Elucidation of Molecular Mechanisms of Hyper-IgE Syndrome

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021015
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MINEGISHI Yoshiyuki 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (10343154)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥20,000,000 (Direct Cost: ¥20,000,000); Fiscal Year 2011: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 2010: ¥10,000,000 (Direct Cost: ¥10,000,000)
• Keywords: 免疫不全症 / 高IgE症候群 / アトピー性疾患 / 高IgE血症 / 黄色ブドウ球菌 / 原発性免疫不全症 / アトピー性皮膚炎 / STAT3 / モデルマウス / 制御性T細胞 / 樹状細胞

Research Abstract

Hyper-IgE syndrome is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. While defective Th17 cell differentiation partly accounts for susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. Here we examined the differentiation and function of Th1, Th2, regulatory T (Treg), and dendritic cells in HIES patients carrying either STAT3 mutation. Although the in vitro differentiation of Th1/Th2 cells and the number and function of Treg cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective response to IL-10 and hence failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired upregulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared to control DCs. Moreover, IL-10-treated DCs from patients displayed little ability to induce the differentiation of naive CD4 + T cells to FOXP3 + induced Treg cells that could suppress the proliferation and cytokine production of other CD4 + T cells. These results suggest that the defective generation of IL-10-induced tolerogenic DCs and iTreg cells might contribute, at least in part, to the development of atopic manifestations in HIES.

Research Products

• [Journal Article] Cutaneous Manifestations of Hyper IgE Syndrome (2012)
  • Author(s): Minegishi Y, Saito M
  • Journal Title: Allergol Int Volume: (in press)
  • NAID: 130004477139
  • Peer Reviewed
• [Journal Article] Th2-mducing cytokines IL-4 and IL-33 synergistically elicit the expression of transmembrane TNF-α on macrophages through the autocrine action of IL-6 (2012)
  • Author(s): Ogawa H, Mukai K, Kawano Y, Minegishi Y, Karasuyama H
  • Journal Title: Biochem Biophys Res Commun Volume: 420 Pages: 114-118
  • Peer Reviewed
• [Journal Article] Functional STAT3 deficiency compromises the generation of human T follicular helper cells (2012)
  • Author(s): Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, Arkwright PD, Kreins AY, Averbuch D, Engelhard D, Magdorf K, Kilic SS, Minegishi Y, Nonoyama S, French MA, Choo S, Smart JM, Peake J, Wong M, Gray P, Cook MC, Fulcher DA, Casanova JL, Deenick EK, Tangye SG
  • Journal Title: Blood Volume: (in press)
  • Peer Reviewed
• [Journal Article] Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells. (2011)
  • Author(s): Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T, Tsuge I, Nonoyama S, Karasuyama H, Minegishi Y.
  • Journal Title: J Exp Med Volume: 208 Pages: 235-249
  • Peer Reviewed
• [Journal Article] NK cell-depleting anti-asialo GM1 Ab exhibits a lethal ‘off-target’ effect on basophils in vivo (2011)
  • Author(s): Nishikado H, Mukai K, Kawano Y, Minegishi Y, Karasuyama H.
  • Journal Title: J Immunol Volume: 186 Pages: 5766-5771
  • Peer Reviewed
• [Journal Article] Hyper IgE syndrome diagnosed in early infancy by gene analysis of STAT3 mutation. (2011)
  • Author(s): Watarai A, Niiyama S, Morita M, Bando Y, Minegishi Y, Katsuoka K.
  • Journal Title: Eur J Dermatol Volume: 21 Pages: 254-255
  • Peer Reviewed
• [Journal Article] Basophil-derived mouse mast cell protease 11 induces microvascular leakage and tissue edema in a mast cell-independent manner (2011)
  • Author(s): Yamagishi H, Mochizuki Y, Hamakubo T, Obata K, Ugajin T, Sato S, Kawano Y, Minegishi Y, Karasuyama H.
  • Journal Title: Biochem Biophy Res Comm Volume: 415 Pages: 709-713
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of the immunological abnormalities in hyper IgE syndrome. (2011)
  • Author(s): Minegishi Y, Saito M.
  • Journal Title: Ann N Y Acad Sci Volume: 1246 Pages: 34-40
  • Peer Reviewed
• [Journal Article] 原発性免疫不全症の新展開 (2011)
  • Author(s): 峯岸克行
  • Journal Title: 炎症と免疫 Volume: 19(5) Pages: 3-4
• [Journal Article] 高IgE症候群における易感染性のメカニズム (2011)
  • Author(s): 峯岸克行
  • Journal Title: 呼吸器内科 Volume: 20 Pages: 83-86
  • NAID: 40018973024
• [Journal Article] 高IgE症候群の病因・病態解析 (2011)
  • Author(s): 齋藤雅子, 峯岸克行
  • Journal Title: アレルギー・免疫 Volume: 18 Pages: 72-76
• [Journal Article] Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells (2011)
  • Author(s): Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T, Tsuge I, Nonoyama S, Karasuyama H, Minegishi Y
  • Journal Title: J Exp Med Volume: 208 Pages: 235-249
  • Peer Reviewed
• [Journal Article] NK cell-depleting anti-asialo GM1 Ab exhibits a lethal 'oif-target' effect on basophils in vivo (2011)
  • Author(s): Nishikado H, Mukai K, Kawano Y, Minegishi Y, Karasuyama H
  • Journal Title: J Immunol Volume: 186 Pages: 5766-5771
  • Peer Reviewed
• [Journal Article] Hyper IgE syndrome diagnosed in early infancy by gene analysis of STAT3 mutation (2011)
  • Author(s): Watarai A, Niiyama S, Morita M, Bando Y, Minegishi Y, Katsuoka K
  • Journal Title: Eur J Dermatol Volume: 21 Pages: 254-255
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of the immunological abnormalities in hyper IgE syndrome (2011)
  • Author(s): Minegishi Y, Saito M
  • Journal Title: Ann N Y Acad Sci Volume: 1246 Pages: 34-40
  • Peer Reviewed
• [Journal Article] Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks. (2010)
  • Author(s): Wada T, Ishiwata K, Koseki H, Ishikura T, Ugajin T, Ohnuma N, Obata K, Ishikawa R, Yoshikawa S, Mukai K, Kawano Y, Minegishi Y, Yokozeki H, Watanabe N, Karasuyama H.
  • Journal Title: J Clin Invest. Volume: 120 Pages: 2867-2875
  • Peer Reviewed
• [Journal Article] An atopic dermatitis-like skin disease with hyper-IgE-emia develops in mice carrying a spontaneous recessive point mutation in the Traf3ip2 (Act1/CIKS) gene. (2010)
  • Author(s): Matsushima Y, Kikkawa Y, Takada T, Matsuoka K, Seki Y, Yoshida H, Minegishi Y, Karasuyama H, Yonekawa H.
  • Journal Title: J Immunol. Volume: 185 Pages: 2340-2349
  • Peer Reviewed
• [Journal Article] IgG-mediated systemic anaphylaxis to protein antigen can be induced eve under conditions oflimited amounts of antibody and antigen. (2010)
  • Author(s): Ishikawa R, Tsujimura Y, Obata K, Kawano Y, Minegishi Y, Karasuyama H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 402 Pages: 742-746
  • Peer Reviewed
• [Journal Article] 特異な皮膚症状を呈し、遺伝子検索にて生後７カ月で診断した１型高IgE症候群の１例 (2010)
  • Author(s): 飯島茂子、渡邉真也、本山景一、後藤昌英、泉 維昌、峯岸克行
  • Journal Title: 日本皮膚科学会雑誌 Volume: 120 Pages: 2203-2211
  • NAID: 10027732331
• [Journal Article] 高IgE症候群の最近の進歩 (2010)
  • Author(s): 高田英俊、峯岸克行
  • Journal Title: 日本臨床免疫学会誌 Volume: 33 Pages: 15-19
• [Journal Article] STAT3の遺伝子異常により発症する免疫不全症 (2010)
  • Author(s): 峯岸克行
  • Journal Title: 細胞工学特集Human Immunologyの新たな構築 Volume: 29(3) Pages: 230-233
• [Journal Article] 高IgE症候群ではなぜ皮膚と肺にのみ黄色ブドウ球菌感染が生じるのか？ (2010)
  • Author(s): 峯岸克行
  • Journal Title: 臨床免疫―アレルギー科 Volume: 53 Pages: 517-520
  • NAID: 40017145127
• [Journal Article] サイトカインのシグナル伝達異常と遺伝性疾患 (2010)
  • Author(s): 峯岸克行
  • Journal Title: 臨床検査 Volume: 54 Pages: 682-686
• [Journal Article] サイトカインのシグナル伝達異常により発症する免疫不全症 (2010)
  • Author(s): 峯岸克行
  • Journal Title: 医学の歩み Volume: 234 Pages: 518-522
• [Journal Article] Selective ablation of basophils in mice reveals their nonredun dant role in acquired immunity against ticks. (2010)
  • Author(s): Wada T, Ishiwata K, Koseki H, Ishikura T, Ugajin T, Ohnuma N, Obata K, Ishikawa R, Yoshikawa S, Mukai K, Kawano Y, Minegishi Y, Yokozeki H, Watanabe N, Karasuya
  • Journal Title: J Clin Invest. Volume: 120 Pages: 2867-2875
  • Peer Reviewed
• [Journal Article] IgG-mediated systemic anaphylaxis to protein antigen can be induced eve under conditions oflimited amounts of antibody and antigen. (2010)
  • Author(s): Ishikawa R, Tsujimura Y, Obata K, Kawano Y, Minegishi Y, Karasuyama H.
  • Journal Title: Biochem Biophys Res Commun Volume: 402 Pages: 742-746
  • Peer Reviewed
• [Journal Article] 特異な皮膚症状を呈し、遺伝子検索にて生後7カ月で診断した1型高IgE症候群の1例 (2010)
  • Author(s): 飯島茂子、渡邉真也、本山景一、後藤昌英、泉維昌、峯岸克行
  • Journal Title: 日本皮膚科学会雑誌 Volume: 120 Pages: 2203-2211
  • NAID: 10027732331
  • Peer Reviewed
• [Journal Article] STAT3の遺伝子異常により発症する免疫不全症 (2010)
  • Author(s): 峯岸克行
  • Journal Title: 細胞工学 Volume: 29 Pages: 230-233
  • Peer Reviewed
• [Presentation] Molecular Mechanisms of Hyper IgE Syndrome (2012)
  • Author(s): Minegishi Y
  • Organizer: International symposium "New Horizons in the Immune System"
  • Place of Presentation: Tokushima
  • Year and Date: 2012-02-10
• [Presentation] 高IgE症候群の病因と病態の解明 (2012)
  • Author(s): 峯岸克行
  • Organizer: 第11回小児免疫・アレルギー研究会
  • Place of Presentation: 大阪エコノホール
  • Year and Date: 2012-02-04
• [Presentation] Molecular Pathogenesis of Hyper IgE Syndrome (2012)
  • Author(s): Minegishi Y
  • Organizer: The 4th international symposium of Immunological Self
  • Place of Presentation: Kyoto
  • Year and Date: 2012-01-28
• [Presentation] Japan's Contribution to PID Research (2011)
  • Author(s): Minegishi Y
  • Organizer: World Immunology Conference
  • Place of Presentation: Rockefeller University, New York, USA
  • Year and Date: 2011-06-05
• [Presentation] Molecular pathology of Hyper IgE Syndrome (2011)
  • Author(s): Minegishi Y
  • Organizer: Pediatric Academic Society 2011
  • Place of Presentation: Denver Convention Center
  • Year and Date: 2011-05-01
• [Presentation] 原発性免疫不全症の病因と病態の解明 (2011)
  • Author(s): 峯岸克行
  • Organizer: 理化学研究所ゲノム医科学センター講演シリーズ
  • Place of Presentation: 理化学研究所横浜研究所
  • Year and Date: 2011-04-15
• [Presentation] 原発性免疫不全症の病因と病態の解明 (2011)
  • Author(s): 峯岸克行
  • Organizer: 理化学研究所ゲノム医科学センター講演
  • Place of Presentation: 理化学研究所横浜研究所
  • Year and Date: 2011-04-15
• [Presentation] アトピー性皮膚炎を合併する免疫不全症高IgE症候群の病因と病態の解明 (2011)
  • Author(s): 峯岸克行
  • Organizer: LO皮膚科学研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-01-27
• [Presentation] Molecular Defects in Hyper IgE Syndrome (2011)
  • Author(s): Minegishi Y.
  • Organizer: First international conference on primary immunodeficiency diseases
  • Place of Presentation: New Delhi, India
• [Presentation] Defects in Hyper IgE Syndrome (2011)
  • Author(s): Minegishi Y. Molecular
  • Organizer: The First international conference on primary immunodeficiency diseases.
  • Place of Presentation: New Delhi, India
• [Presentation] Molecular pathology of Hyper IgE Syndrome (2011)
  • Author(s): Minegishi Y
  • Organizer: Pediatric Academic Society 2011
  • Place of Presentation: Denver Convention Center, Denver, USA
• [Presentation] Molecular pathogenesis of Hyper IgE Syndrome (2011)
  • Author(s): Minegishi Y
  • Organizer: The Third EMBO Conference on Host Genetic Control of Infectious Diseases
  • Place of Presentation: Pasteur Institute, Paris, France
• [Presentation] マウスモデルを利用した高IgE症候群の病態解明 (2010)
  • Author(s): 峯岸克行
  • Organizer: 日本アレルギー学会ワークショップ
  • Place of Presentation: 東京
  • Year and Date: 2010-11-27
• [Presentation] アトピー性皮膚炎を合併する免疫不全症高IgE症候群の病因と病態の解明 (2010)
  • Author(s): 峯岸克行、齋藤雅子、烏山 一
  • Organizer: 和歌山県立医大 大学院特別講義
  • Place of Presentation: 和歌山
  • Year and Date: 2010-10-29
• [Presentation] アトピー性皮膚炎を合併する免疫不全症高IgE症候群の病因と病態の解明 (2010)
  • Author(s): 峯岸克行
  • Organizer: 和歌山県立医大特別講義
  • Place of Presentation: 和歌山
  • Year and Date: 2010-10-29
• [Presentation] 遺伝子性アトピーを呈する免疫不全症高IgE症候群の病因と病態の解明 特別講演 (2010)
  • Author(s): 峯岸克行、齋藤雅子、烏山 一
  • Organizer: 第25回九州血液免疫研究会
  • Place of Presentation: 福岡
  • Year and Date: 2010-10-23
• [Presentation] 遺伝子性アトピーを呈する免疫不全症 高IgE症候群の病因と病態の解明 (2010)
  • Author(s): 峯岸克行
  • Organizer: 第25回九州血液免疫研究会
  • Place of Presentation: 福岡
  • Year and Date: 2010-10-23
• [Presentation] ヒトの遺伝子性シグナル遺伝子変異とその病態 (2010)
  • Author(s): 峯岸克行、齋藤雅子、烏山 一
  • Organizer: 第75回日本インターフェロン・サイトカイン学会シンポジウム
  • Place of Presentation: 北九州
  • Year and Date: 2010-06-26
• [Presentation] ヒトの遺伝子性シグナル遺伝子変異とその病態 (2010)
  • Author(s): 峯岸克行
  • Organizer: 第75回日本インターフェロン・サイトカイン学会
  • Place of Presentation: 北九州
  • Year and Date: 2010-06-26
• [Presentation] アトピー性皮膚炎を合併する免疫不全症、高IgE症候群の病因と病態の解明 (2010)
  • Author(s): 峯岸克行、齋藤雅子、烏山 一
  • Organizer: 皮膚科免疫セミナー特別講演
  • Place of Presentation: 東京
  • Year and Date: 2010-03-06
• [Presentation] 高IgE症候群における骨と歯牙の異常の発症機序の検討 (2010)
  • Author(s): 峯岸克行、齋藤雅子、烏山 一
  • Organizer: 厚生労働省原発性免疫不全症調査研究班第１回班会議
  • Place of Presentation: 東京
  • Year and Date: 2010-01-29
• [Presentation] Molecular origins and mechanism of hyper-IgE syndrome. (2010)
  • Author(s): Minegishi Y. Saito M. Karasuyama H.
  • Organizer: Primary Immunodeficiency in Asia
  • Place of Presentation: Kazusa Academia Hall
• [Presentation] Hyper-IgE Syndrome and STAT3 (2010)
  • Author(s): Minegishi Y. Saito M. Karasuyama H.
  • Organizer: European Society for Immunodeficiency
  • Place of Presentation: Istanbul, Turkey
• [Presentation] マウスモデルを利用した高IgE症候群の病態解明 (2010)
  • Author(s): 峯岸克行、齋藤雅子、烏山 一
  • Organizer: 第60回日本アレルギー学会ワークショップ
  • Place of Presentation: 東京
• [Presentation] Japan’s Contribution to PID Research
  • Author(s): Minegishi Y
  • Organizer: World Immunology Conference
  • Place of Presentation: Rockefeller University, New York, USA