイツ)
• [Int'l Joint Research] Max-Planck-Institute(ドイツ)
• [Journal Article] Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice (2020)
  • Author(s): Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K.
  • Journal Title: Science Volume: 367 Issue: 6481 Pages: 8429-8429
  • DOI: 10.1126/science.aaw8429
  • Peer Reviewed / Open Access
• [Journal Article] Osteoprotegerin-dependent Mcell self-regulation balances gut infection and immunity. (2020)
  • Author(s): Kimura S, Nakamura Y, Kobayashi N, Shiroguchi K, KawakamiE, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, KaishoT, Iwanaga T, Hase K.
  • Journal Title: Nat Commun Volume: 11 Issue: 1 Pages: 234-234
  • DOI: 10.1038/s41467-019-13883-y
  • Peer Reviewed / Open Access
• [Journal Article] Microfold cell-dependent antigen transport alleviates infectious colitis by inducing antigen-specific cellular immunity (2020)
  • Author(s): Nakamura Yutaka、Mimuro Hitomi、Kunisawa Jun、Furusawa Yukihiro、Takahashi Daisuke、Fujimura Yumiko、Kaisho Tsuneyasu、Kiyono Hiroshi、Hase Koji
  • Journal Title: Mucosal Immunology Volume: in press Issue: 4 Pages: 679-690
  • DOI: 10.1038/s41385-020-0263-0
  • Peer Reviewed / Open Access
• [Journal Article] Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon. (2020)
  • Author(s): Junya Isobe, Shintarou Maeda, Yuuki Obata, Keito Iizuka, Yutaka Nakamura, Yumiko Fujimura, Tatsuki Kimizuka, Kouya Hattori, Yun-Gi Kim, Tatsuya Morita, Ikuo Kimura, Stefan Offermanns, Takahiro Adachi, Atsuhito Nakao, Hiroshi Kiyono, Daisuke Takahashi, Koji Hase
  • Journal Title: International Immunology Volume: 32 Issue: 4 Pages: 243-258
  • DOI: 10.1093/intimm/dxz078
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces (2019)
  • Author(s): Mabbott Neil A.、Hase Koji
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 2773-2773
  • DOI: 10.3389/fimmu.2019.02773
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases (2019)
  • Author(s): Kobayashi Nobuhide、Takahashi Daisuke、Takano Shunsuke、Kimura Shunsuke、Hase Koji
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 2345-2345
  • DOI: 10.3389/fimmu.2019.02345
  • Peer Reviewed / Open Access
• [Journal Article] Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses (2019)
  • Author(s): Nagai M、Noguchi R、Takahashi D、Morikawa T、Koshida K、Komiyama S、Ishihara N、Yamada T、Kawamura YI.、Muroi K、Hattori K、Kobayashi N、Fujimura Y、Hirota M、Matsumoto R、Aoki R、Tamura-Nakano M、Sugiyama M、Katakai T、Sato S、Takubo K、Dohi T、Hase K
  • Journal Title: Cell Volume: 178 Issue: 5 Pages: 1072-1087
  • DOI: 10.1016/j.cell.2019.07.047
  • Peer Reviewed
• [Journal Article] Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis (2019)
  • Author(s): Yamada Takahiro、Hino Shingo、Iijima Hideki、Genda Tomomi、Aoki Ryo、Nagata Ryuji、Han Kyu-Ho、Hirota Masato、Kinashi Yusuke、Oguchi Hiroyuki、Suda Wataru、Furusawa Yukihiro、Fujimura Yumiko、Kunisawa Jun、Hattori Masahira、Fukushima Michihiro、Morita Tatsuya、Hase Koji
  • Journal Title: EBioMedicine Volume: 48 Pages: 513-525
  • DOI: 10.1016/j.ebiom.2019.09.008
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of inflammatory response of macrophages and induction of regulatory T cells by using retinoic acid-loaded nanostructured lipid carrier (2019)
  • Author(s): Zai Khadijah、Ishihara Narumi、Oguchi Hiroyuki、Hirota Masato、Kishimura Akihiro、Mori Takeshi、Hase Koji、Katayama Yoshiki
  • Journal Title: Journal of Biomaterials Science, Polymer Edition Volume: 30 Issue: 1 Pages: 1-11
  • DOI: 10.1080/09205063.2018.1493671
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A partial agonist for retinoid X receptor mitigates experimental colitis (2018)
  • Author(s): Onuki Masayoshi、Watanabe Masaki、Ishihara Narumi、Suzuki Koichiro、Takizawa Kei、Hirota Masato、Yamada Takahiro、Egawa Aiko、Shibahara Osamu、Nishii Midori、Fujihara Michiko、Makishima Makoto、Takahashi Daisuke、Furusawa Yukihiro、Kakuta Hiroki、Hase Koji
  • Journal Title: International Immunology Volume: 31 Issue: 4 Pages: 251-262
  • DOI: 10.1093/intimm/dxy089
  • Peer Reviewed / Open Access
• [Journal Article] Oral Administration of Porphyromonas gingivalis Alters the Gut Microbiome and Serum Metabolome (2018)
  • Author(s): Kato Tamotsu、Yamazaki Kyoko、Nakajima Mayuka、Date Yasuhiro、Kikuchi Jun、Hase Koji、Ohno Hiroshi、Yamazaki Kazuhisa
  • Journal Title: mSphere Volume: 3 Issue: 5 Pages: 1-11
  • DOI: 10.1128/msphere.00460-18
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic effect of vitamin D3-containing nanostructured lipid carriers on inflammatory bowel disease (2018)
  • Author(s): Zai Khadijah、Hirota Masato、Yamada Takahiro、Ishihara Narumi、Mori Takeshi、Kishimura Akihiro、Suzuki Koichiro、Hase Koji、Katayama Yoshiki
  • Journal Title: Journal of Controlled Release Volume: 286 Pages: 94-102
  • DOI: 10.1016/j.jconrel.2018.07.019
  • Int'l Joint Research
• [Journal Article] Intestinal Epithelial Cell-specific Deletion of α-Mannosidase II Ameliorates Experimental Colitis (2018)
  • Author(s): Suzuki K., Yamada T, Yamazaki K, Hirota M, Ishihara N, Sakamoto M, Takahashi D, Iijima H, Hase K.
  • Journal Title: Cell Structure and Function Volume: 43 Issue: 1 Pages: 25-39
  • DOI: 10.1247/csf.17022
  • NAID: 130006513071
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] Macrophage extracellular chromatin release induced by Mac-1 mediated platelet-macrophage interactions triggers acute kidney injury in rhabdomyolysis. (2018)
  • Author(s): Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A, Yamamoto K, Hase K, Homma K, Sasaki J, Miyauchi H, Hoshino T, Hayashi M, Mayadas TN, Hirahashi J.
  • Journal Title: Nat. Med. Volume: 24 Issue: 2 Pages: 232-238
  • DOI: 10.1038/nm.4462
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake. (2017)
  • Author(s): Jinnohara T, Kanaya T, Hase K, Sakakibara S, Kato T, Tachibana N, Sasaki T, Hashimoto Y, Sato T, Watarai H, Kunisawa J, Shibata N, Williams I, Kiyono H, and Ohno H.
  • Journal Title: J. Exp. Med. Volume: 214 Issue: 6 Pages: 1607-1618
  • DOI: 10.1084/jem.20160770
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 栄養シグナルによる免疫バリアの制御 (2020)
  • Author(s): 長谷耕二
  • Organizer: 東邦大学研究ブランディング事業最終シンポジウム
  • Invited
• [Presentation] 栄養シグナルによるパイエル板リンパ球動態制御 (2019)
  • Author(s): 長谷耕二
  • Organizer: 30th Forum in DOJIN “Nutrio-Metabolomic Pathology”
  • Invited
• [Presentation] Nutritional signals regulate lymphocyte homing to gut-associated lymphoid tissue (2019)
  • Author(s): Koji Hase
  • Organizer: The 7th International Conference on Food Factors (ICoFF2019)
  • Int'l Joint Research / Invited
• [Presentation] 栄養シグナルによるパイエル板リンパ球動態制御 (2019)
  • Author(s): 長谷耕二
  • Organizer: Science Pioneers Consortium (SPC) 2019
  • Invited
• [Presentation] 腸内細菌を標的とした創薬イノベーション (2019)
  • Author(s): 長谷耕二
  • Organizer: JASIS2019ライフサイエンスイノベーション
  • Invited
• [Presentation] Nutritional Signals regulate lymphocyte homing to gut-associated lymphoid tissue (2019)
  • Author(s): Koji Hase
  • Organizer: The 48th Annual Meeting of Japanese Society for Immunology
  • Int'l Joint Research / Invited
• [Presentation] 食物アレルギーの発症に及ぼす腸内代謝物の影響 (2019)
  • Author(s): 長谷耕二
  • Organizer: 第68回日本アレルギー学会
  • Invited
• [Presentation] 栄養シグナルによるパイエル板リンパ球動態制御 (2019)
  • Author(s): 長谷耕二
  • Organizer: 日本食品免疫学会設立15周年記念学術集会
  • Invited
• [Presentation] 腸管における免疫監視機構 (2019)
  • Author(s): 長谷耕二
  • Organizer: 第22回 日本臨床腸内微生物学会総会・学術集会
  • Invited
• [Presentation] Microbiota-derived metabolites shape mucosal barrier and immunity (2017)
  • Author(s): Koji Hase
  • Organizer: Korean Society of Nephrology (KSN) 2017
  • Int'l Joint Research / Invited