Previously-unappreciated roles for basophils in health and disease

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15H05786
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 烏山 一 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (60195013)
• Project Period (FY): 2015-05-29 – 2019-03-31
• Keywords: 好塩基球 / アレルギー / 炎症 / プロテアーゼ / トロゴサイト－シス / 抗原提示

Outline of Annual Research Achievements

これまでの研究で、好塩基球がIgE依存性皮膚慢性アレルギー炎症（IgE-CAI）の発症に必須の役割を果たしていることを明らかにしてきた。好塩基球に選択的に発現するプロテアーゼmMCP-11を欠損したマウスではIgE-CAIの皮膚病変部への白血球浸潤が半減することから、mMCP-11が白血球遊走に関与する可能性が強く示唆された。リコンビナントmMCP-11とトランスウェルを用いた解析から、mMCP-11が血中・組織中の蛋白質に作用して、その分解産物がG蛋白質共役受容体を介して好塩基球、好酸球や単球・マクロファージの遊走をひきおこすことが判明した。好塩基球特異的に発現するもうひとつプロテアーゼmMCP-8に関してもリコンビナント蛋白を作製して皮内注射したところ、好中球を主とした白血球浸潤が観察された。この場合、mMCP-11とは異なり、皮膚常在の細胞に作用してケモカイン産生を誘導することで、白血球遊走をひきおこすことが示唆された。
好塩基球がMHCクラスII分子（MHC-II）を発現して抗原提示細胞として機能するかどうかに関しては相反する実験結果が報告されたため、未解決のままであった。そこで本研究では好塩基球におけるMHC-II発現を詳細に検討した。その結果、好塩基球自体はMHC-II蛋白質を産生することはできないが、トロゴサイト－シス機構により樹状細胞から抗原ペプチド・MHC-II複合体を獲得して、Ｔ細胞に抗原提示することが出来るという新事実が明らかとなった。すなわち、好塩基球はこのトロゴサイト－シスを介した抗原ペプチド・MHC-II複合体獲得とともにIL-4を産生することで、ナイーブCD4 T細胞をTh2細胞へと分化させる能力を有することが判明した。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

予定通りmMCP-11ならびにmMCP-8のアレルギー炎症惹起の分子メカニズムの解析が進んだ。また、これまで結論が出ていなかった「好塩基球のMHC-IIの発現ならびに抗原提示能」に関して、トロゴサイト－シスを介するMHC-II獲得という予想外のメカニズムが存在することを見いだした。

Strategy for Future Research Activity

mMCP-8ならびにmMCP-11ノックアウトマウスの解析を進め、これら好塩基球由来プロテアーゼの生体内での役割を明らかにしていくとともに、その標的細胞・分子の同定を進める。また、好塩基球由来の脂質メディエーターの生体内での機能解析、好塩基球の遊走機構の解析もおこない、アレルギー疾患治療のための創薬標的の絞り込みを進める。

Research Products

• [Int'l Joint Research] Stanford Univ./Harvard Univ.(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Stanford Univ./Harvard Univ.
• [Int'l Joint Research] University of Regensburg(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: University of Regensburg
• [Int'l Joint Research] Imperial College London(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: Imperial College London
• [Journal Article] Basophil-specific protease mMCP-8 provokes an inflammatory response in the skin with microvascular hyperpermeability and leukocyte infiltration. (2017)
  • Author(s): Tsutsui, H., Yamanishi, Y., Ohtsuka, H., Sato, S., Yoshikawa, S., and Karasuyama, H.
  • Journal Title: J. Biol. Chem. Volume: 292 Pages: 1061-1067
  • DOI: 10.1074/jbc.M116.754648
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Trogocytosis of peptide-MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils (2017)
  • Author(s): Miyake, K., Shiozawa, N., Nagao, T., Yoshikawa, S., Yamanishi, Y., and Karasuyama, H.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 114 Pages: 1111-1116
  • DOI: 10.1073/pnas.1615973114
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis (2017)
  • Author(s): Balbino, B., Sibilano, R., Starkl, P., Marichal, T., Gaudenzio, N., Karasuyama, H., Bruhns, P., Tsai, M., Reber, L.L., and Galli, S.J.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 139 Pages: 584-596
  • DOI: 10.1016/j.jaci.2016.05.047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differences in the importance of mast cells, basophils, IgE and IgG, versus CD4+ T cells and ILC2 cells, in primary and secondary immunity to Strongyloides venezuelensis (2017)
  • Author(s): Mukai, K., Karasuyama, H., Kabashima, K., Kubo, M., and Galli, S.
  • Journal Title: Infect. Immun. Volume: 85 Pages: e-00053-17
  • DOI: 10.1128/IAI.00053-17
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differential usage of COX-1 and COX-2 in prostaglandin production by mast cells and basophils (2017)
  • Author(s): Bando, T., Fujita, S., Nagano, N., Hayashi, A., Yoshikawa, S., Yamanishi, Y., Minami, M., Tada, H., Kishikawa, K., and Karasuyama, H.
  • Journal Title: Biochem Biophys Rep. Volume: 10 Pages: 82-87
  • DOI: 10.1016/j.bbrep.2017.03.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MIP-1a/CCL3-expressing basophil-lineage cells drive the leukemic hematopoiesis of chronic myeloid leukemia in mice (2016)
  • Author(s): Baba, T., Tanabe, Y., Yoshikawa, S., Yamanishi, Y., Morishita, S., Komatsu, N., Karasuyama, H., Hirano, A., and Mukaida, N.
  • Journal Title: Blood Volume: 127 Pages: 2607-2617
  • DOI: 10.1182/blood-2015-10-673087
  • Peer Reviewed
• [Journal Article] Basophils trigger fibroblast activation in cardiac allograft fibrosis development (2016)
  • Author(s): Schiechl, G., Hermann, F.J., Rodriguez Gomez, M., Kutzi, S., Schmidbauer, K., Talke, Y., Neumayer, S., Goebel, N., Renner, K., Bruehl, H., Karasuyama, H., Obata-Ninomiya, K., Utpatel, K., Evert, M., Hirt, S.W., Geissler, E.K., Fichtner-Feigl, S., Mack, M.
  • Journal Title: Am. J. Transplant. Volume: 16 Pages: 2574-2588
  • DOI: 10.1111/ajt.13764
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Basophils and mast cells in immunity and inflammation. (2016)
  • Author(s): Yamanishi, Y., and Karasuyama, H.
  • Journal Title: Semin. Immunopathol. Volume: 38 Pages: 535-537
  • DOI: 10.1007/s00281-016-0582-0
  • Peer Reviewed
• [Journal Article] Basophil-derived IL-4 plays versatile roles in immunity (2016)
  • Author(s): Yamanishi, Y., and Karasuyama, H.
  • Journal Title: Semin. Immunopathol. Volume: 38 Pages: 615-622
  • DOI: 10.1007/s00281-016-0568-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Real-time imaging of mast cell degranulation in vitro and in vivo (2016)
  • Author(s): Horiguchi, K., Yoshikawa, S., Saito, A., Haddad, S., Ohta, T., Miyake, K., Yamanishi, Y., and Karasuyama, H.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 479 Pages: 517-522
  • DOI: 10.1016/j.bbrc.2016.09.100
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Allergic skin sensitization promotes eosinophilic esophagitis via the interleukin-33-basophil axis (2016)
  • Author(s): Venturelli, N., Lexmond, W.S., Ohsaki, A., Nurko, S., Karasuyama, H., Fiebiger E., and Oyoshi, M.K.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 138 Pages: 1367-1380
  • DOI: 10.1016/j.jaci.2016.02.034
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel CD200 homologues iSEC1 and iSEC2 are gastrointestinal secretory cell-specific ligands of inhibitory receptor CD200R (2016)
  • Author(s): Kojima, T., Tsuchiya, K., Ikemizu, S., Yoshikawa, S., Yamanishi, Y., Watanabe, M., and Karasuyama, H.
  • Journal Title: Sci. Rep. Volume: 6 Pages: 36457
  • DOI: 10.1038/srep36457
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Basophil tryptase mMCP-11 plays a crucial role in IgE-mediated, delayed-onset allergic inflammation in mice (2016)
  • Author(s): Iki, M., Tanaka, K., Deki, H., Fujimaki, M., Sato, S., Yoshikawa, S., Yamanishi, Y., and Karasuyama, H.
  • Journal Title: Blood Volume: 128 Pages: 2909-2918
  • DOI: 10.1182/blood-2016-07-729392
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Basophils in immune-related disease (2017)
  • Author(s): Karasuyama, H.
  • Organizer: Third International Symposium on IgG4-RD and Fibrosis
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2017-02-16
  • Int'l Joint Research / Invited
• [Presentation] Emerging roles of basophils in allergy and immunity (2016)
  • Author(s): Karasuyama, H.
  • Organizer: 41th JSID Annual Meeting
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2016-12-09
  • Invited
• [Presentation] Basophils gain the capacity of antigen presentation by acquiring MHC class II molecules from dendritic cells through trogocytosis (2016)
  • Author(s): Miyake, K., Shiozawa, N., Nagao, T., Kawawa, M., Yoshikawa, S., Yamanishi, Y., Karasuyama, H.
  • Organizer: The 45th Annual Meeting of the JSI
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-12-05 – 2016-12-07
• [Presentation] Basophil-selective mMCP-11 plays crucial roles in the development of IgE-mediated chronic allergic inflammation in the skin (2016)
  • Author(s): Iki, M., Tanaka, K., Deki, H., Nagao, T, Horibe, M., Sato, S., Yoshikawa, S., Yamanishi Y., Karasuyama, H.
  • Organizer: The 45th Annual Meeting of the JSI
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-12-05 – 2016-12-07
• [Presentation] STIM2 plays an essential role in IL-4 production by IL-33-stimulated basophils (2016)
  • Author(s): Yoshikawa, S, Oh-hora, M., Yamanishi, Y., Karasuyama, H.
  • Organizer: The 45th Annual Meeting of the JSI
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-12-05 – 2016-12-07
• [Presentation] Emerging roles of basophils in acquired protective immunity to tick infestation (2016)
  • Author(s): Karasuyama, H.
  • Organizer: XXV International Congress of Entomology
  • Place of Presentation: Orland, USA
  • Year and Date: 2016-09-29
  • Int'l Joint Research / Invited
• [Presentation] mMCP-8, a basophil specific protease, triggers an inflammatory response by stimulating fibroblasts to produce chemokines (2016)
  • Author(s): Tsutsui, H., Yamanishi, Y., Yoshikawa, S., Sato, S., Karasuyama, H.
  • Organizer: The 16th International Congress of Immunology
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21 – 2016-08-26
  • Int'l Joint Research
• [Presentation] STIM1/2 plays essential roles in basophil activation and development of IgE-mediated chronic allergic inflammation (2016)
  • Author(s): Yoshikawa, S, Oh-hora, M., Adachi, T., Yamanishi, Y., Karasuyama, H.
  • Organizer: The 16th International Congress of Immunology
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-08-21 – 2016-08-26
• [Presentation] Sugar modification of carrier protein in allergen determines the magnitude of IgE- and basophil-mediated allergic inflammation (2016)
  • Author(s): Nagao, T., Takahashi, S., Kawawa, M., Miyake, K., Yoshikawa, S., Yamanishi, Y., Karasuyama, H.
  • Organizer: The 16th International Congress of Immunology
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2016-08-21 – 2016-08-26
• [Presentation] Emerging roles of basophils and IgE in allergy and immunity (2016)
  • Author(s): Karasuyama, H.
  • Organizer: FASEB Conference “IgE and Allergy”
  • Place of Presentation: West Palm Beach, USA
  • Year and Date: 2016-07-26
  • Int'l Joint Research / Invited
• [Remarks] 東京医科歯科大学・大学院医歯学総合研究科・免疫アレルギー分野
  • URL: http://immune-regulation.org
• [Remarks] プレス報道 「 希少細胞である好塩基球によるアレルギー誘導の謎が解けた! 」
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20170117.pdf
• [Remarks] プレス報道 「 アレルギー炎症を引き起こす新たな鍵分子を発見 」
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20161028.pdf