Studies aiming the establishing self-tolerance for the cure of autoimmune disease

• Project/Area Number: 25293223
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUMOTO Mitsuru 徳島大学, 疾患酵素学研究センター, 教授 (60221595)
• Co-Investigator(Kenkyū-buntansha): NISHIJIMA Hitoshi 徳島大学, 疾患酵素学研究センター, 助教 (60425410) ; MOURI Yasuhiro 徳島大学, 疾患酵素学研究センター, 助教 (80464353)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: AIRE / thymus / autoimmunity / 胸腺髄質上皮細胞 / Aire / ノックインマウス / 自己免疫疾患 / 胸腺

Outline of Final Research Achievements

Cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs) play essential roles in the positive and negative selection, respectively. Aire in mTECs plays an essential role in the latter. We used BAC technology to establish a semiknockin strain expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein, cTECs expressing Aire ectopically did not confer transcriptional expression of Aire-dependent tissue-restricted antigen genes. We also established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s).

Research Products

• [Journal Article] Ectopic Aire expression in 1 the thymic cortex reveals inherent properties of Aire as a tolerogenic factor within the medulla (2015)
  • Author(s): Nishijima H, Kitano S, Miyachi H, Morimoto J, Kawano H, Hirota F, Morita R, Mouri Y, Masuda K, Imoto I, Ikuta K, Matsumoto M.
  • Journal Title: J Immunol Volume: 195 Issue: 10 Pages: 4641-4649
  • DOI: 10.4049/jimmunol.1501026
  • Peer Reviewed / Open Access
• [Journal Article] Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program. (2015)
  • Author(s): Kawano H, Nishijima H, Morimoto J, Hirota F, Morita R, Mouri Y, Nishioka Y, Matsumoto M.
  • Journal Title: Journal of Immunology Volume: 195 Issue: 11 Pages: 5149-5158
  • DOI: 10.4049/jimmunol.1501000
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Switching on the Aire conditioner. (2015)
  • Author(s): Mitsuru Matsumoto
  • Journal Title: European Journal of Immunology Volume: 45 Issue: 12 Pages: 3237-3240
  • DOI: 10.1002/eji.201546098
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NIK in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells (2014)
  • Author(s): Mouri, Y., Nishijima, H., Kawano, H., Hirota, F., Sakaguchi, N., Morimoto, J., Matsumoto, M.
  • Journal Title: J. Immunol. Volume: 193 Issue: 9 Pages: 4356-4367
  • DOI: 10.4049/jimmunol.1400389
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program (2014)
  • Author(s): Nishikawa, Y., Nishijima, H., Matsumoto, M., Morimoto, J., Hirota, F., Takahashi, S., Luche, H., Fehling, H.J., Mouri, Y., Matsumoto, M.
  • Journal Title: J. Immunol Volume: 192 Issue: 6 Pages: 2585-2592
  • DOI: 10.4049/jimmunol.1302786
  • Peer Reviewed / Open Access
• [Journal Article] Androgen receptor promotes sex-independent angiogenesis in response to ischemia and is required for activation of vascular endothelial growth factor receptor signaling (2013)
  • Author(s): Yoshida S, Aihara K, Ikeda Y, Sumitomo-Ueda Y, Uemoto R, Ishikawa K, Ise T, Yagi S, Iwase T, Mouri Y, Sakari M, Matsumoto T, Takeyama K, Akaike M, Matsumoto M, Sata M, Walsh K, Kato S, Matsumoto T.
  • Journal Title: Circulation Volume: 128 Issue: 1 Pages: 60-71
  • DOI: 10.1161/circulationaha.113.001533
  • Peer Reviewed
• [Journal Article] TGF-β type II receptor expression in thymic epithelial cells inhibits the development of Hassall’s corpuscles in mice (2013)
  • Author(s): Odaka, C., Hauri-Hohl, M., Takizawa, K., Nishikawa, Y., Yano, M., Matsumoto, M., Boyd, R., Hollander, G.A.
  • Journal Title: Int. Immunol. Volume: 25 Issue: 11 Pages: 633-642
  • DOI: 10.1093/intimm/dxt026
  • Peer Reviewed
• [Journal Article] Which model better fits the role of Aire in the establishment of self-tolerance: the transcription model or the maturation model? (2013)
  • Author(s): Matsumoto, M., Nishikawa, Y., Nishijima, H., Morimoto, J., Matsumoto, M., Mouri, Y.
  • Journal Title: Front. Immunol. Volume: 4 Pages: 1-4
  • DOI: 10.3389/fimmu.2013.00210
  • Peer Reviewed
• [Presentation] AIRE遺伝子と自己免疫疾患と胸腺について (2016)
  • Author(s): 松本 満
  • Organizer: 第35回日本胸腺研究会
  • Place of Presentation: 徳島大学藤井節郎記念医科学センター（徳島県・徳島市）
  • Year and Date: 2016-02-06
  • Invited
• [Presentation] Role of Aire in the establishment of self-tolerance. (2015)
  • Author(s): Mitsuru Matsumoto
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-20
  • Invited
• [Presentation] Paradoxical development of polymyositis-like autoimmunity by the additive expression of AIRE. (2015)
  • Author(s): Hitoshi Nishijima, Yasuhiro Mouri, Junko Morimoto, Hiroshi Kawano, and Mitsuru Matsumoto
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-19
• [Presentation] A novel Aire-dependent subset of medullary thymic epithelial cells that express Ly6 family protein. (2015)
  • Author(s): Junko Morimoto, Yumiko Nishikawa, Hiroshi Kawano, Yasuhiro Mouri, Hitoshi Nishijima, and Mitsuru Matsumoto
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-19
• [Presentation] Aire expression is inherent to all medullary thymic epithelial cells during their differentiation program. (2015)
  • Author(s): Hiroshi Kawano, Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri and Mitsuru Matsumoto
  • Organizer: The 4th European Congress of Immunology
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2015-09-07
  • Int'l Joint Research
• [Presentation] Aire expression is inherent properties of all medullary thymic epithelial cells during their differentiation program. (2015)
  • Author(s): Mitsuru Matsumoto, Hiroshi Kawano, Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri and Yasuhiko Nishioka
  • Organizer: Venice Thymus Meeting
  • Place of Presentation: Venice (Italy)
  • Year and Date: 2015-04-09
  • Int'l Joint Research
• [Presentation] Unexpected disturbance of the development of medullary thymic epithelial cells at immature stages by the long-term ablation of Aire-expressing cells (2015)
  • Author(s): Kawano, H., Matsumoto, M.
  • Organizer: Controversies in Rheumatology and Autoimmunity 2015
  • Place of Presentation: Hilton Hotel Sorrento (Sorrento, Italy)
  • Year and Date: 2015-03-12 – 2015-03-14
• [Presentation] Unexpected disturbance of the development of medullary thymic epithelial cells at immature stages by the long-term ablation of mature Aire-expressing cells (2014)
  • Author(s): Kawano, H., Morimoto, J., Mouri, Y., Nishijima, H., Nishioka, Y., Matsumoto, M.
  • Organizer: 第43回日本免疫学会総会
  • Place of Presentation: 京都国際会議場（京都府・京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Approaches to identify Aire-regulated non-tissue-restricted antigen genes by the ectopic expression of Aire in thymic cortex (2014)
  • Author(s): Nishijima, H., Morimoto, J., Mouri, Y., Kawano, H., Ikuta, K., Matsumoto, M.
  • Organizer: 第43回日本免疫学会総会
  • Place of Presentation: 京都国際会議場（京都府・京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Ectopic Aire expression in thymic cortex reveals inherent properties of Aire as a medullary stromal factor (2014)
  • Author(s): Matsumoto, M., Nishijima, H.
  • Organizer: European Society for Immunodeficiencies 2014
  • Place of Presentation: Prague Congress Centre (Prague, Czech Republic)
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] 胸腺皮質上皮細胞への異所性発現による Aire の機能解析 (2014)
  • Author(s): 西嶋 仁、生田宏一、松本 満
  • Organizer: 第24回 Kyoto T Cell Conference
  • Place of Presentation: 京都平安ホテル（京都府・京都市）
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] Ectopic Aire expression in thymic cortex reveals inherent properties of Aire as a stromal factor for medullary thymic microenvironment (2014)
  • Author(s): Nishijima, H., Morimoto, J., Kawano, H., Mouri, Y., Ikuta, K., Matsumoto, M.
  • Organizer: ThymOz 7
  • Place of Presentation: Heron Island (Australia)
  • Year and Date: 2014-04-02 – 2014-04-07
• [Presentation] Temporal lineage tracing of Aire-expressing cells reveals a requirement of Aire for their full maturation program (2013)
  • Author(s): Nishikawa, Y., Mouri, Y., Nishijima, H., Matsumoto, M.
  • Organizer: Controversies in Rheumatology and Autoimmunity
  • Place of Presentation: Hotel Novotel Budapest City（Hungary）
• [Presentation] Temporal fate-mapping study reveals essential roles of Aire in the maturation program of Aire-expressing cell lineage (2013)
  • Author(s): Matsumoto, M., Nishikawa, Y., Mouri, Y., Nishijima, H.
  • Organizer: IMMUNOLOGY 2013-AAI Annual Meeting
  • Place of Presentation: Hawaii Convention Center（USA）
• [Presentation] AIRE遺伝子を導入したHeLa細胞における細胞周期依存的なAIREタンパク質のリン酸化 (2013)
  • Author(s): 西嶋 仁、毛利安宏、西川裕美子、松本 満
  • Organizer: 第54回日本生化学中国・四国支部例会
  • Place of Presentation: 徳島大学大塚講堂（徳島県）
• [Presentation] Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program (2013)
  • Author(s): Matsumoto, M., Nishikawa, Y., Nishijima, H., Matsumoto, M., Morimoto, J., Hirota, F., Takahashi, S., Luche, H., Fehling, H.J., Mouri, Y.
  • Organizer: The 6th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 芝蘭会館（京都府）
• [Presentation] Temporal lineage tracing of Aire-expressing cells reveals a requirement of Aire for their maturation program
  • Author(s): Matsumoto, M., Nishikawa, Y., Mouri, Y., Nishijima, H.
  • Organizer: 15th ICI2013
  • Place of Presentation: MiCo Milano Congressi（Italy）
• [Presentation] Requirement of Aire expression within thymic medulla but not cortex for establishing self-tolerance
  • Author(s): Nishijima, H., Morimoto, J., Mouri, Y., Nishikawa, Y., Ikuta, K., Matsumoto, M.
  • Organizer: 第42回日本免疫学会総会
  • Place of Presentation: 幕張メッセ（千葉県）
• [Remarks] http://www.tokushima-u.ac.jp/ier/autoimmunity/