プロテアソーム機能異常により惹起される免疫病態の分子基盤の解明

2022 Fiscal Year Annual Research Report

• Project/Area Number: 21K19384
• 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)
• Co-Investigator(Kenkyū-buntansha): 金澤 伸雄 兵庫医科大学, 医学部, 教授 (90343227)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: プロテアソーム / タンパク質分解 / 自己炎症 / 免疫不全

Outline of Annual Research Achievements

免疫不全と自己炎症を併発する独立した2症例に共通して認められた、プロテアソームサブユニットβ1iのアミノ酸置換を引き起こす遺伝子バリアント（PSMB9 p.G156D）をヘテロで有するマウス（Psmb9 G156Dヘテロ変異マウス）においては、T細胞、B細胞、樹状細胞が減少している一方で、好中球、単球は増加していた。6－8週令においては、B細胞の減少はそれほど顕著ではなかったが、血中免疫グロブリンレベルは低下しており、免疫アジュバントとしてアラムを用いた場合の抗原特異的な抗体価の上昇も全く認められなかった。そこで脾臓からB細胞を調製し、リポ多糖（LPS）あるいはLPS＋IL-4で刺激したところ、ヘテロ変異マウスにおいて、増殖はほぼ正常で免疫グロブリンのクラススイッチも起こっていたが、抗体産生細胞の生成および培養上清中の抗体産生が顕著に低下していた。また、ヘテロ変異マウスの脾臓好中球を解析したところ、数が増加していたが、本来未分化好中球に発現しているはずの転写因子、顆粒生成に関わる酵素などの遺伝子発現が亢進し、成熟好中球に発現しているはずの転写因子などの遺伝子発現が低下していた。さらに、単球を解析したところ、骨髄での分化は正常であったが、脾臓における成熟分化が障害されていた。これらの結果から、Psmb9 G156Dヘテロ変異マウスにおいて、B細胞、好中球、単球の分化障害が生じていることが示唆され、プロテアソームにより制御される免疫担当細胞分化機構の存在が示唆された。

Remarks

免疫不全を伴うプロテアソーム関連自己炎症症候群の発見とそのモデルマウスhttps://www.wakayama-med.ac.jp/intro/press/r3/211207/07_menekifuzen.html
COPA症候群（自己炎症性疾患）モデルマウス　https://www.wakayama-med.ac.jp/intro/press/r3/210628/28_seitai.html

Research Products

• [Int'l Joint Research] Yale Univ./Harverd Medical School/Emory Univ.(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Yale Univ./Harverd Medical School/Emory Univ.
  • # of Other Institutions: 35
• [Int'l Joint Research] Univ. of Melbourne/Australia National Univ./Telethon Kids Institute(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Univ. of Melbourne/Australia National Univ./Telethon Kids Institute
  • # of Other Institutions: 1
• [Int'l Joint Research] Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hostital Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hostital Cologne
  • # of Other Institutions: 15
• [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: 10
• [Journal Article] 免疫不全を伴うプロテアソーム関連自己炎症症候群. Proteasome-associated autoinflammatory syndrome with immunodeficiency. (2023)
  • Author(s): 改正恒康
  • Journal Title: アレルギーの臨床 Volume: 43 Pages: 30-34
• [Journal Article] Conventional Type 1 dendritic cells in intestinal immune homeostasis. (2022)
  • Author(s): I. Sasaki, T. Kato, H. Hemmi, Y. Fukuda-Ohta, N. Wakaki-Nishiyama, A. Yamamoto, T. Kaisho.
  • Journal Title: Front Immunol Volume: 13 Pages: 857954
  • DOI: 10.3389/fimmu.2022.857954
  • Peer Reviewed / Open Access
• [Journal Article] Preparation and Inflammasome Activation of Murine Bone Marrow-Derived and Resident Peritoneal Macrophages. (2022)
  • Author(s): I. Sasaki, T. Kaisho.
  • Journal Title: Methods Mol Biol Volume: 2427 Pages: 95-104
  • DOI: 10.1007/978-1-0716-1971-1_9
  • Peer Reviewed
• [Journal Article] Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches. (2022)
  • Author(s): S. Daehling, A. M. Mansilla, K. Knopper, A. Grafen, D. T Utzschneider, M. Ugur, P. G Whitney, A. Bachem, P. Arampatzi, F. Imdahl, T. Kaisho, D. Zehn, F. Klauschen, N. Garbi, A. Kallies, A.-E. Saliba, G. Gasteiger, S. Bedoui, W. Kastenmuller.
  • Journal Title: Immunity Volume: 55 Pages: 656-670
  • DOI: 10.1016/j.immuni.2022.03.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer. (2022)
  • Author(s): A. L. Burrack, Z. C. Schmiechen, M. T. Patterson, E. A. Miller, E. J. Spartz, M. R. Rollins, J. F. Raynor, J. S. Mitchell, T. Kaisho, B. T. Fife, I. M. Stromnes.
  • Journal Title: JCI Insight Volume: 7 Pages: e151593
  • DOI: 10.1172/jci.insight.151593
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The liver contains distinct interconnected networks of CX3CR1+ macrophages, XCR1+ type 1 and CD301a+ type 2 conventional dendritic cells embedded within portal tracts. (2022)
  • Author(s): K. English, S. Yang Tan, R. Kwan, L. E Holz, F. Sierro, C. McGuffog, T. Kaisho, W. R Heath, K. Pa MacDonald, G. W McCaughan, D. G Bowen, P. Bertolino.
  • Journal Title: Immunol Cell Biol Volume: 100 Pages: 394-408
  • DOI: 10.1111/imcb.12559
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A vaccine targeting resistant tumours by dual T cell plus NK cell attack. (2022)
  • Author(s): S. Badrinath, MO. Dellacherie, A. Li, S. Zheng, X. Zhang, M. Sobral, JW. Pyrdol, KL. Smith, Y. Lu, S. Haag, H. Ijaz, F. Connor-Stroud, T. Kaisho, G. Dranoff, GC. Yuan, DJ. Mooney, KW. Wucherpfennig.
  • Journal Title: Nature Volume: 606 Pages: 992-998
  • DOI: 10.1038/s41586-022-04772-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. (2022)
  • Author(s): D. A Michelson, K. Hase, T. Kaisho, C. Benoist, D. Mathis.
  • Journal Title: Cell Volume: 85 Pages: 2542-2558
  • DOI: 10.1016/j.cell.2022.05.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depletion of cDC1 cells upon immunotherapy of established tumors precludes efficacy. (2022)
  • Author(s): A. Teijeira, S. Garasa, C. luri, C. de Andrea, M. Gato, C. Molina, T. Kaisho, A. Cirella, A. Azpilikueta, S. Wculek, J. Egea, I. Olivera, I. Rodriguez, A. Rouzaut, V. Verkhusha, K. Valencia, D. Sancho, P. Berraondo, I. Melero.
  • Journal Title: Cancer Research Volume: 82 Pages: 4373-4385
  • DOI: 10.1158/0008-5472.CAN-22-1046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spi-B alleviates food allergy by securing mucosal barrier and immune tolerance in the intestine. (2022)
  • Author(s): N. Ishihara,Y. Nakamura, K. Yakabe, S. Komiyama, Y. Fujimura, T. Kaisho, S. Kimura, K. Hase.
  • Journal Title: Front Allergy Volume: 3 Pages: 996657
  • DOI: 10.3389/falgy.2022.996657
  • Peer Reviewed / Open Access
• [Journal Article] Tmem45b is essential for inflammation- and tissue injury-induced mechanical pain hypersensitivity. (2022)
  • Author(s): T. Tanioku, M. Nishibata, Y. Tokinaga, K. Konno, M. Watanabe, H. Hemmi, Y. Fukuda-Ohta, T. Kaisho, H. Furue, T. Kawamata.
  • Journal Title: Proc Natl Acad Sci USA Volume: 119 Pages: e2121989119
  • DOI: 10.1073/pnas.2121989119
  • Peer Reviewed / Open Access
• [Journal Article] Androgen-regulated MafB drives cell migration via MMP11-dependent extracellular matrix remodeling in mice. (2022)
  • Author(s): M.C. Alcantara, K. Suzuki, AR. Acebedo, D. Kajioka, S. Hirohata,T. Kaisho, Y. Hatano, K. Yamagata, S. Takahashi, G. Yamada.
  • Journal Title: iScience Volume: 25 Pages: 105609
  • DOI: 10.1016/j.isci.2022.105609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections. (2022)
  • Author(s): E. Domenjo Vila, V. Casella, R. Iwabuchi, E. Fossum, M. Pedragosa, Q. Castellvi, P. Cebollada Rica, T. Kaisho, K. Terahara, G. Bocharov, J. Argilaguet, A. Meyerhans.
  • Journal Title: Cell Rep Volume: 42 Pages: 112123
  • DOI: 10.1016/j.celrep.2023.112123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Hypomorphic mutation of Lig4 gene in mice predisposes to intestinal inflammation driven by Th1 cells. (2022)
  • Author(s): Y. Yamashita, T. Kato, H. Kosako, S. Iwabuchi, K. Tanaka, K. Nakashima, I. Sasaki, S. Hashimoto, K. Ohshima, T. Kaisho, T. Sonoki, S. Tamura.
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Model mice of human inborn errors of immunity showing mixed manifestations of aouoinflammation,immunodeficiency and/or autoimmunity. (2022)
  • Author(s): T. Kaisho.
  • Organizer: 第51回日本免疫学会総会・学術集会
  • Invited
• [Presentation] γδT cells in Peyer’s patches acquire the encephalitogenic phenotype through the activation by commensals and exacerbates autoimmune ncephaomyelitis. (2022)
  • Author(s): S. Komiyama, D. Takahashi, T.Kaisho, K. Hase.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] Dendritic and T cell abnormalities in an autoinflammatory disease with interstitial lung disease and type 1 interferonopathy caused by a disability of retrongrade protein trafficking. (2022)
  • Author(s): T. Kato, I.Sasaki, H. Hemmi, Y. Honda. K. Izawa, R. Nishikomori, T. Kaisho.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] Type 1 conventional dendritic cells of bone marrow assistthe prograession of multiple myeloma and consist of tumor microenvironment in the transplanted Vk*MYC mouse model. (2022)
  • Author(s): S.Suzuki, S.Tsuda, T.Takubo, H.Toyoshima, M.Yoshino, T.Kaisho, T.Fukuda, K.Tokoyoda.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] The role of Rnase T2 in macrophage homeostasis. (2022)
  • Author(s): R. Sato, K.Liu, T.Shibata, R.Fukui, K.Hoshino, T.Kaisho, K.Miyake.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] 遺伝子改変マウスを用いた組織常在マクロファージの免疫学的解析 (2022)
  • Author(s): 加治汐梨、佐々木泉、加藤喬、西山奈央子、山本明日美、脇村一輝、北野雅之、改正恒康
  • Organizer: 第29回日本免疫毒性学会学術年会
• [Presentation] Activation of type 1 interferon signaling in dendritic cells and T cells of the mouse model of COPA syndrome. (2022)
  • Author(s): T.Kato, R.Yamasaki, N.W-Nishiyama. I.Sasaki, S.Kaji, K.Murakami, H.Hemmi, Y.Honda, K.Izawa, Y.Otsuki, T.Matsubayashi, R.Nishikomori, T.Kaisho.
  • Organizer: 第29回日本免疫毒性学会学術年会
• [Presentation] Lig4遺伝子の低形成性変異を有したマウスは異常Th1細胞による炎症性腸疾患を発症する (2022)
  • Author(s): 田村志宜、山下友佑、小浴秀樹、加藤喬、岩淵貞弘、佐々木泉、橋本真一、改正恒康
  • Organizer: 第6回日本免疫不全・自己炎症学会総会・学術集会
• [Presentation] Immunotherapy of chronic virus infections: exhausted CD8+ T cell subsets are differentially regulated by XCR1+ DC. (2022)
  • Author(s): A.Meyerhans, E.D-Vila, V.Casella, R.Iwabuxhi, E.Fossum, M.Pedragosa, Q.Castellvi, T.Kaisho, K.Terahara, G.Bocharov, J.Argilaguet.
  • Organizer: The 16th International Symposium on Dendritic Cells 2022
  • Int'l Joint Research
• [Presentation] γδT17 cells in Peyer’s patches acquire the encephalitogenic phenotype through the activation by commensals. (2022)
  • Author(s): S. Komiyama, D. Takahashi, T. Kaisho, H. Watarai, K. Hase.
  • Organizer: The 9th Congress of International Human Microbiome Consortium
  • Int'l Joint Research