Studies on thyroid autoimmunity: anti-mouse TSH receptor immune response and central tolerance in mice

• Project/Area Number: 15K09437
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Nagasaki University
• Principal Investigator: NAGAYAMA Yuji 長崎大学, 原爆後障害医療研究所, 教授 (30274632)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 甲状腺 / 自己免疫 / バセドウ病 / TSH受容体 / マウスモデル

Outline of Final Research Achievements

Mice respond well to immunization with human thyrotropin receptor (TSHR), but not to immunization with mouse TSHR. We have previously found that peripheral immune tolerance plays a minor role in immune tolerance against mouse TSHR. The present studies was therefore designed to study a role for central tolerance in immune tolerance against mouse TSHR in BALB/c mice. By using deleton of thymic cells with anti-RANKL antibody and alos SKG mice which have a point mutation in ZAP-70 gene, we here clearly showed a significant role for central tolerance in immune tolerance against mouse TSHR in mice.

Research Products

• [Journal Article] Long-term follow-up of a patient with sporadic non-autoimmune hyperthyroidism due to a thyrotropin receptor mutation (D619G). (2018)
  • Author(s): Nishihara E, Tsugawa M, Ozaki Y, Nagayama Y, Fukata S, Hirokawa M, Ito M, Nishikawa M, Nakamura H, Ito Y, Miyauchi A.
  • Journal Title: AACE Clin Case Rep. Volume: 1
  • Peer Reviewed / Open Access
• [Journal Article] Radiation Related Thyroid Autoimmunity and Dysfunction. (2018)
  • Author(s): Nagayama Y
  • Journal Title: J Radiat Res Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation. (2017)
  • Author(s): Tomomi Kurashige, Mika Shimamura, Yuji Nagayama.
  • Journal Title: Radiation and Environmental Biophysics Volume: 56 Issue: 4 Pages: 405-412
  • DOI: 10.1007/s00411-017-0711-8
  • Peer Reviewed / Open Access
• [Journal Article] バセドウ病と甲状腺機能異常：バセドウ病のモデル動物 (2017)
  • Author(s): 永山雄二
  • Journal Title: 最新医学社 Volume: 72 (10) Pages: 38-43
• [Journal Article] バセドウ病研究の最近の進展. (2017)
  • Author(s): 永山雄二
  • Journal Title: 医学のあゆみ Volume: 260(9) Pages: 711-715
• [Journal Article] Aldehyde dehydrogenase activity plays no functional role in stem cell-like properties in anaplastic thyroid cancer cell lines. (2017)
  • Author(s): Shimamura M, Kurashige T, Mitsutake N, Nagayama Y.
  • Journal Title: Endocrine Volume: 55 Issue: 3 Pages: 934-943
  • DOI: 10.1007/s12020-016-1224-y
  • Peer Reviewed / Open Access
• [Journal Article] Differences in quantification of DNA double-strand breaks assessed by 53BP1/γH2AX focus formation assays and the comet assay in mammalian cells treated with irradiation and N-acetyl-L-cysteine. (2016)
  • Author(s): Kurashige T, Shimamura M, Nagayama Y.
  • Journal Title: Journal of Radiation Research Volume: 印刷中 Issue: 3 Pages: 312-317
  • DOI: 10.1093/jrr/rrw001
  • Peer Reviewed / Open Access
• [Journal Article] Targeted Foxe1 overexpression in mouse thyroid causes the development of multinodular goiter but does not promote carcinogenesis. (2016)
  • Author(s): Nikitski A, Saenko V, Shimamura M, Nakashima M, Matsuse M, Suzuki K, Rogounovitch T, Bogdanova T, Shibusawa N, Yamada M, Nagayama Y, Yamashita S, Mitsutake N
  • Journal Title: Endocrinology Volume: 印刷中 Issue: 5 Pages: 2182-2195
  • DOI: 10.1210/en.2015-2066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer stem cells in the thyroid. (2016)
  • Author(s): Nagayama Y, Shimamura M, Mitsutake N.
  • Journal Title: Frontiers in Endocrinology Volume: 7 Pages: 20-20
  • DOI: 10.3389/fendo.2016.00020
  • Peer Reviewed / Open Access
• [Journal Article] XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency. (2015)
  • Author(s): Guo C, Nakazawa Y, Woodbine L, Bjorkman A, Shimada M, Fawcett H, Jia N, Ohyama K, Li TS,Nagayama Y, Mitsutake N, Pan-Hammarström Q, Gennery AR, Lehmann AR, Jeggo PA, Ogi T.
  • Journal Title: J Allergy Clin Immunol. Volume: 136 (4) Issue: 4 Pages: 1007-1017
  • DOI: 10.1016/j.jaci.2015.06.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A rapid, comprehensive system for assaying DNA repair activity and cytotoxic effects of DNA-damaging reagents. (2015)
  • Author(s): Nan Jia, Yuka Nakazawa, Chaowan Guo, Mayuko Shimada, Mieran Sethi, Yoshito Takahashi, Hiroshi Ueda, Yuji Nagayama, Tomoo Ogi
  • Journal Title: Nature Protocols Volume: 10 Issue: 1 Pages: 12-24
  • DOI: 10.1038/nprot.2014.194
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer stem cell theory and intratumor heterogeneity in thyroid carcinogenesis. (2015)
  • Author(s): Nakashima M, Shimamura M, Yasui K, Mitsutake N, Matsuu-Matsuyama M, Matsuda K, Nagayama Y.
  • Journal Title: J Basic Clin Med. Volume: 4 (1) Pages: 8-12
• [Journal Article] Animal models of Graves’ disease and Graves’ orbitopathy. (2015)
  • Author(s): Nagayama Y, Nakahara M, Abiru N.
  • Journal Title: Curr Opin Endocrinol Diabetes Obes. Volume: 22 (5) Issue: 5 Pages: 381-386
  • DOI: 10.1097/med.0000000000000186
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in non-obese diabetic mice. (2015)
  • Author(s): Akazawa S, Kobayashi K, Kuriya G, Horie I, Yu L, Yamasaki H, Okita M, Nagayama Y, Matsuyama T, Akbari M, Yui K, Kawakami A, Abiru N.
  • Journal Title: Diabetologia Volume: 58 (11) Issue: 11 Pages: 2606-2614
  • DOI: 10.1007/s00125-015-3724-3
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Mouse Models of Sporadic Thyroid Cancer with Lung Metastasis Derived from BRAF－V600E Alone or in Combination with PTEN Loss. (2017)
  • Author(s): Nagayama Y
  • Organizer: 87th annual meeting of American thyroid association.
  • Int'l Joint Research
• [Presentation] マウスにおいて、BRAFV600Eは単独で肺転移を伴う甲状腺癌を誘発し、PTEN欠失共存で低分化へ向かう (2017)
  • Author(s): 永山雄二、嶋村美加、蔵重智美、渋沢信行、山田正信、中島正洋
  • Organizer: 第６０回日本甲状腺学会
• [Presentation] Thyroid cancer in Nagasaki/Hiroshima, Chernobyl and Fukushima. (2017)
  • Author(s): Nagayama Y.
  • Organizer: The 2nd summit Italy-Japan
  • Place of Presentation: ロベレート（イタリア）
  • Int'l Joint Research
• [Presentation] 放射線と甲状腺癌・最近の知見 (2017)
  • Author(s): 永山雄二
  • Organizer: 原子爆弾被爆者指定医療機関等医師研究会
  • Place of Presentation: 長崎県農協会館（長崎県長崎市）
  • Invited
• [Presentation] TSH受容体の構造と機能－四半世紀の進展 (2016)
  • Author(s): 永山雄二
  • Organizer: 第58回甲状腺学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2016-11-03
  • Invited
• [Presentation] Thyroid cancer stem cells do not exist. (2016)
  • Author(s): Nagayama Y.
  • Organizer: 86th annual meeting of American thyroid association.
  • Place of Presentation: デンバー（アメリカ）
  • Year and Date: 2016-09-21
  • Int'l Joint Research / Invited
• [Presentation] Animal models of Graves' diseases. (2015)
  • Author(s): Nagayama Y.
  • Organizer: The 15th International Thyroid Congress
  • Place of Presentation: フロリダ（米国）
  • Year and Date: 2015-10-18
  • Int'l Joint Research / Invited
• [Presentation] バセドウ病研究：マウスモデルで何がわかったか？ (2015)
  • Author(s): 永山雄二
  • Organizer: 第４回広島甲状腺疾患研究会
  • Place of Presentation: オリエンタルホテル広島（広島県、広島市）
  • Year and Date: 2015-10-02
• [Presentation] Comparison of Radiation Disaster Between Nagasaki, Chernobyl and Fukushima. (2015)
  • Author(s): Nagayama Y.
  • Organizer: NASHIM symposium
  • Place of Presentation: テグ（韓国）
  • Year and Date: 2015-09-07
• [Presentation] 被爆70年間に果たした長崎大原研の役割－総括と展望 (2015)
  • Author(s): 永山雄二
  • Organizer: 第56回原子爆弾後障害研究会
  • Place of Presentation: 広島国際会議場（広島県、広島市）
  • Year and Date: 2015-06-07