Induction of autoimmune diseases through activation of B-1 cells by Helicobacter pylori urease

• Project/Area Number: 18590705
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nippon Medical School
• Principal Investigator: TAKAHASHI Hidemi Nippon Medical School, 大学院・医学研究科, 教授 (40221361)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥600,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: Helicobacter pylori / urease / B-1細胞 / 自己抗体 / 自己免疫疾患 / リウマチ因子 / ピロリ菌 / ウレアーゼ / T細胞非依存性 / 抗DNA抗体 / CD5

Research Abstract

報告者らは、ピロリ菌より採取・精製した菌体制分ウレアーゼが、ヘルパーT細胞の非存在下でマウス由来のB-1細胞を選択的に活性化すること、そしてこうしたB-1細胞をピロリ菌ウレアーゼで刺激したところ、培養上清中に自己抗体としてのリウマチ因子(RF)や抗DNA抗体が放出されることを発見した。また、ピロリ菌の培養上清中には全く菌体由来ウレアーゼ蛋白は検出されないこと、ならびに菌体表面に多量のウレアーゼ蛋白が発現していることを確認した。そこで、ウレアーゼを欠損したピロリ菌を入手し、このウレアーゼ欠損株と非欠損株ピロリ菌をプレート上に固着させ、B-1細胞を添加培養し、上清中のリウマチ因子や抗DNA抗体の放出量を測定したところ、ウレアーゼ非欠損株とともに培養した場合においてのみ、これらの自己抗体が検出された。こうした事実は、ピロリ菌表面のLPSなどではなく、菌体表面に発現したウレアーゼが直接にB-1細胞を刺激し、自己抗体の産生・放出を促したことを示している(論文投稿中)。

Research Products

• [Journal Article] Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage (2009)
  • Author(s): Yamashita, T., Tamura, H., Satoh, C., Shinya, E., Takahashi, H., Chen, L., Kondo, A., Tsuji, T., Dan, K., Ogata, K.
  • Journal Title: Clin. Cancer Res 75 Pages: 152-158
  • Peer Reviewed
• [Journal Article] アレルギー疾患における漢方薬の作用機序に対する一考察 (2009)
  • Author(s): 高橋秀実
  • Journal Title: 日本小児科学会雑誌 (印刷中)
  • Peer Reviewed
• [Journal Article] Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advanlago. (2009)
  • Author(s): Yamashita, T., Tamura, H., Saloh, C, Shinya, E., Takahashi, H., Chen, L., Kondo, A., Tsuji, T., Dan, K., Ogata, K.
  • Journal Title: Clin. Cancer Res. 15 Pages: 770-777
  • Peer Reviewed
• [Journal Article] A possible mechanism of intravesical BCG therapy for human bladder carcinoma : involvement of innatc cffeciorcells for the inhibition of tumor growth. (2009)
  • Author(s): Higuchi. T., Shimizu. M., Owaki, A., Takakahashi, M., Shinya, E., Nishimura, T., Takahashi, H.
  • Journal Title: Cancer Immunol. Immunother. Jan 19. On line issued(印刷中)
  • Peer Reviewed
• [Journal Article] Disruption of lFN signaling and HCV svnergisticaily enhance lympho-proliferation through type)II CD95 and interleukins. (2009)
  • Author(s): Machida, K., Tsukiyama-Kohara, K., Sckiguch, S., Seike, E., T溶e, S., Hayashi, Y., Tobita. Y., Kasama, Y., Shimizu, M., Takahashi, H., Tava, C, Yonekawa, H., Tanaka N Kobara. M
  • Journal Title: Gastroenterology (印刷中)
  • Peer Reviewed
• [Journal Article] Suppression of Already Established Tumor Growing through Activated Mucosal CTLs Induced by Oral Administration of Tumor Antigen with Cholera Toxin (2008)
  • Author(s): Wakabayashi A., Nakagawa Y., Shimizu M., Moriya K., Nishiyama Y., Takahashi H.
  • Journal Title: J. Immunol 180 Pages: 4000-4010
  • Peer Reviewed
• [Journal Article] Small intestine CD4+ T cells are profoundly depleted during acute simian-human immunodeficiency virus infection, regardless of viral pathogenicity (2008)
  • Author(s): Fukazawa, Y., Miyake, A., Ibuki, K., Inaba, K., Saito, N., Motohara, M., Horiuchi, R., Himeno, A., Matsuda, K., Matsuyama, M., Takahashi, H., Hayami, M., Igarashi, T., Miura, T.
  • Journal Title: J. Virol 82 Pages: 6039-6044
  • Peer Reviewed
• [Journal Article] 遊離抗原によるCD8+T細胞のアポトーシス誘導の可能性 (2008)
  • Author(s): 高橋めぐみ、高橋秀実
  • Journal Title: 臨床免疫・アレルギー科 49 Pages: 223-238
• [Journal Article] HIVに対する防御・細胞性免疫の役割 (2008)
  • Author(s): 高橋秀実
  • Journal Title: 治療 42 Pages: 72-76
• [Journal Article] 感染症と栄養・機能性食品 (2008)
  • Author(s): 若林あや子、高橋秀実
  • Journal Title: 日本機能性食品学会誌 4 Pages: 373-380
  • Peer Reviewed
• [Journal Article] HIV感染伝播における母乳中細胞の役割 (2008)
  • Author(s): 高橋秀実
  • Journal Title: 血液フロンティア 18 Pages: 45-51
• [Journal Article] HIV : ヒト免疫不全ウイルス感染と樹状細胞 (2008)
  • Author(s): 高橋秀実
  • Journal Title: 実験医学 26 Pages: 157-163
• [Journal Article] Suppression of an already established lumor growing through activated mucosal CTLs induced by oraladministration of tumor antigen with cholera toxin. (2008)
  • Author(s): Wakabavashi A., Nakagawa Y., Shimizu M., Moriya, K., Nishiyama, Y., Takahashi, H.
  • Journal Title: J. Immunol. 180 Pages: 4000-4010
  • Peer Reviewed
• [Journal Article] Small intestino CD4+T cells are profoundly depleted during acutc simian-human immunodelicieney virusinfection, regardless of viral pathogenicity. (2008)
  • Author(s): Fukazawa, Y., Miyake, A., Ibuki, K., lnaba, K., Saito, N., Motohara, M., Horiuchi, R., Himono, A., Matsuda, K., Matsuyama, M., Takahashi, H., Hayami, M., lgarashi. T., Miura. T
  • Journal Title: J. Virol. 82 Pages: 6039-6044
  • Peer Reviewed
• [Journal Article] Suppression of an already established tumor growing through activated mucosal CTLs induced by oral administration of tumor antigen with cholera toxin. (2008)
  • Author(s): Wakabayashi, A., Nakagawa, Y., Shimizu, M., Moriya, K., Nishiyama, Y., Takahashi, H.
  • Journal Title: J. Immunol. 180 Pages: 4000-4010
  • Peer Reviewed
• [Journal Article] Importance of gastrointestinal ingestion and macromolecular antigens in the vein for oral tolerance induction (2007)
  • Author(s): Wakabayashi, A., Kumagai, Y., Watari, E., Shimizu, M., Utsuyama, M., Hirokawa, K., Takahashi, H.
  • Journal Title: Immunology 119 Pages: 167-177
  • Peer Reviewed
• [Journal Article] Molecular analysis of TCR and peptide/MHC interaction using P18-I10-derived peptides with a single D-amino acid substitution (2007)
  • Author(s): Nakagawa Y, Kikuchi H, Takahashi H
  • Journal Title: 92 Pages: 2570-2582
  • Peer Reviewed
• [Journal Article] Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells (2007)
  • Author(s): Takahashi M, Watari E, Shinya E, Shimizu T, Takahashi H.
  • Journal Title: Antiviral Res 75 Pages: 152-158
  • Peer Reviewed
• [Journal Article] A possible mechanism of intravesical BCG therapy for human bladder carcinoma : involvement of innate effector cells for the inhibition of tumor growth (2007)
  • Author(s): Higuchi, T., Shimizu, M., Owaki, A., Takahashi, M., Shinya, E., Nishimura, T., Takahashi, H.
  • Journal Title: Cancer Immunol. Immunother. Jan 13, online published
  • Peer Reviewed
• [Journal Article] ピロリ菌ウレアーゼによるB-1細胞活性化作用と自己免疫疾患誘導の可能性 (2007)
  • Author(s): 山西慎吾、神谷茂、高橋秀実
  • Journal Title: 日本ヘリコバクター学会誌 8 Pages: 222-26
  • Peer Reviewed
• [Journal Article] 母乳を介したエイズウイルスの感染伝播 (2007)
  • Author(s): 高橋秀実
  • Journal Title: 日本エイズ学会誌 9 Pages: 11-16
  • NAID: 10026900447
  • Peer Reviewed
• [Journal Article] ワクチンによる特異的免疫機能の誘導 : ヒトにおける抗原特異的免疫機構 (2007)
  • Author(s): 高橋秀実
  • Journal Title: 治療学 41 Pages: 1041-1045
• [Journal Article] γδT細胞とリウマチ様関節炎 (2007)
  • Author(s): 高橋秀実
  • Journal Title: リウマチ科 38 Pages: 565-570
• [Journal Article] 樹状細胞の機能とHIV-1 Nef (2007)
  • Author(s): 新谷英滋、高橋秀実
  • Journal Title: 48 Pages: 623-629
• [Journal Article] Molecular analysis of TCR and peptide/MHC interaction using P18-I10-derived peptides with a single D-amino acid substitution. (2007)
  • Author(s): Nakagawa, Y., Kikuchi, H., Takahashi, H.
  • Journal Title: Biophysical J. 92 Pages: 2570-2582
  • Peer Reviewed
• [Journal Article] Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells. (2007)
  • Author(s): Takahashi, M., Watari, E., Shinya, E., Shimizu, M., Takahashi, H.
  • Journal Title: Antiviral Res. 75 Pages: 152-158
  • Peer Reviewed
• [Journal Article] ピロリ菌ウレアーゼによるB-1細胞活性化作用と自己免疫疾患誘導の可能性. (2007)
  • Author(s): 山西慎吾、神谷茂、高橋秀実
  • Journal Title: 日本ヘリコバクター学会誌 8 Pages: 22-26
  • Peer Reviewed
• [Journal Article] Molecular analysis of TCR and peptide/MHC interaction using P18-110-derived peptides with a single D-amino acid substitution. (2007)
  • Author(s): Nakagawa, Y., Kikuchi, H., Takahashi, H.
  • Journal Title: Biophysical J. 92・7 Pages: 2570-2582
• [Journal Article] Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells. (2007)
  • Author(s): Takahashi, M., Watari, E., Shinya, E., Shimizu, M., Takahashi, H.
  • Journal Title: Antiviral Res. (In press)
• [Journal Article] Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease (2006)
  • Author(s): Yamanishi, S., Iizumi, T., Watanabe, E., Shimizu, M., Kamiya, S., Nagata, K., Kumagai, Y., Fukunaga, Y., Takahashi, H.
  • Journal Title: Infect. Immune 74 Pages: 248-256
  • Peer Reviewed
• [Journal Article] Induction of immunological tolerance by oral, but not intravenous and intraportal, administration of ovalbumin and the difference between young and old mice (2006)
  • Author(s): Wakabayashi A., Utsuyama, M., Hosoda, T., Sato., Takahashi, H., Hirokawa, K.
  • Journal Title: J. Nutr. Health Aging 10 Pages: 183-191
  • Peer Reviewed
• [Journal Article] BCG vaccine elicits both T-cell mediated and humoral immune responses directed against mycobacterial lipid components (2006)
  • Author(s): Watanabe Y, Watari E, Matsunaga I, Hiromatsu K, Dascher C D, Kawashima T, Norose Y, Simizu K, Takahashi H, Yano I, Sugita M
  • Journal Title: Vaccine 24 Pages: 5700-5707
  • Peer Reviewed
• [Journal Article] 癌の免疫療法 : 丸山ワクチンの作用機序に関する一考察 (2006)
  • Author(s): 高橋秀実
  • Journal Title: 日本医科大学医会誌 2 Pages: 1-2
  • Peer Reviewed
• [Journal Article] 免疫システムの新たな実態 : 基本免疫と獲得免疫 (2006)
  • Author(s): 高橋秀実
  • Journal Title: 日本感染症学会雑誌 80 Pages: 463-468
  • Peer Reviewed
• [Journal Article] DsRed2を用いたエイズウイルスnef遺伝子産物と脂質抗原提示分子CD1a相互作用の解析 (2006)
  • Author(s): 新谷英滋、大脇敦子、高橋秀実
  • Journal Title: 日本医科大学医会誌 2 Pages: 134-135
  • Peer Reviewed
• [Journal Article] 体表面に配置された自然免疫システムと体内を循環する獲得免疫システム (2006)
  • Author(s): 高橋秀実
  • Journal Title: 炎症と免疫 14 Pages: 449-450
• [Journal Article] 粘膜組織におけるHIVの拡散と制御 (2006)
  • Author(s): 高橋秀実
  • Journal Title: 炎症と免疫 14 Pages: 479-485
• [Journal Article] Helicobacter pylori由来ureaseの酵素活性を増強させる特異的抗体 (2006)
  • Author(s): 飯泉匡、熊谷善博、高橋秀実
  • Journal Title: 臨床免疫・アレルギー科 46 Pages: 205-207
  • NAID: 40007394142
• [Journal Article] ヒト免疫不全ウイルスNefによる免疫抑制の機序 (2006)
  • Author(s): 新谷英滋、高橋秀実
  • Journal Title: 臨床免疫・アレルギー科 46 Pages: 222-226
  • NAID: 40007394146
• [Journal Article] HIVとnef (2006)
  • Author(s): 高橋秀実
  • Journal Title: 炎症と免疫 14 Pages: 816-821
• [Journal Article] Implications for induction of autoimmunity via activation of B-l cells by Helicobacter pylori urease. (2006)
  • Author(s): Yamanishi, S., lizumi, T., Watanabe, E., Shimizu, M., Kamiya, S., Nagata, K., Kumagai, Y., Fukunaga, Y., Takahashi, H.
  • Journal Title: Infect. Immune. 74・1 Pages: 248-256
• [Journal Article] Induction of immunological tolerance by oral, but not intravenous and Intraportal, administration of ovalbumin and the diffrence between young and old mice, (2006)
  • Author(s): Wakabayashi, A., Utsuyama, M., Hosoda, T., Sato, K., Takahashi, H., Hirokawa, K.
  • Journal Title: J. Nutr. Health Aging 10・3 Pages: 183-191
• [Journal Article] BCG vaccine elicits both T-cell mediated and humoral immune responses directed against mycobacterial lipid components. (2006)
  • Author(s): Watanabe, Y., Watari, E., Matsunaga, I, Hiromatsu, K., Dascher, C.D., Kawashima, T., Norose, Y., Shimizu, K., Takahashi, H., Yano, I., Sugita, M.
  • Journal Title: Vaccine 24・29-30 Pages: 5700-5707
• [Journal Article] Importance of gastrointestinal ingestion and macromolecular antigens in the vein for oral tolerance Induction (2006)
  • Author(s): Wakabayashi, A., Kumagai, Y., Watari, E., Shimizu, M., Utsuyama, M., Hirokawa, K., Takahashi, H.
  • Journal Title: Immunology 119・2 Pages: 167-177
• [Journal Article] BCGによる自然免疫の活性化
  • Author(s): 高橋秀実
  • Journal Title: 泌尿器外科
• [Presentation] Inhibition of DC-SICN-mediated HIV-1 transmission via breast-feeding by IFN-βreleased through T1, R3 mediated signaling. (2008)
  • Author(s): Takahashi H.
  • Organizer: Jnpan-US Cooperative Medical Science Program : The 21st Joint Scientific Meeting of AIDS Pancls.
  • Place of Presentation: 東京(ポテル・オークラ)
  • Year and Date: 2008-09-13
• [Presentation] 自然免疫システムと疾病:慢性関節リウマチに対する新たなアプローチ. (2008)
  • Author(s): 高橋秀実
  • Organizer: 第7回小児感染免疫研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-02-16
• [Presentation] HIV感染と免疫応答 (2007)
  • Author(s): 高橋秀実
  • Organizer: 第21回日本エイズ学会学術集会
  • Place of Presentation: 広島
  • Year and Date: 2007-11-29
• [Presentation] Cross-reactive cytotoxicity of CD1d-NKT cell system between primates and rodents. (2007)
  • Author(s): Takahashi H., Saito N., Shimizu M., Owaki A., Watanabe E., Takahashi M., Ohmi K., Takaku C., Shinya E.
  • Organizer: 第37回日本免疫学会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-22
• [Presentation] 麻疹ウイルス変異株の持続感染に関与する宿主因子・その3 (2007)
  • Author(s): 高橋めぐみ、渡理英二、清水真澄、新谷英滋、高橋秀実
  • Organizer: 第55回日本ウイルス学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2007-10-22
• [Presentation] Cellular HIV dissemination and expansion at the mucosal compartment. (2007)
  • Author(s): Takahashi, H.
  • Organizer: Japan-US Cooperative Medical Science Program: The 20th Joint Scientific Meeting of AIDS Panels.
  • Place of Presentation: 米国、モントレー市
  • Year and Date: 2007-09-14
• [Presentation] 免疫学的な視点から見たSARSに対する温病学的治療の意義. (2007)
  • Author(s): 高橋秀実
  • Organizer: 第5回日本中医学交流会大会
  • Place of Presentation: 東京
  • Year and Date: 2007-08-05
• [Presentation] ピロリ菌ウレアーゼによるB-1細胞活性化作用と自己免疫疾患誘導の可能性. (2007)
  • Author(s): 山西慎吾、神谷茂、高橋秀実
  • Organizer: 第13回日本ヘリコバクター学会
  • Place of Presentation: 神戸
  • Year and Date: 2007-06-22
• [Book] リッピンコット・イラストレイテッド免疫学 (2009)
  • Author(s): 高橋秀実、書籍全体
  • Publisher: 丸善出版(発刊)
• [Book] 細胞制免疫(CTL)の誘導と樹状細胞、臨床粘膜免疫学 (2009)
  • Author(s): 高橋秀実
  • Publisher: (印刷中)
• [Book] リッピコット・イラストレイテッド免疫学 (2009)
  • Author(s): 矢田純一, 高橋秀実
  • Total Pages: 353
  • Publisher: 丸善出版
• [Book] 特異免疫およびその賦活法に関する基本原理、ブラック微生物学 (2007)
  • Author(s): 高橋秀実
  • Publisher: 丸善出版(発刊)
• [Book] ブラック微生物学(第2版) (2007)
  • Author(s): 林英生, 岩本愛吉, 神谷茂, 高橋秀実
  • Total Pages: 911
  • Publisher: 丸善出版
• [Patent(Industrial Property Rights)] ヒト免疫不全ウイルスを認識するキラーT細胞レセプター (2006)
  • Acquisition Date: 2006-07-25