Study on the chronic inflammation and cell growth transformation induced by gammaherpesvirus infection

• Project/Area Number: 24590550
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Osaka University
• Principal Investigator: YASUI Teruhito 大阪大学, 微生物病研究所, 准教授 (60283074)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Epstein-Barrウイルス / ウイルス発がん / Latent membrane protein / B細胞 / リンパ腫 / ノックインマウス / 持続感染 / 自己免疫疾患 / Immunoediting / LMP1 / ヘルペスウイルス / 上皮がん / 慢性炎症 / EBV / MHV68 / 胚中心 / リンパ球 / 抗体 / 発がん

Outline of Final Research Achievements

Epstein-Barr virus (EBV) infects into the 90 % of human being in the world-wide and is thought to a causative agent for some malignancies. Of the EBV-coding genes, Latent membrane protein (LMP) has been known to be involved in the tumorigenesis. Here this study demonstrates that molecular pathogenesis by which both LMP1 and LMP2a expression in B cells gives rise to lymphomagenesis. Depletion of T cells resulted in the development of splenomegaly induced by aberrant B cell growth. In conclusion, this study clearly indicates that T cells is responsible for the regulation of EBV-induced cell growth transformation in vivo.

Research Products

• [Journal Article] Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis. (2014)
  • Author(s): Tada S, Okuno T, Hitoshi Y, Yasui T, Honorat JH, Takata K, Koda T, Shimagami H, Chi-Jing C, Namba A, Sugimoto T, Sakoda S, Mochizuki H, Kikutani H, Nakatsuji Y.
  • Journal Title: J Neuroinflammation Volume: 11 Pages: 179-186
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] BAFF controls neural cell survival through BAFF receptor. (2013)
  • Author(s): Tada S, Yasui T, Nakatsuji Y, Okuno T, Koda T, Mochizuki H, Sakoda S, Kikutani H
  • Journal Title: PLoS One. Volume: 29;8(7) Issue: 7 Pages: e70924-e70924
  • DOI: 10.1371/journal.pone.0070924
  • Peer Reviewed
• [Journal Article] Significance of GPI-anchored protein enrichment in lipid rafts for the control of autoimmunity (2013)
  • Author(s): Wang, Y., Y. Murakami, T. Yasui, S. Wakana, H. Kikutani, T. Kinoshita and Y. Maeda
  • Journal Title: J. Biol. Chem Volume: 288 Issue: 35 Pages: 25490-25499
  • DOI: 10.1074/jbc.m113.492611
  • Peer Reviewed
• [Journal Article] Morihana T, Goya S, Mizui M, Yasui T, Prasad DV, Kumanogoh A, Tamura M, Shikina T, Maeda Y, Iwamoto Y, Inohara H, Kikutani H. (2013)
  • Author(s): An inhibitory role for Sema4A in antigen-specific allergic asthma
  • Journal Title: J Clin Immunol. Volume: 33(1) Issue: 1 Pages: 200-9
  • DOI: 10.1007/s10875-012-9798-5
  • Peer Reviewed
• [Journal Article] Protein kinase N1, a cell inhibitor of Akt kinase, has a central role in quality control of germinal center formation (2012)
  • Author(s): Yasui T, Sakakibara-Yada K, Nishimura T, Morita K, Tada S, Mosialos G, Kieff E, Kikutani H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109(51) Issue: 51 Pages: 21022-7
  • DOI: 10.1073/pnas.1218925110
  • Peer Reviewed
• [Journal Article] Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor. (2012)
  • Author(s): Nakahashi-Oda, C., Tahara-Hanaoka, S., Shoji, M., Okoshi, Y., Nakano-Yokomizo, T., Ohkohchi, N., Yasui, T., Kikutani, H., Honda, S., Shibuya, K., Nagata, S. and Shibuya, A.
  • Journal Title: J Exp. Med. Volume: 209 Issue: 8 Pages: 1493-1503
  • DOI: 10.1084/jem.20120096
  • Peer Reviewed
• [Presentation] Averrant activation of Akt in antigen-committed B cells results in selective IgA deficiency (2014)
  • Author(s): Minamitani T,Sakakibara S, Tsai Chau-Yuang, Kikutani H, Yasui T
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Generation and evolution of autoreactive B cells in systemic lupus erythematosus patients (2014)
  • Author(s): Sakakibara S, Takeda K, Yasui T, Kikutani H
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] EBV LMP1/LMP2a誘発B細胞不死化過程における宿主Immunoediting制御 (2014)
  • Author(s): 安居輝人、南谷武春、Chiau-Yuang Tsai、菊谷仁
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Generation and evolution of autoreactive B cells in systemic lupus erythematosus (2014)
  • Author(s): Sakakibara S, Takeda T, Jinzai H, Yasui T, Kikutani H
  • Organizer: The 13th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Nara, Japan
  • Year and Date: 2014-09-23 – 2014-09-26
• [Presentation] Epstein-Barr virus LMP2a accelerates B cell survival and plasma cell differentiation in germinal centers (2014)
  • Author(s): Minamitani T, Yasui T, Tsai CY,sakakibara S, Kikutani H
  • Organizer: The 39th International Herpesvirus workshop
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] EBウイルス LMP1/LMP2a誘導性Bリンパ腫形成とCancer Immunoediting制御 (2014)
  • Author(s): 安居輝人、南谷武春、Chiau-Yuang Tsai、菊谷仁
  • Organizer: 第11回EBウイルス研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-06-27
• [Presentation] プロスタグランジン12アゴニストであるONO‐1301はALSモデル動物の神経変性を抑制する (2014)
  • Author(s): 多田智、奥野龍禎、安居輝人、中辻裕司、酒井芳紀、宮川繁、菊谷仁、佐古田三郎、望月秀樹
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] EBV LMP2a reduces the stringency of B cell selection in germinal centers. (2014)
  • Author(s): Yasui, T., T. Minamitani, C.-Y. Tsai, S. Sakakibara, M. Busslinger, E. Kieff, and H. Kikutani
  • Organizer: EBV 50th Anniversary 2014
  • Place of Presentation: オックスフォーオド大学（イギリス）
• [Presentation] Direct and indirect inhibition of germinal cnter formation and humoral immune responses by Epstein-Barr virus LMP1. (2013)
  • Author(s): Tsai, C.-Y., T. Yasui, T. Minamitani, S. Sakakibara, and H. Kikutani
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Epstein-Barr virus LMP2a reduces the stringency of B cell selection in germinal center by augmenting BCR signal strength and enhancing plasma cell differentiation. (2013)
  • Author(s): Minamitani, T., T. Yasui, S. Sakakibara, C.-Y. Tsai, and H. Kikutani
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Generation of polyreactive B cells during murine herpesvirus infection. (2013)
  • Author(s): Sakakibara, S., T. Yasui, T. Minamitani, and H. Kikutani
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Signal-cell biology技術を用いたヒト抗HSV1抗体の単離‐持続感染ウイルスに対するヒト液性免疫応答の推移 (2013)
  • Author(s): 安居輝人、渡部明子、榊原修平、義江修、菊谷仁
  • Organizer: 第61回日本ウイルス学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] Epstein-Barr virus-encoded latent membrane protein 2A impairs B cell selection in germinal centers but not germinal center formation. (2013)
  • Author(s): Minamitani, T., S. Sakakibara, T. Yasui, and H. Kikutani
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milano Congressi (ミラノ市、イタリア）
• [Presentation] Generation of autoreactive and poly-reactive antibody producing cells during gamma-herpevirus infection. (2013)
  • Author(s): Sakakibara, S., T. Yasui, T. Minamitani, H. Jinzai, and H. Kikutani
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milano Congressi (ミラノ市、イタリア）
• [Presentation] Inhibition of germinal center formation and humoral immune responses by EB virus protein LMP1. (2013)
  • Author(s): Tsai, C.-Y., T.Yasui, T. Minamitani, K. Morita, S. Sakakibara, and H. Kikutani
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milano Congressi (ミラノ市、イタリア）
• [Presentation] ヒトHSV1 gD抗体の作成 (2013)
  • Author(s): 安居輝人、渡部明子、榊原修平、義江修、菊谷仁
  • Organizer: 第28回ヘルペスウイルス研究会
  • Place of Presentation: 淡路夢舞台国際会議場（淡路市）
• [Presentation] Inhibition of germinal center formation and humoral immune responses by EB virus protein LMP1 (2012)
  • Author(s): Chiau-Yuang Tsai
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸市
• [Presentation] Epstein-barr virus LMP2a affects affinity maturation but not germina. (2012)
  • Author(s): Minamitan, T.
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸市
• [Presentation] Generation and selection of virus- and self-reactive B cells during herpesvirus infection. (2012)
  • Author(s): Sakakibara, S.
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸市
• [Presentation] Population analysis of effector CD4+ T cells in MHV68 infection by single cell-based RT-PCR. (2012)
  • Author(s): Morita, K.
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸市
• [Presentation] ガンマヘルペスウイルス感染による自己抗原産生。 (2012)
  • Author(s): 榊原修平
  • Organizer: 第60回日本ウイルス学会
  • Place of Presentation: 大阪市
• [Presentation] Pathogenic activation and evasion of humoral immune responses by γ-herpesvirus infection. (2012)
  • Author(s): Yasui, T.
  • Organizer: The 11th Awaji International Forum on Infection and Immunity.
  • Place of Presentation: 兵庫県淡路市
  • Invited
• [Presentation] Population analysis of effector CD4+ T cells in MHV68 infection by single cell-based RT-PCR. (2012)
  • Author(s): Morita, K.
  • Organizer: The 11th Awaji International Forum on Infection and Immunity.
  • Place of Presentation: 兵庫県淡路市
• [Presentation] Generation of virus-and self-reactive B cells during herpesvirus infection. (2012)
  • Author(s): Sakakibara, S.
  • Organizer: The 11th Awaji International Forum on Infection and Immunity.
  • Place of Presentation: 兵庫県淡路市
• [Presentation] Expression of EB virus LMP2a modifies the selection of B cells in germinal center. (2012)
  • Author(s): Minamitani, T.
  • Organizer: International Congress on Oncogenic Herpesviruses and Associated Diseases.
  • Place of Presentation: Philadelphia, USA
• [Presentation] EBウイルスLMP1は関連腫瘍発生の必要十分分子となり得るか？－胚中心B細胞特異的LMP1発現マウスの解析。 (2012)
  • Author(s): 安居輝人
  • Organizer: 第27回ヘルペスウイルス研究会
  • Place of Presentation: 愛知県知多郡東浦町
• [Presentation] EBウイルス関連腫瘍の発症メカニズム‐胚中心B細胞特異的LMP1発現マウスの解析
  • Author(s): 安居輝人
  • Organizer: 第9回EBウイルス研究会
  • Place of Presentation: 米子市