自己免疫疾患末梢抗原に対する免疫寛容獲得機構の解明

2008 年度 研究成果報告書

• 研究課題/領域番号: 17109012
• 研究種目: 基盤研究(S)
• 配分区分: 補助金
• 研究分野: 皮膚科学
• 研究機関: 慶應義塾大学
• 研究代表者: 天谷 雅行 慶應義塾大学, 医学部, 教授 (90212563)
• 研究分担者: 小安 重夫 慶應義塾大学, 医学部, 教授 (90153684) ; 桑名 正隆 慶應義塾大学, 医学部, 准教授 (50245479) ; 石河 晃 慶應義塾大学, 医学部, 准教授 (10202988)
• 研究期間 (年度): 2005 – 2008
• キーワード: 自己免疫 / 免疫寛容 / モデルマウス / 天疱瘡 / カドヘリン

研究概要

本研究では、デスモグレイン3(Dsg3)に対するIgG自己抗体による尋常性天疱瘡をモデル疾患として、自己免疫発症機序の解明を目指した。Dsg3反応性T 細胞には、自己抗体産生において病原性があるものとないものがあり、IL-4が病的抗体産生に重要であることが明らかにされた。また、ひとつのT細胞クローンが複数のB細胞に作用し、ポリクローナルな病的抗体を産生することが示された。病原性自己抗体による組織障害により、Dsg3反応性B細胞が除去される新しいB細胞末梢免疫寛容機序の存在が示唆された。

研究成果

• [雑誌論文] A single helper T cell clone is sufficient to commit polyclonal naive B cells to produce pathogenic IgG in experimental pemphigus vulgaris (2009)
  • 著者名/発表者名: Takahashi H, Kuwana M, Amagai M
  • 雑誌名: J Immunol 182(3) ページ: 1740-1745
• [雑誌論文] Pemphigus mouse model as a tool to evaluate various immunosuppressive therapies. (2009)
  • 著者名/発表者名: Takae Y, Nishikawa T, Amagai M
  • 雑誌名: Exp Dermatol 18(3) ページ: 252-260
• [雑誌論文] Genetic characterization of human Dsg3-specific B cells isolated by flow cytometry from the peripheral blood of patients with pemphigus vulgaris. (2008)
  • 著者名/発表者名: Yamagami J, Takahashi H, Ota T, Amagai M
  • 雑誌名: J Dermatol Sci 52(2) ページ: 98-107
• [雑誌論文] Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen: implications for peripheral tolerance. (2008)
  • 著者名/発表者名: Ota T, Aoki-Ota M, Tsunoda K, Nishikawa T, Koyasu S, Amagai M
  • 雑誌名: Int Immunol 20(10) ページ: 1351-1360
• [雑誌論文] Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris. (2008)
  • 著者名/発表者名: Takahashi H, Amagai M, Nishikawa T, Fujii Y, Kawakami Y, Kuwana M
  • 雑誌名: J Immunol 181(2) ページ: 1526-1535
• [雑誌論文] Staphylococcal exfoliative toxins: "Molecular scissors" of bacteria that attack the cutaneous defense barrier in mammals. (2008)
  • 著者名/発表者名: Nishifuji K, Sugai M, Amagai M
  • 雑誌名: J Dermatol Sci 49(1) ページ: 21-31
• [雑誌論文] Evaluating efficacy of plasmapheresis for patients with pemphigus using desmoglein enzyme-linked immunosorbent assay. (2008)
  • 著者名/発表者名: Nagasaka T, Fujii Y, Ishida A, Handa M, Tanikawa A, Amagai M, Nishikawa T
  • 雑誌名: Br J Dermatol 158(4) ページ: 685-690
• [雑誌論文] Development of tissue-targeting hemagglutinating virus of Japan envelope vector for successful delivery of therapeutic gene to mouse skin. (2007)
  • 著者名/発表者名: Kawachi M, Tamai K, Saga K, Yamazaki T, Fujita H, Shimbo T, Kikuchi Y, Nimura K, Nishifuji K, Amagai M, Uitto J, Kaneda Y
  • 雑誌名: Hum Gene Ther 18(10) ページ: 881-894
• [雑誌論文] No activation of urokinase plasminogen activator by anti-desmoglein 3 monoclonal IgG antibodies in cultured human keratinocytes. (2007)
  • 著者名/発表者名: Yamamoto Y, Aoyama Y, Shu E, Tsunoda K, Amagai M, Kitajima Y
  • 雑誌名: J Dermatol Sci 47(2) ページ: 119-125
• [雑誌論文] Anti-desmoglein 3 (Dsg3) monoclonal antibodies deplete desmosomes of Dsg3 and differ in their Dsg3-depleting activities related to pathogenicity. (2007)
  • 著者名/発表者名: Yamamoto Y, Aoyama Y, Shu E, Tsunoda K, Amagai M, Kitajima Y
  • 雑誌名: J Biol Chem 282(24) ページ: 17866-17876
• [雑誌論文] T helper type 2-biased natural killer cell phenotype in patients with pemphigus vulgaris. (2007)
  • 著者名/発表者名: Takahashi H, Amagai M, Tanikawa A, Suzuki S, Ikeda Y, Nishikawa T, Kawakami Y, Kuwana M
  • 雑誌名: J Invest Dermatol 127 ページ: 324-330
• [雑誌論文] Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. (2006)
  • 著者名/発表者名: Stanley J R, Amagai M
  • 雑誌名: N Engl J Med 355 ページ: 1800-1810
• [雑誌論文] Synergistic pathogenic effects of combined mouse monoclonal anti-desmoglein 3 IgG antibodies on pemphigus vulgaris blister formation. (2006)
  • 著者名/発表者名: Kawasaki H, Tsunoda K, Hata T, Ishii K, Yamada T, Amagai M
  • 雑誌名: J Invest Dermatol 126 ページ: 2621-2630
• [雑誌論文] Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model. (2006)
  • 著者名/発表者名: Aoki-Ota M, Kinoshita M, Ota T, Tsunoda K, Iwasaki T, Tanaka S, Koyasu S, Nishikawa T, Amagai M
  • 雑誌名: J Invest Dermatol 126 ページ: 105-113
• [雑誌論文] Enzyme-linked immunosorbent assay using bacterial recombinant proteins of human BP230 as a diagnostic tool for bullous pemphigoid. (2006)
  • 著者名/発表者名: Yoshida M, Hamada T, Amagai M, Hashimoto K, Uehara R, Yamaguchi K, Imamura K, Okamoto E, Yasumoto S, Hashimoto T
  • 雑誌名: J Dermatol Sci 41 ページ: 21-30
• [雑誌論文] Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. (2006)
  • 著者名/発表者名: Calkins C C, Setzer S V, Jennings J M, Summers S, Tsunoda K, Amagai M, Kowalczyk A P
  • 雑誌名: J Biol Chem 281 ページ: 7623-7634
• [雑誌論文] Pathogenic monoclonal antibody against desmoglein 3 augments phosphorylation of desmoglein 3 and p38 MAP K in a human squamous carcinoma cell line. (2006)
  • 著者名/発表者名: Kawasaki Y, Aoyama Y, Tsunoda K, Amagai M, Kitajima Y
  • 雑誌名: Autoimmunity 39 ページ: 587-590
• [雑誌論文] Production of Low Titers of Anti-Desmoglein 1 IgG Autoantibodies in Some Patients with Staphylococcal Scalded Skin Syndrome. (2006)
  • 著者名/発表者名: Anzai H, Stanley J R, Amagai M
  • 雑誌名: J Invest Dermatol 126 ページ: 2139-2141
• [雑誌論文] Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just 'witnesses of disease'? (2006)
  • 著者名/発表者名: Amagai M, Ahmed A R, Kitajima Y, Bystryn J C, Milner Y, Gniadecki R, Hertl M, Pincelli C, Fridkis-Hareli M, Aoyama Y, Frusic-Zlotkin M, Muller E, David M, Mimouni D, Vind-Kezunovic D, Michel B, Mahoney M, Grando S
  • 雑誌名: Exp Dermatol 15 ページ: 815-831
• [雑誌論文] Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. (2005)
  • 著者名/発表者名: Payne A S, Ishii K, Kacir S, Lin C, Li H, Hanakawa Y, Tsunoda K, Amagai M, Stanley J R, Siegel D L
  • 雑誌名: J Clin Invest 115 ページ: 888-899
• [雑誌論文] Cutaneous type pemphigus vulgaris: a rare clinical phenotype of pemphigus. (2005)
  • 著者名/発表者名: Yoshida K, Takae Y, Saito H, Oka H, Tanikawa A, Amagai M, Nishikawa T
  • 雑誌名: J Am Acad Dermatol 52 ページ: 839-845
• [雑誌論文] n vitro keratinocyte dissociation assay for evaluation of the pathogenicity of anti-desmoglein 3 IgG autoantibodies in pemphigus vulgaris. (2005)
  • 著者名/発表者名: Ishii K, Harada R, Matsuo I, Shirakata Y, Hashimoto K, Amagai M
  • 雑誌名: J Invest Dermatol 124 ページ: 939-946
• [雑誌論文] In vivo ultrastructural localization of the desmoglein 3 adhesive interface to the desmosome mid-line. (2005)
  • 著者名/発表者名: Shimizu A, Ishiko A, Ota T, Saito H, Oka H, Tsunoda K, Amagai M, Nishikawa T
  • 雑誌名: J Invest Dermatol 124 ページ: 984-989
• [学会発表] Characterization of T cells that regulate pathogenic IgG production in pemphigus model mice (2009)
  • 著者名/発表者名: Amagai M
  • 学会等名: 2009 Shanghai International Academic Meeting on Bullous Disease
  • 発表場所: Shanghai, China
  • 年月日: 2009-03-21
• [学会発表] Cell adhesion molecules: targets of skin diseases (2008)
  • 著者名/発表者名: Amagai M
  • 学会等名: The 6th Wor ld Congr ess of Veter inary Dermatology
  • 発表場所: Hong Kong
  • 年月日: 20081119-20081122
• [学会発表] Pemphigus from molecules to mice to human (2008)
  • 著者名/発表者名: Amagai M
  • 学会等名: The 60th Annual Fall Meeting of Kor ean Dermatological Association
  • 発表場所: Seoul, Korea
  • 年月日: 20081018-20091019
• [学会発表] Proteolytic processing of precursor desmoglein 1 (Dsg1) unmarks pathogenic epitope (2008)
  • 著者名/発表者名: Yokouchi M, Ishii K, Stanley JR, Amagai M
  • 学会等名: Post IID 2008 Satellite: International Meeting on Autoimmune Bullous Diseases Otsu
  • 発表場所: Japan
  • 年月日: 20080517-20080519
• [学会発表] Mechanisms of desmosome disassembly in pemphigus vulgaris (2008)
  • 著者名/発表者名: Kowalczyk A, Kottke M, Jennings JM, Delva E, Hanakawa Y, Amagai M
  • 学会等名: Post IID 2008 Satellite: International Meeting on Autoimmune Bullous Diseases Otsu
  • 発表場所: Japan
  • 年月日: 20080517-20080519
• [学会発表] CD4+CD25+ regulatory T cells suppressing anti-Dsg3 antibody production in pemphigus vulgaris develop in the absence of Dsg3 (2008)
  • 著者名/発表者名: Yokoyama T, Matsuda S, Takae Y, Amagai M, Koyasu S
  • 学会等名: The International Investigative Dermatology 2008
  • 発表場所: Kyoto, Japan
  • 年月日: 20080514-20080517
• [学会発表] Pathogenic pemphigus foliaceus (PF) and vulgaris (PV) antibodies share a consensus amino acid motif in their CDR3 regions (2008)
  • 著者名/発表者名: Yamagami J, Ishii K, Payne AS, Kacir S, Amagai M, Siegel DL, Stanley JR
  • 学会等名: The International Investigative Dermatology 2008
  • 発表場所: Kyoto, Japan
  • 年月日: 20080514-20080517
• [学会発表] IgM to IgG isotype switching of anti-desmoglein 3 antibodies is an essential step for pathogenesis of pemphigus vulgaris (2008)
  • 著者名/発表者名: Tsunoda K, Ota T, Hata T, Shimizu A, Yamada T, Nakagawa T, Amagai M
  • 学会等名: The International Investigative Dermatology 2008
  • 発表場所: Kyoto, Japan
  • 年月日: 20080514-20080517
• [学会発表] Single desmoglein 3-reactive CD4+ T cell clones activate polyclonal naive B cells and promote the production of pathogenic IgG in experimental pemphigus vulgaris (2008)
  • 著者名/発表者名: Takahashi H, Kuwana M, Amagai M
  • 学会等名: The International Investigative Dermatology 2008
  • 発表場所: Kyoto, Japan
  • 年月日: 20080514-20080517
• [学会発表] Two pathogenic anti-desmoglein 1 (Dsg1) monoclonal antibodies isolated from one pemphigus foliaceus (PF) patient define major Dsg1 epitopes recognized by most pemphigus patients (2008)
  • 著者名/発表者名: Ishii K, Adly M, Yokouchi M, Stanley JR, Amagai M
  • 学会等名: The International Investigative Dermatology 2008
  • 発表場所: Kyoto, Japan
  • 年月日: 20080514-20080517
• [学会発表] Induction of both humoral and cellular immune response against desmoglein 3 provides a mouse model mimicking an immunological aspect of paraneoplastic pemphigus (2008)
  • 著者名/発表者名: Hata T, Nishifuji K, Yamada T, Shimoda K, Amagai M
  • 学会等名: The International Investigative Dermatology 2008
  • 発表場所: Kyoto, Japan
  • 年月日: 20080514-20080517
• [学会発表] Development of targeted therapies for autoimmune bullous diseases (2007)
  • 著者名/発表者名: Amagai M
  • 学会等名: 21st World Congr ess of Dermatology
  • 発表場所: Buenos Aires, Argentina
  • 年月日: 20071001-20071005
• [学会発表] Animal models- Do they tell us about human disease? (2007)
  • 著者名/発表者名: Amagai M
  • 学会等名: 21st Wor ld Congr ess of Dermatology
  • 発表場所: Buenos Aires, Argentina
  • 年月日: 20071001-20071005
• [学会発表] Genetic characterlization of human Dsg3-specific B cells isolated by flow cytmetry from peripheral blood of patients with pemphigus vulgaris (2007)
  • 著者名/発表者名: Yamagami J, Takahashi H, Ota T, Amagai M
  • 学会等名: The 37th Annual Meeting of European Society for Dermatological Resear ch (ESDR)
  • 発表場所: Zurich, Switzland
  • 年月日: 20070905-20070908
• [学会発表] Suppressive effects of CD4+ CD25+ regulatory T cells on the development of phenotypes in a mouse model of pemphigus vulgaris (2007)
  • 著者名/発表者名: Yokoyama T, Matsuda S, Takae Y, Amagai M, Koyasu S
  • 学会等名: The 37th Annual Meeting of European Society for Dermatological Research (ESDR)
  • 発表場所: Zurich, Switzland
  • 年月日: 20070905-20070508
• [学会発表] Effective B cell depletion therapy in a pemphigus mouse model (2007)
  • 著者名/発表者名: Takae Y, Hamaguchi Y, Tedder TF, Amagai M
  • 学会等名: The 68th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: Los Angeles, USA
  • 年月日: 20070509-20070512
• [学会発表] Genetic restriction of anti-desmoglein(Dsg)1 antibodies in pemphigus foliaceus (PF) (2006)
  • 著者名/発表者名: Ishii K, Li H, Lin C, Kacir S, Amagai M, Siegel DL, Stanley JR
  • 学会等名: The 67th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: Philadelphia, PA, USA
  • 年月日: 20060503-20060506
• [学会発表] Characterization of desmoglein 3-reactive helper T cells involved in pathogenic IgG production in a mouse model for pemphigus vulgaris (2006)
  • 著者名/発表者名: Takahashi H, Amagai M, Nishikawa T, Kawakami Y, Kuwana M
  • 学会等名: The 67th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: Philadelphia, PA, USA
  • 年月日: 20060503-20060506
• [学会発表] Binding kinetic analysis of anti-desmoglein 3 monoclonal antibodies by surface plasmon resonance technology (2006)
  • 著者名/発表者名: Tsunoda K, Iemura S, Nakagawa T, Natsume T, Amagai M
  • 学会等名: The 67th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: Philadelphia, PA, USA
  • 年月日: 20060503-20060506
• [学会発表] Dsg1 transgenic rescue of loss of cell adhesion in Dsg3 deficient mice (2005)
  • 著者名/発表者名: Hata T, Nishifuji K, Shimoda K, Yamada T, Nishikawa T, Amagai M
  • 学会等名: The 66th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: St. Louis, Missouri, USA
  • 年月日: 20050504-20050507
• [学会発表] Danger signal by pathogenic IgG eliminates autoreactive B cells against desmoglein 3 (2005)
  • 著者名/発表者名: Ota T, Aoki-Ota M, Tsunoda K, Nishikawa T, Koyasu S, Amagai M
  • 学会等名: desmoglein 3. The 66th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: St. Louis, Missouri, USA
  • 年月日: 20050504-20050507
• [学会発表] Expression of desmoglein 3 in medullary thymic epithelial cells in thymus (2005)
  • 著者名/発表者名: Wada N, Nishifuji K, Yamada T, Kudoh J, Shimizu N, Peltonen L, Nagafuchi S, Amagai M
  • 学会等名: The 66th Annual Meeting of the Society for Investigative Dermatology
  • 発表場所: St. Louis, Missouri, USA
  • 年月日: 20050504-20050507
• [図書] Pemphigus. Dermatology 2nd Edition (2008)
  • 著者名/発表者名: Amagai M
  • 総ページ数: 417-429
  • 出版者: Mosby Elsevier
• [備考]
  • URL: http://web.sc.itc.keio.ac.jp/derma/