ネオ・セルフ生成における免疫プロテアソームの機能的および病理的意義の解明

• Project Area: Creation, function and structure of neo-self
• Project/Area Number: 19H04813
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 自己炎症性疾患 / タンパク質輸送 / 獲得免疫 / I型インターフェロン / プロテアソーム / 炎症 / 遺伝子変異 / 樹状細胞 / 血球分化

Outline of Research at the Start

不要なタンパクを分解除去するシステム、つまりプロテアソームの異常は自己炎症性疾患と呼ばれる難治性炎症病態を引き起こす。本研究では、自己炎症性疾患患者から見出されたプロテアソームの構成サブユニットの新規遺伝子変異を導入したマウスの解析を通じて、プロテアソームの異常が炎症病態とどのように関連するのか解明し、自己炎症性疾患の新たな治療的手段の獲得を目指す。

Outline of Annual Research Achievements

COPA症候群は、間質性肺炎や関節炎を呈する常染色体優性遺伝の自己炎症性疾患であり、I型インターフェロン（IFN）により誘導される遺伝子群（ISG）の発現が増強しているが、自己抗体の産生や異常なT細胞の活性化など獲得免疫の異常も認められる。ゴルジ体から小胞体へのタンパク質輸送を担うタンパク質複合体coat protein complex I (COPI)を構成するサブユニットタンパク質Coatomer subunit α (COPA)のアミノ酸置換をきたすヘテロ変異が原因遺伝子変異であることが明らかになっているものの、その病態はほとんど不明である。今年度は、COPA症候群患者で同定された新規のアミノ酸置換変異（X変異とする）を導入したマウスを樹立し、その解析を進めた。Copa Xヘテロ変異マウスでは、外見はほぼ正常であったが、炎症細胞浸潤を伴う間質性肺炎が高率に認められ、脾臓細胞ではISGの発現が亢進していた。樹状細胞を解析したところ、細胞質内DNAセンサーSTINGシグナルによるI型IFN産生誘導が亢進しており、STINGの下流のシグナル伝達分子が過剰に活性化されていた。また、脾臓でのISGの発現亢進はSTING阻害剤により減弱した。これらの結果から、Copa Xヘテロ変異マウスにおいて、COPA症候群の病態が再現されていること、そしてその病態異常にSTINGシグナルの亢進が関与することが示唆された。今後、Copa X変異マウスにおいて、自然免疫、獲得免疫両面から解析を進め、間質性肺炎など自己炎症性疾患の病態を解明する。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2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: 32
• [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: 1
• [Int'l Joint Research] Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hospital Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hospital Cologne
  • # of Other Institutions: 14
• [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: 1
• [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: 5
• [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: 31
• [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: 1
• [Int'l Joint Research] Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hospital Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hospital Cologne
  • # of Other Institutions: 11
• [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: 1
• [Int'l Joint Research] San Raffaele Scientific Institute/ICGEB(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: San Raffaele Scientific Institute/ICGEB
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• [Journal Article] Augmentation of STING‐induced type I interferon production in COPA syndrome (2021)
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• [Journal Article] 自然免疫が関与する炎症―自然炎症と自己炎症性疾患 (2020)
  • Author(s): 改正恒康
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  • Journal Title: Mucosal Immunology Volume: Epub Pages: Epub
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• [Journal Article] Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade. (2020)
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  • Journal Title: Br J Cancer Volume: 122 Pages: 1185-1193
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• [Journal Article] The mechanism of action of Spi-B in the transcriptional activation of the interferon-α4 gene. (2020)
  • Author(s): R. Miyazaki, H. Saiga, T. Kato, T. Bakoshi, R. Senba, A. Shintani, M. Suzuki, K. Takao, I. Sasaki, A. Iizuka, M. Sugiyama, N. Iwami, Y. Fukuda-Ohta, H. Hemmi, T. Tanaka, M. Miyake, T. Kaisho, K. Hoshino.
  • Journal Title: Biochem Biophys Res Commun Volume: 30;525 Pages: 477-482
  • DOI: 10.1016/j.bbrc.2020.02.101.
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• [Journal Article] IL-12 From Endogenous cDC1, and Not Vaccine DC, Is Required for Th1 Induction. (2020)
  • Author(s): D. Ashour, P. Arampatzi, V. Pavlovic, K. U Forstner, T. Kaisho, A. Beilhack, F. Erhard, M. B Lutz.
  • Journal Title: JCI Insight Volume: 21;5 Pages: 135143
  • DOI: 10.1172/jci.insight.135143.
  • Peer Reviewed / Open Access
• [Journal Article] A defined commensal consortium induces CD8 T cells and anti-cancer immunity. (2019)
  • Author(s): T. Tanoue, et al. 全著者28名中15番目
  • Journal Title: Nature Volume: 565 Pages: 600-605
  • DOI: 10.1038/s41586-019-0878-z
  • Peer Reviewed / Open Access
• [Journal Article] Cholera toxin B induces interleukine-1β production from resident peritoneal macrophages through pyrin as well as NLRP3 inflammasome. (2019)
  • Author(s): 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: Int Immunol Volume: 31 Pages: 657-668
  • 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): K. Ikumi, M. Odanaka, H. Shime, M. Imai, S. Osaga, O. Taguchi, E. Nishida, H. Hemmi, T. Kaisho, A. Morita, S. Yamazaki.
  • Journal Title: J Invest Dermatol Volume: 139 Pages: 1329-1338.e7
  • DOI: 10.1016/j.jid.2019.01.029
  • Peer Reviewed / Open Access
• [Journal Article] Sox8 is essential for M-cell maturation to accelerate IgA response at the early stage after weaning in mice. (2019)
  • Author(s): S. Kimura, N. Kobayashi, Y. Nakamura, T. Kanaya, D. Takahashi, R. Fujiki, M. Mutoh, Y. Obata, T. Iwanaga, T. Nakagawa, N. Kato, S. Sato, T. Kaisho, H. Ohno, K. Hase.
  • Journal Title: J Exp Med Volume: 216 Pages: 831-846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed / Open Access
• [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): Y. Yamashita, A. Nishikawa, Y. Iwahashi, M. Fujimoto, I. Sasaki, H. Mishima, A. Kinoshita, H. Hemmi, N. Kanazawa, K. Ohshima, K.-i. Imadome. S.-i. Murata, K.-i. Yoshiura, T. Kaisho, T. Sonoki, S. Tamura.
  • Journal Title: Int J Hematol Volume: 109 Pages: 744-750
  • DOI: 10.1007/s12185-019-02595-0
  • Peer Reviewed / Open Access
• [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): T. Yahata, M. Mizoguchi, A. Kimura, T. Orimo, S. Toujima, Y. Kuninaka, M. Nosaka, Y. Ishida, I. Sasaki, Y. Fukuda-Ohta, H. Hemmi, N. Iwahashi, T. Noguchi, T. Kaisho, T. Kondo, K. Ino.
  • Journal Title: Cancer Sci. Volume: 110 Pages: 1279-1292
  • DOI: 10.1111/cas.13958.
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• [Journal Article] Systems analysis reveals complex biological processes during virus infection fate decisions. (2019)
  • Author(s): Argilaguet. J, Pedragosa. M, Esteve-Codina. A, Riera. G, Vidal. E, Peligero-Cruz. C, Casella. V, Andreu. D, Kaisho. T, Bocharov. G, Ludewig. B, Heath. S, Meyerhans. A.
  • Journal Title: Genome Res Volume: 29 Pages: 907-919
  • DOI: 10.1101/gr.241372.118
  • Peer Reviewed / Open Access
• [Journal Article] Type I interferon delivery by iPSC-derived myeloid cells elicits antitumor immunity via XCR1+ dendritic cells. (2019)
  • Author(s): N. Tsuchiya, R. Zhang, T. Iwama, N. Ueda, T. Liu, M. Tatsumi, Y. Sasaki, R. Shimoda, Y. Osako, Y. Sawada, Y. Kubo, A. Miyashita, S. Fukushima, Z. Cheng, R. Nakaki, K. Takubo, S. Okada, S. Kaneko, H. Ihn, T. Kaisho, Y. Nishimura, S. Senju, I. Endo, T. Nakatsura, Y. Uemura.
  • Journal Title: Cell Rep. Volume: 29 Pages: 162-175
  • DOI: 10.1016/j.celrep.2019.08.086.
  • Peer Reviewed / Open Access
• [Presentation] The roles of unfold protein responses in cholera toxinB-induced interleukin-1β production. (2020)
  • Author(s): 佐々木泉、折茂貴是、張江伊水、滝沢優子、古川綱一、改正恒康
  • Organizer: 第27回日本免疫毒性学会学術年会（WEB開催）
• [Presentation] 遺伝性炎症性疾患COPA症候群の分子基盤の解明 (2020)
  • Author(s): 田中日尚子、林茉里、加藤喬、折茂貴是、大田（福田）有里、西山奈央子、中井千尋、佐々木泉、改正恒康
  • Organizer: 第88回和歌山医学会総会（WEB開催）
• [Presentation] 遺伝性炎症性疾患COPA症候群のモデルマウスの樹立とその解析 (2020)
  • Author(s): 張江伊水、滝沢優子、加藤喬、折茂貴是、大田（福田）有里、西山奈央子、中井千尋、佐々木泉、改正恒康
  • Organizer: 第88回和歌山医学会総会（WEB開催）
• [Presentation] 自然免疫応答における小胞体ストレスセンサ ー IREla の機能的意義 (2020)
  • Author(s): 三並桃花、石田エヴァ如月、加藤喬、折茂貴是、大田（福田）有里、西山奈央子、中井千尋、佐々木泉、改正恒康
  • Organizer: 第88回和歌山医学会総会（WEB開催）
• [Presentation] Role of cross-presenting dendritic cells in anti-PD-L1 immunotherapy of chronic viral infections. (2020)
  • Author(s): E. Domenjo-Vila, V. Casella, R. Iwabuchi, E. Fossum, M. Pedragosa, Q. Castellvi, T. Kaisho, K. Terahara, G. Bocharov, J. Argilaguet, A. Meyerhans.
  • Organizer: 2nd Research Symposium on Coronavirus / XIX Jornada de Virologia / Virology Meeting 2020. Online meeting.
  • Int'l Joint Research
• [Presentation] Impaired development of myeloid cells in mice carrying a patient-derived proteasome subunit mutation. (2020)
  • Author(s): 邊見弘明、折茂貴是、佐々木泉、加藤喬、大田(福田)有里、金城紀子、濱田聡、木下晃、吉浦孝一郎、大西秀典、金澤伸雄、改正恒康
  • Organizer: 第3回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] Novel proteasome-related autoinflammation and immunodeficiency disease caused by a distinct heterozygous missense mutation in the PSMB9 gene. (2019)
  • Author(s): N. Kanazawa, Y. Nakatani, Y. Inaba, K. Kunimoto, N. Kinjo, S. Hamada, T. Mizushima, A. Kinoshita, K. Yoshiura, J. Hamazaki, S. Murata, H. Ohnishi, T. Orimo, H. Hemmi, T. Kaisho.
  • Organizer: The 44th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Invited
• [Presentation] 乳児期から発熱と凍瘡様皮疹を反復し、新規のインターフェロン調節遺伝子異常が疑われた親子例 (2019)
  • Author(s): 本田尭、土橋隆俊、番場正博、大方詩子、渡辺絵美子、宮川俊一、杉浦仁、稲葉豊、神人正寿、井澤和司、邊見弘明、改正恒康、三嶋博之、木下晃、吉浦孝一郎、金澤伸雄
  • Organizer: 第2回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] 複合免疫不全症を来す新規LIG4症候群モデルマウスは炎症性腸疾患を自然発症する (2019)
  • Author(s): 田村志宣、山下友佑、大田（福田）有里、小笹俊哉、金澤伸雄、安岡弘直, 邊見弘明, 大島孝一、改正恒康、園木孝志
  • Organizer: 第59回リンパ網内系学会
  • Invited
• [Presentation] コレラ毒素Bサブユニットは細胞内病原体センサーNLRP3とPyrinを介して炎症性サイトカインIL-1βの産生を誘導する (2019)
  • Author(s): 佐々木泉、折茂貴是、邊見弘明、古川鋼一、改正恒康
  • Organizer: 第29回日本樹状細胞研究会
  • Invited
• [Presentation] ヒト疾患由来プロテアソームサブユニット突然変異導入マウスにおける樹状細胞分化障害 (2019)
  • Author(s): 邊見弘明、小笹俊哉、加藤喬、折茂貴是、大田（福田）有里、金澤伸雄、改正恒康
  • Organizer: 第29回日本樹状細胞研究会
  • Invited
• [Presentation] Lig4遺伝子改変マウスを用いた腸管免疫寛容破綻の病態解明 (2019)
  • Author(s): 田村志宣、山下友佑、折茂貴是、大田（福田）有里、小笹俊哉、中嶋一貴、金澤伸雄、邊見弘明、大島孝一、改正恒康、園木孝志
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [Presentation] 実験的自己免疫性脳脊髄炎の病態形成における腸管免疫系の重要性の検証 (2019)
  • Author(s): 込山星河、江川愛子、高橋大輔、改正恒康、長谷耕二
  • Organizer: 日本薬学会関東支部会
  • Invited
• [Presentation] コレラ毒素Bサブユニットによる炎症性サイトカインIL-1β産生誘導機構 (2019)
  • Author(s): 佐々木泉、折茂貴是、邊見弘明、土屋慧馬、井上正一、熊谷直光、古川鋼一、改正恒康
  • Organizer: 第26回日本免疫毒性学会学術年会
  • Invited
• [Presentation] Akimichi Morita, Sayuri Yamazaki.Successful treatment of psoriatic inflammation improves hyperglycemia in humans and mice. (2019)
  • Author(s): M. Odanaka, K. Ikumi, H. Shime, M. Imai, E. Nishida, H. Hemmi, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Defective dendritic cell and monocyte development in proteasome subunit mutant miceDefective dendritic cell and monocyte development in proteasome subunit mutant mice. (2019)
  • Author(s): H. Hemmi, T. Orimo, I. Sasaki, T. Kato, Y. Fukuda-Ohta, N. Kinjo, S. Hamada, A. Kinoshita, K. Yoshiura, H. Ohnishi, N. Kanazawa, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Roles of endoplasmic reticulum stress in cholera toxinB-induced interleukine-1β production from resident peritoneal macrophages. (2019)
  • Author(s): I. Sasaki, S. Morita, D. Okuzaki, T. Orimo, H. Hemmi, K. Furukawa, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Novel proteasome-related autoinflammation and immunodeficiency disease caused by a distinct heterozygous missense mutation in the PSMB9 gene. (2019)
  • Author(s): N. Kanazawa, N. Kinjo, S. Hamada, T. Mizushima, A. Kinoshita, K. Yoshiura, J. Hamazaki, S. Murata, H. Ohnishi, T. Orimo, H. Hemmi, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Generation and analysis of mice carrying a novel heterozygous missense mutation of a protease subunit, PSMB9, in patients with autoinflammation and immunodeficiency. (2019)
  • Author(s): H. Hemmi, N. Kanazawa, N. Kinjo, S. Hamada, H. Ohnishi, T. Mizushima, A. Kinoshita, K.-I. Yoshiura, T. Kaisho.
  • Organizer: The 10th Biannual Meeting of the International Society of Systemic Auto-Inflammatory Diseases (ISSAID)
  • Int'l Joint Research
• [Presentation] A case of neonatal-onset proteasome-associated autoinflammation and immunodeficiency disease resembling but distinct from Nakajo-Nishimura syndrome. (2019)
  • Author(s): Kinjo, S. Hamads, K. Nakanishi, H. Mishima, A. Kinoshita, K.-I. Yoshiura, T. Mizushima, J. Hamazaki, S. Murata, H. Hemmi, T. Kaisho, N. Kanazawa.
  • Organizer: The 10th Biannual Meeting of the International Society of Systemic Auto-Inflammatory Diseases
  • Int'l Joint Research
• [Presentation] Regulatory T cells with a distinctive feature expand through dermal dendritic cells in the ultraviolet B exposed skin. (2019)
  • Author(s): S. Yamazaki, M. Odanaka, H. Shime, M. Imai, H. Hemmi, T. Kaisho, N. Ohkura, S. Sakaguchi, A. Morita.
  • Organizer: 16th International Workshop on Langerhans Cells
  • Int'l Joint Research
• [Presentation] Sox8 is essential for the maturation of M cells and accelerates IgA response at the early stage after weaning. The 18th Awaji International Forum on Infection and Immunity. (2019)
  • Author(s): N. Kobayashi, S. Kimura, Y. Nakamura, T. Kanaya, T. Kaisho, H. Ohno, T. Iwanaga, K. Hase.
  • Organizer: Awaji Yumebutai International Conference Center
  • Int'l Joint Research
• [Presentation] Cholera toxin B can induce interleukine-1β production from resident peritoneal macrophages in synergy with lipopolysaccharides. (2019)
  • Author(s): I. Sasaki, T. Orimo, H. Hemmi, K. Furukawa, T. Kaisho.
  • Organizer: The 18th Awaji International Forum on Infection and Immunity.
  • Int'l Joint Research
• [Presentation] ケモカイン受容体XCR1を発現する樹状細胞サブセットによる免疫制御 (2019)
  • Author(s): 改正恒康.
  • Organizer: 近畿大学薬学部
  • Invited
• [Remarks] 新規抗がんワクチン開発 県立医大が成果を発表
  • URL: https://www.wakayamashimpo.co.jp/2020/03/20200317_92750.html
• [Remarks] 県立医科大研究チームが新がんワクチン開発
  • URL: https://www.hidakashimpo.co.jp/news1/2020/03
• [Remarks] 抗がん活性の強い樹状細胞へがん抗原ペプチドを選択的に送達させる新規抗がんワクチンの開発
  • URL: https://research-er.jp/articles/view/87282