ネオ・セルフ生成機構としての免疫プロテアソームの機能的意義

2018 Fiscal Year Annual Research Report

• Project Area: Creation, function and structure of neo-self
• Project/Area Number: 17H05799
• Research Institution: Wakayama Medical University
• Principal Investigator: 改正 恒康 和歌山県立医科大学, 先端医学研究所, 教授 (60224325)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 炎症 / 自己炎症性疾患 / 免疫プロテアソーム / T細胞 / 遺伝子変異

Outline of Annual Research Achievements

免疫プロテアソームはいくつかのサブユニットから構成されるタンパク複合体であり、不要または不良のタンパク質の分解除去と共に、MHCクラスIと会合する抗原の生成にも必須であり、ネオセルフの生成にも重要な役割を果たしていると考えられる。免疫プロテアソームのサブユニットの変異により難治性の炎症性疾患が生じることがわかってきており、そのような疾患群をproteasome-associated autoinflammatory syndrome (PRAAS)と総称することが提唱されている。我々は、PRAAS様の症状を呈する患者においてみとめられた、免疫プロテアソームのサブユニットβ1iのアミノ酸置換をきたすde novoの新規のヘテロ遺伝子変異（β1iX）を、CRISPR法によりマウスに導入した。β1iXヘテロ変異マウスは外見には特に異常を認めなかったが、胸腺の細胞数が顕著に減少し、皮髄境界が不明瞭になっていた。また、脾臓においては、CD8陽性T細胞ばかりでなく、CD4陽性T細胞、B細胞の減少が認められ、濾胞の形成が障害されていた。さらに血中では、IgMを含むすべてのアイソタイプの免疫グロブリンが低下していた。一方、脾臓や骨髄などで、好中球、単球など骨髄系の細胞の増加が認められた。これらのマウスの表現型は、患者の症状に似た点が多く認められた。これまでに報告されている免疫プロテアソームのサブユニット欠損マウスでは、CD8陽性T細胞の減少以外の表現型はほとんど報告されていないことから、β1iXヘテロ変異により、単に免疫プロテアソームの機能低下が生じたのではなく、機能修飾が生じている可能性が示唆された。β1iXヘテロ変異マウスの解析をネオセルフの生成という観点から進めることにより、PRAASの病態と共に、免疫プロテアソームの新たな役割が明らかになることが期待される。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Yale Univ./Harvard Medical School/Emory Univ.(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Yale Univ./Harvard Medical School/Emory Univ.
  • # of Other Institutions: 28
• [Int'l Joint Research] Univ.of Melbourne/Australian National Univ./Telethon Kids Institute(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Univ.of Melbourne/Australian National Univ./Telethon Kids Institute
  • # of Other Institutions: 2
• [Int'l Joint Research] Mainz Univ./Bonn Univ./Univ. Hospital Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Mainz Univ./Bonn Univ./Univ. Hospital Cologne
  • # of Other Institutions: 13
• [Int'l Joint Research] London Research Institute/Imperial College/Cardiff Univ.(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: London Research Institute/Imperial College/Cardiff Univ.
  • # of Other Institutions: 2
• [Int'l Joint Research] San Raffaele Scientific Institute/ICGEB(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: San Raffaele Scientific Institute/ICGEB
• [Int'l Joint Research]
  • # of Other Countries: 4
• [Journal Article] A defined commensal consortium elicits CD8 T cells and anti-cancer immunity (2019)
  • Author(s): T.Tanoue, S.Morita, D.R.Plichta, A.N.Skelly, W.Suda, Y.Sugiura, S.Narushima, H.Vlamakis, I.Motoo, K.Sugita, A.Shiota, K.Takeshita, K.Yasuma, D.Riethmacher, T.Kaisho, J.M.Norman, D.Mucida, M.Suematsu, T.Yaguchi, V.Bucci, T.Inoue, Y.Kawakami, B.Olle, B.Roberts, M.Hattori, R.J.Xavier, K.Atarashi, K.Honda
  • Journal Title: Nature Volume: 565 Pages: 600～605
  • DOI: 10.1038/s41586-019-0878-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cholera toxin B induces interleukin-1β production from resident peritoneal macrophages through the pyrin inflammasome as well as the NLRP3 inflammasome (2019)
  • Author(s): 5.T. Orimo, I. Sasaki, H. Hemmi, T. Ozasa, Y. Fukuda-Ohta, T. Ohta, M. Morinaka, M. Kitauchi, T. Yamaguchi, Y. Sato, T. Tanaka, K. Hoshino, K. I. Katayama, S. Fukuda, K. Miyake, M. Yamamoto, T. Satoh, K. Furukawa, E. Kuroda, K. J. Ishii, K. Takeda, T. Kaisho
  • Journal Title: International Immunology Volume: 未定 Pages: 未定
  • DOI: 10.1093/intimm/dxz004
  • Peer Reviewed / Open Access
• [Journal Article] Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice (2019)
  • Author(s): Ikumi Kyoko、Odanaka Mizuyu、Shime Hiroaki、Imai Masaki、Osaga Satoshi、Taguchi Osamu、Nishida Emi、Hemmi Hiroaki、Kaisho Tsuneyasu、Morita Akimichi、Yamazaki Sayuri
  • Journal Title: Journal of Investigative Dermatology Volume: 未定 Pages: 未定
  • DOI: 10.1016/j.jid.2019.01.029
  • Peer Reviewed
• [Journal Article] Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice (2019)
  • Author(s): Kimura Shunsuke、Kobayashi Nobuhide、Nakamura Yutaka、Kanaya Takashi、Takahashi Daisuke、Fujiki Ryoji、Mutoh Mami、Obata Yuuki、Iwanaga Toshihiko、Nakagawa Tomoo、Kato Naoya、Sato Shintaro、Kaisho Tsuneyasu、Ohno Hiroshi、Hase Koji
  • Journal Title: The Journal of Experimental Medicine Volume: 216 Pages: 831～846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed
• [Journal Article] Identification of a novel CCDC22 mutation in a patient with severe Epstein Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia (2019)
  • Author(s): Yamashita Yusuke、Nishikawa Akinori、Iwahashi Yoshifumi、Fujimoto Masakazu、Sasaki Izumi、Mishima Hiroyuki、Kinoshita Akira、Hemmi Hiroaki、Kanazawa Nobuo、Ohshima Kouichi、Imadome Ken-Ichi、Murata Shin-ichi、Yoshiura Koh-ichiro、Kaisho Tsuneyasu、Sonoki Takashi、Tamura Shinobu
  • Journal Title: International Journal of Hematology Volume: 未定 Pages: 未定
  • DOI: 10.1007/s12185-019-02595-0
  • Peer Reviewed
• [Journal Article] Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cacer progression (2019)
  • Author(s): Yahata Tamaki、Mizoguchi Mika、Kimura Akihiko、Orimo Takashi、Toujima Saori、Kuninaka Yumi、Nosaka Mizuho、Ishida Yuko、Sasaki Izumi、Fukuda‐Ohta Yuri、Hemmi Hiroaki、Iwahashi Naoyuki、Noguchi Tomoko、Kaisho Tsuneyasu、Kondo Toshikazu、Ino Kazuhiko
  • Journal Title: Cancer Science Volume: 110 Pages: 1279～1292
  • DOI: 10.1111/cas.13958
  • Peer Reviewed / Open Access
• [Journal Article] antibiotics enhances host resistance to viral infections in a microbiota-independent manner (2018)
  • Author(s): Smita Gopinath, Myoungjoo Kim, Tasfia Rakib, Patrick Wong, Michael Van Zandt, Natasha Barry, Tsuneyasu Kaisho, Andrew Goodman, Akiko Iwasaki
  • Journal Title: Nature MicrobiologyTopical application of aminoglycoside Volume: 3 Pages: 611～621
  • DOI: 10.1038/s41564-018-0138-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles (2018)
  • Author(s): Kayama Hisako、Kohyama Masako、Okuzaki Daisuke、Motooka Daisuke、Barman Soumik、Okumura Ryu、Muneta Masato、Hoshino Katsuaki、Sasaki Izumi、Ise Wataru、Matsuno Hiroshi、Nishimura Junichi、Kurosaki Tomohiro、Nakamura Shota、Arase Hisashi、Kaisho Tsuneyasu、Takeda Kiyoshi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Pages: 8418～8423
  • DOI: 10.1073/pnas.1808426115
  • Peer Reviewed / Open Access
• [Journal Article] XCR1+樹状細胞による腸管免疫制御機構 (2018)
  • Author(s): 小笹俊哉、改正恒康
  • Journal Title: 医学のあゆみ Volume: 265(13) Pages: 1241-1247
• [Journal Article] 生体内における樹状細胞への腫瘍抗原送達システムによる新規がんペプチドワクチン療法 (2018)
  • Author(s): 2.水本有紀、勝田将裕、宮澤基樹、北畑裕司、宮本篤、中森幹人、尾島敏康、松田健司、邊見弘明、玉田耕治、改正恒康、山上裕機
  • Journal Title: 癌と化学療法 Volume: 45 Pages: 1469 - 1471
• [Presentation] Analysis of mice carrying a novel mutation in a proteasome subunit gene identifed in an autoinammatory disease patient (2019)
  • Author(s): 金澤伸雄、小笹俊哉、邊見弘明、加藤喬、折茂貴是、佐々木泉、福田(大田)有里、改正恒康、木下晃、吉浦孝一郎、金城紀子、水島恒裕
  • Organizer: 第2回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] 皮膚科医に知っていただきたい樹状細胞の機能的および病理的意義 (2018)
  • Author(s): 改正恒康、邊見弘明、小笹俊哉
  • Organizer: 第117回日本日本皮膚科学会総会
  • Invited
• [Presentation] プロテアソーム関連自己炎症性症候群のマウスモデル (2018)
  • Author(s): 改正恒康、邊見弘明、金澤伸雄、加藤喬、稲葉豊、小笹俊哉
  • Organizer: 第39回日本炎症・再生学会
  • Invited
• [Presentation] Current overview of functions and development of dendritic cells (2018)
  • Author(s): Tsuneyasu Kaisho
  • Organizer: 第47回日本免疫学会総会
  • Invited
• [Presentation] 中條－西村症候群からプロテアソーム関連自己炎症/免疫不全症候群へ (2018)
  • Author(s): 金澤伸雄、中谷友美、原知之、稲葉豊、国本佳代、古川福実、神人正寿、金城紀子、水島恒裕、三嶋博之、木下晃、吉浦孝一郎、加藤喬、福田有里、邊見弘明、改正恒康
  • Organizer: 第25回分子皮膚科学フォーラム
• [Presentation] 新規LIG4遺伝子変異を導入したLIG4症候群モデルマウス A mouse model of LIG4 syndrome with novel LIG4 mutation (2018)
  • Author(s): 山下友佑、田村志宣、福田有里、小笹俊哉、金澤伸雄、邊見弘明、吉浦孝一郎、改正恒康、園木孝志
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Impaired development of dendritic cells in proteasome subunit mutant mice (2018)
  • Author(s): Hiroaki Hemmi, Toshiya Ozasa, Akira Kinoshita, Takashi Kato, Takashi Orimo, Izumi Sasaki, Yuri Fukuda-Ohta, Noriko Kinjo, Koh-Ichiro Yoshiura, Tsunehiro Mizushima,Nobuo Kanazawa, Tsuneyasu Kaisho
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Cholera toxin B can induce interleukine-1β production in peritoneal macrophages through activation of pyrin inflammasome (2018)
  • Author(s): Izumi Sasaki, Takashi Orimo, Hiroaki Hemmi, Toshiya Ozasa, Yuri Fukuda-Ohta, Mio Morinaka, Shinji Fukuda, Koichi Furukawa, Etsushi Kuroda, Ken J. Ishii, Tsuneyasu Kaisho
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] The mechanism of action of Spi-B in transcriptional activation of the interferon-α4 gene (2018)
  • Author(s): Ryo Miyazaki, Hiroyuki Saiga, Tsuneyasu Kaisho, Katsuaki Hoshino
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Cancer Vaccine Composed of Whole Tumor Cells Genetically Modified to Secrete the XCL1 (2018)
  • Author(s): Atsushi Miyamoto, Hemmi Hiroaki, Yuki Mizumoto, Masahiro Katsuda, Yuri Ohta,Katsuaki Hoshino, Hiroki Yamaue, Tsuneyasu Kaisho
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Dendritic cells expressing a unique set of genes associated with immunological tolerance are specialized to expand thymus-derived Foxp3+ regulatory T cells in the ultraviolet B-exposed skin (2018)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Akiko Nishioka, Hiroaki Shime, Hiroaki Hemmi,Masaki Imai, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Hyperglycemia is associated with psoriatic inflammation in both humans and mice (2018)
  • Author(s): Mizuyu Odanaka, Kyoko Ikumi, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Akimichi Morita, Sayuri Yamazaki
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Sox8 is essential for the differentiation of M cells and antigen-specific IgA response (2018)
  • Author(s): Nobuhide Kobayashi, Shunsuke Kimura, Yutaka Nakamura, Takashi Kanaya, Tsuneyasu Kaisho, Hiroshi Ohno, Koji Hase
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Osteoprotegerin-dependent M-cell self-regulation balances gut infection and immunity (2018)
  • Author(s): Shunsuke Kimura, Yutaka Nakamura, Nobuhide Kobayashi, Tsuneyasu Kaisho, Koji Hase
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] M-cell-dependent antigen uptake mitigates infectious colitis by shaping mucosal barrier function (2018)
  • Author(s): Yutaka Nakamura, Hitomi Mimuro, Jun Kunisawa, Tsuneyasu Kaisho, Hiroshi Kiyono, Koji Hase
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] A case of neonatal-onset proteasome-associated autoinflammatory syndrome resembling but distinct from Nakajo-Nishimura syndrome (2018)
  • Author(s): Noriko Kinjo, Hiroyuki Mishima, Akira Kinoshita, Koh-Ichiro Yoshiura,Tsunehiro Mizushima, Jun Hamazaki, Shigeo Murata, Hiroaki Hemmi, Tsuneyasu Kaisho,Nobuo Kanazawa
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] Analysis of mice carrying a novel mutation in a proteasome subunit gene identified in anautoinflammatory disease patient (2018)
  • Author(s): Toshiya Ozasa, Hiroaki Hemmi, Akira Kinoshita, Takashi Kato, Takashi Orimo, Izumi Sasaki, Yuri Fukuda-Ohta, Noriko Kinjo, Koh-Ichiro Yoshiura, Tsunehiro Mizushima, Nobuo Kanazawa, Tsuneyasu Kaisho
  • Organizer: 第47回日本免疫学会総会・学術集会記録
• [Presentation] XCR1+DCへの選択的な送達を目的とした新規抗がんワクチンの開発 (2018)
  • Author(s): 宮本篤、勝田将裕、邊見弘明、宮澤基樹、北畑裕司、水本有紀、小林良平、改正恒康、山上裕機
  • Organizer: 第46回和歌山悪性腫瘍研究会
• [Presentation] CRISPR/Cas9による腫瘍上のPD-L1欠損はマウス卵巣癌モデルにおいて抗腫瘍免疫を促進し、腫瘍進展を抑制する (2018)
  • Author(s): 八幡環、岩橋尚幸、野口智子、溝口美佳、東嶋左緒里、改正恒康、近藤稔和、井篦一彦
  • Organizer: 第46回和歌山悪性腫瘍研究会
• [Presentation] Immune regulation by a dendritic cell subset expressing a chemokine receptor, XCR1 (2018)
  • Author(s): Tsuneyasu Kaisho
  • Organizer: 15th International Symposium on Dendritic Cells
  • Int'l Joint Research / Invited
• [Presentation] Foxp3+ regulatory T cells are expanded by ultraviolet B-exposed PD-L1+ skin dendritic cell expressing a unique set of genes in a CSF1-independent manner (2018)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Akiko Nishioka, Saori Kasuya, Dieter Riethmacher, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research / Invited
• [Presentation] Successful treatment of psoriatic inflammation restores hyperglycemia (2018)
  • Author(s): Kyoko Ikumi, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Osamu Taguchi, Hiroaki Hemmi, Tsuneyasu Kaisho, Sayuri Yamazaki, Akimichi Morita
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research
• [Presentation] Time-resolved systems analysis of virus infection fate regulation: the XCL1-XCR1 communication axis links T cell exhaustion with effector maintenance (2018)
  • Author(s): J. Argilaguet, M. Pedragosa, A. Esteve-Codina, G. Riera, E. Vidal, C. Peligero-Cruz, D. Andreu, T. Kaisho, G. Bocharov, B. Ludewig, S. Heath, A. Meyerhans
  • Organizer: 15th International Symposium on Dendritic Cells
  • Int'l Joint Research
• [Presentation] Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections (2018)
  • Author(s): Chikako Shimokawa, Takashi Kanaya, Masami Hachisuka, Kenji Ishiwata, Hajime Hisaeda, Yosuke Kurashima, Hiroshi Kiyono, Tomohiro Yoshimoto, Tsuneyasu Kaisho, Hiroshi Ohno
  • Organizer: The 3rd International Conference on Innate Lymphoid Cells (ILC2018)
  • Int'l Joint Research