Establishment of genetic diagnosis system and identification of molecular origin for primary immunodeficiencies

• Project/Area Number: 19390282
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MINEGISHI Yoshiyuki Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 准教授 (10343154)
• Co-Investigator(Kenkyū-buntansha): 烏山 一 東京医科歯科大学, 医歯学総合研究科, 教授 (60195013)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 免疫不全症 / サイトカイン / シグナル伝達 / アレルギー / 黄色ブドウ球菌 / 遺伝子診断 / 高IgE症候群 / STAT3 / TYK2 / Th17細胞 / アトピー性皮膚炎 / IgE / Tyk2

Research Abstract

高IgE症候群は、難治性のアトピー性皮膚炎、高IgE血症、細菌に対する易感染性を3主徴とする免疫不全症である。その原因遺伝子は、細菌まで明らかにとれていなかったが、2006年我々が単純ヘルペスウイルス感染症と細胞内寄生細菌感染症を合併する高IgE症候群の1つの原因遺伝子TYK2を発見した。さににこの発見を契機として、TYK2欠損症で障害が見られたサイトカインジナル遺達を詳細に検討することにより、古典的高IgE症候群の原因遺伝子がSTAT3であるとを我々が世界に先駆けて発見した。以上の発見により高IgE症候群は、いくつかのサイトカインのシグナル伝達の異常が原因で発症する症候群である可能性が示唆された。

Research Products

• [Journal Article] The skewed heavy-chain repertoire in peritoneal B-1 cells is predetermined by the selection via pre-B cell receptor duting B cell ontogeny in the fetal liber (2009)
  • Author(s): Yoshikawa S, Kawano Y, Minegishi Y, Karasuyama H
  • Journal Title: Int Immunol 21 Pages: 43-52
  • Peer Reviewed
• [Journal Article] Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome : Lessons from a primary immunodeficiency (2009)
  • Author(s): Minegishi Y., Karasuyama H.
  • Journal Title: Int.Immunol 21 Pages: 105-112
  • NAID: 10025384109
  • Peer Reviewed
• [Journal Article] Molecular explanation for the comtradiction between systemic Th17 defect and localized bacterial infection in hyper-IfE syndrome (2009)
  • Author(s): Minegishi Y.,Saito M.,Nagasawa M.,Tskada H.,Kawamura N.,Ariga T.,Tsuge I.,Karasuyama H
  • Journal Title: J.Exp.Med 206(in press)
  • Peer Reviewed
• [Journal Article] Basophils play a pivotal role in IgG-but not IgE-mediated systemic anaphylaxis in contrast to mast cells (2008)
  • Author(s): Tsujimura Y, Obata K, Mukai K, Shindou H, Yoshida M, NishikadolH, Kawano Y, Minegishi Y, Shimizu T Karasuyama H
  • Journal Title: Immunity 28 Pages: 581-589
  • Peer Reviewed
• [Journal Article] ついに明らかにされた高IgE症候群の原因遺伝子 (2008)
  • Author(s): 峯岸克行
  • Journal Title: 医学のあゆみ 224 Pages: 237-238
• [Journal Article] アレルギー疾患関連遺伝子 (2008)
  • Author(s): 峯岸克行, 島山一
  • Journal Title: 感染・炎症・免疫 38 Pages: 24-31
• [Journal Article] ヒト先天性免疫不全症の原因と病態 (2008)
  • Author(s): 峯岸克行
  • Journal Title: 細胞工学 27 Pages: 602-606
  • NAID: 40016077813
• [Journal Article] 高IgE症候群の遺伝学 (2008)
  • Author(s): 峯岸克行
  • Journal Title: アレルギー・免疫 15 Pages: 62-67
• [Journal Article] 重症アトピー性皮膚炎を合併する免疫不全症の原因遺伝子同定 (2008)
  • Author(s): 峯岸克行
  • Journal Title: 生体の科学 59 Pages: 296-301
• [Journal Article] 高IgEの遺伝学-ついに明らかにされたその原因遺伝子と病態 (2008)
  • Author(s): 峯岸克行
  • Journal Title: 小児科臨床 61 Pages: 1799-1803
• [Journal Article] 高IgE症候群 (2008)
  • Author(s): 齋岸克行・峯岸克行
  • Journal Title: アレルギー・免疫 15 Pages: 96-101
• [Journal Article] BTK欠損を伴わない無ガンマグロブリン血症 (2008)
  • Author(s): 峯岸克行
  • Journal Title: 小児内科 40 Pages: 1271-1274
• [Journal Article] 高IgE症候群 (2008)
  • Author(s): 峯岸克行
  • Journal Title: 小児内科 40 Pages: 1294-1296
• [Journal Article] STAT3シグナルと免疫疾患 (2008)
  • Author(s): 峯岸克行, 島山一
  • Journal Title: 実験医学 26 Pages: 2432-2436
• [Journal Article] 単一遺伝子異常にとり発症するアレルギー (2008)
  • Author(s): 峯岸克行, 島山一
  • Journal Title: 高IgE症候群小児科 49 Pages: 1766-1774
• [Journal Article] Genetic origins of hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y. Karasuyama H
  • Journal Title: Cutt Allergy Asthnna Rep 8 Pages: 386-391
  • Peer Reviewed
• [Journal Article] Basophils play a pivotal role in IgG- but not IgE-mediated systemic anaphylaxis in contrast to mast cells. (2008)
  • Author(s): Tsujimura Y, Obata K, Mukai K, Shindou H, Yoshida M, Nishikadol H, Kawano Y, Minegishi Y, Shimizu T, Karasuyama H
  • Journal Title: Immunity 28 Pages: 581-589
  • Peer Reviewed
• [Journal Article] Genetic origins of hyper-IgE syndrome. (2008)
  • Author(s): Minegishi Y., Karasuyama H.
  • Journal Title: Curr Allergy Asthma Rep 8 Pages: 386-391
  • Peer Reviewed
• [Journal Article] Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome (2007)
  • Author(s): Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Arga T, Pasic S, Stojkovic O, Metin A, Karasuyma H
  • Journal Title: Nature 448 Pages: 1058-1062
• [Journal Article] Basophils are essential initiators of a novel type of chronic allergic inflammation (2007)
  • Author(s): Obata K, Mukai K, Tsujimura Y, Ishiwata K, Kawano Y, Minegishi Y, Watanabe N, Karasuyama H
  • Journal Title: Blood 110 Pages: 913-920
  • Peer Reviewed
• [Journal Article] Response : The hyper IgE syndrome and mutations in TYK2 (2007)
  • Author(s): Minegishi Y, Saito M, Karasuyama H
  • Journal Title: Immunity 26 Pages: 536-536
• [Journal Article] Mast Cells and Basophils Are Selectively Activated In Vitro and In Vivo through CD200R3 in an IgE-Independent Manner (2007)
  • Author(s): Kojima T, Obata K, Mukai K, Sato S, Takai T, Minegishi Y,and Karasuyama H
  • Journal Title: J Immunol 179 Pages: 7093-7100
  • Peer Reviewed
• [Journal Article] Hyper IgE syndrome and Tyk2 deficiency (2007)
  • Author(s): Minegishi Y. Karasuyama H.
  • Journal Title: Current Opinion in Allergy Clinical Immunol 7 Pages: 506-509
  • Peer Reviewed
• [Journal Article] 高IgE症候群の原因遺伝子 (2007)
  • Author(s): 峯岸克行、島山一
  • Journal Title: Annual Review 免疫 Pages: 288-294
  • Peer Reviewed
• [Journal Article] Tyk2欠損と高IgE症候群 (2007)
  • Author(s): 峯岸克行
  • Journal Title: 臨床免疫・アレルギー科 48 Pages: 547-552
  • NAID: 40015753878
• [Journal Article] 重症アトピー伴う難病原因遺伝子をついに発見 (2007)
  • Author(s): 峯岸克行、島山一
  • Journal Title: Medical Bio 4 Pages: 14-15
• [Journal Article] ことばのカルテ151先天性免疫不全 (2007)
  • Author(s): 峯岸克行
  • Journal Title: Medical Tribune
• [Journal Article] Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. (2007)
  • Author(s): Minegishi Y, Saito M, Karasuyama H., et. al.,
  • Journal Title: Nature 448 Pages: 1058-1062
  • Peer Reviewed
• [Journal Article] Basophils are essential initiators of a novel type of chronic allergic inflammation. (2007)
  • Author(s): Obata K, Minegishi Y, WKarasuyama H.
  • Journal Title: Blood 110 Pages: 913-920
  • Peer Reviewed
• [Journal Article] Hyper IgE syndrome and Tyk2 deficiency. (2007)
  • Author(s): Minegishi Y. Karasuyama H.
  • Journal Title: Curr. Opin. Allergy Clin. Immunol. 7 Pages: 506-509
  • Peer Reviewed
• [Presentation] 日本免疫学会第11回日本免疫学会受賞記念講演原発性免疫不全症の病因・病態の解明 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第38回日本免疫学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-12
• [Presentation] Molecular origin and pathogenesis of hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y., Saito M., Karasuyama H.
  • Organizer: Symposium for PID in Asia at RIKEN Yokohama
  • Place of Presentation: Institute
  • Year and Date: 2008-12-11
• [Presentation] 原発性免疫不全症の病因・病態の解明 (2008)
  • Author(s): 峯岸克行
  • Organizer: 日本免疫学会 第11回日本免疫学会賞受賞記念講演
  • Place of Presentation: 京都
  • Year and Date: 2008-12-02
• [Presentation] STAT3 and cutaneous or lung hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y., Saito M., Karasuyama H.
  • Organizer: Pierre Graber Lecture the Annual meeting of French Society for Immunology
  • Place of Presentation: Paris
  • Year and Date: 2008-11-27
• [Presentation] STAT3 and cutaneous or lung hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y.
  • Organizer: Pierre Graber Lecture the Annual meeting of French Society for Immunology
  • Place of Presentation: Paris, France
  • Year and Date: 2008-11-27
• [Presentation] 高IgE症候群の原因遺伝子と易感染性の発症メカニズム (2008)
  • Author(s): 峯岸克行
  • Organizer: 第40回日本小児感染症学会総会・学術集会教育講演
  • Place of Presentation: 名古屋
  • Year and Date: 2008-11-15
• [Presentation] 高IgE症候群の原因遺伝子と易感染性の発症メカニズム (2008)
  • Author(s): 峯岸克行
  • Organizer: 第40回日本小児感染症学会総会・学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-11-15
• [Presentation] Signaling defect due to the mutations in TYK2 and STAT3 resulting in hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y.
  • Organizer: European Society for Immunodeficiency
  • Place of Presentation: 's-Hertogenbosch, Netherlands
  • Year and Date: 2008-10-18
• [Presentation] Molecular origin and pathogenesis of hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y.
  • Organizer: Symposium for Primary Immunodeficiency in Asia
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2008-10-11
• [Presentation] 高IgE症候群とTh17細胞 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第10回福岡小児感染免疫・血液カンファレンス
  • Place of Presentation: 福岡
  • Year and Date: 2008-08-01
• [Presentation] 高IgE症候群の原因遺伝子同定と (2008)
  • Author(s): 峯岸克行
  • Organizer: Th17細胞分化異常 第5回宮崎アレルギー疾患研究会
  • Place of Presentation: 宮崎
  • Year and Date: 2008-07-31
• [Presentation] 高IgE症候群の原因遺伝子同定とTh17細胞分化異常 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第5回宮崎アレルギー疾患研究会
  • Place of Presentation: 宮崎
  • Year and Date: 2008-07-31
• [Presentation] 高IgE症候群の原因遺伝子同定とTh17細胞分化異常 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第4回金沢大学十全医学会
  • Place of Presentation: 金沢
  • Year and Date: 2008-07-26
• [Presentation] 高IgE症候群の原因遺伝子 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第111回小児科学会学術集会 教育講演
  • Place of Presentation: 東京
  • Year and Date: 2008-04-27
• [Presentation] 高IgE症候群の原因遺伝子 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第111回日本小児科学会学術集会 教育講演
  • Place of Presentation: 東京
  • Year and Date: 2008-04-27
• [Presentation] "Molecular origin and signaling defecg in hyper-IgE syndrome"Seminasr in Pediatric Immunology, Hematology, and Rheumatology at the Hospital Necker-Enfants Malades Paris (2008)
  • Author(s): Minegishi Y., Saito M.,Kaarasuyama H.
  • Place of Presentation: France
  • Year and Date: 2008-04-10
• [Presentation] Molecular origin and signaling defect in hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y.
  • Organizer: Seminar in Pediatric Immunology, Hematology, and Rheumatology at the Hospital Necker-Enfants
  • Place of Presentation: Paris, France
  • Year and Date: 2008-04-10
• [Presentation] Singnaling defects in hyper-IgE syndrome (2008)
  • Author(s): Minegishi Y., Saito M., Karasuyama H.
  • Organizer: Keystone Symposium"Lymphocyte activation and signaling"
  • Place of Presentation: Snowbird,Utah,USA,Feburary
  • Year and Date: 2008-03-08
• [Presentation] 先天性免疫不全症の原因遺伝子 (2008)
  • Author(s): 峯岸克行
  • Organizer: 第9回川野小児医学賞 受賞記念講演
  • Place of Presentation: 川越
  • Year and Date: 2008-03-01
• [Presentation] 高IgE症候群の原因遺伝子と病態解析 (2008)
  • Author(s): 峯岸克行
  • Organizer: 日本免疫不全研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-01-19
• [Presentation] "Signaling defect due to the mutations in TYK2 and STAT3 resulting in hyper-IgE syndrome",'s-Hertogenbosch, (2008)
  • Author(s): Minegishi Y.,Saito M .,Karasuyama H
  • Organizer: European Society for Immunodeficiency
  • Place of Presentation: Netherlands
• [Presentation] Signaling defects in hyper-IgE syndrome. (2008)
  • Author(s): Minegishi Y
  • Organizer: Keystone Symposium "Lymphocyte activation and signaling",
  • Place of Presentation: Snowbird, Utah, USA
• [Presentation] Dominat negative mutations in the DNA-binding domain of STAT3causse hyper-IgE syndrome (2007)
  • Author(s): Minegishi Y
  • Organizer: 37^<th> annual meeting of Japanese Socity for Immunology
  • Place of Presentation: Shinagawa
  • Year and Date: 2007-11-22
• [Presentation] 高IgE症候群の原因遺伝子の検討 (2007)
  • Author(s): 峯岸克行、齋藤雅子、高田英俊、原寿郎、川村信明、有賀正、土屋滋、柘植郁哉、鳥山一
  • Organizer: 日本アレルギー学会秋季学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2007-11-02
• [Presentation] 高IgE症候群の原因遺伝子 (2007)
  • Author(s): 峯岸克行、齋藤雅子、鳥山一
  • Organizer: 信州免疫アレルギー懇話会
  • Place of Presentation: 松本
  • Year and Date: 2007-10-05
• [Presentation] Molecular genetics and funnctijonal characterization of human hypir-IgE (2007)
  • Author(s): Minegishi Y.
  • Organizer: JSI-RCAI workshop 2007"Lessons learned fromprimary immunodeficienty"
  • Place of Presentation: RCAI,Yokohama
  • Year and Date: 2007-05-25
• [Presentation] Human Tyk2 deficiency revealals repuisite roles of Tyk2 in multiple cytokine signals involved in innate and acpuired immunity (2007)
  • Author(s): Minegishi Y., saito M., Nonoyama S. Karasuyama H.
  • Organizer: Keystone Symposium"Jsks,STATs,and Immunitu"Steamboat springs
  • Place of Presentation: Colorado, USA
• [Presentation] Primasry Immunodeficiengy ; Identification and elucidation of complex primary immunodeficiency, hyper-IgE syndrome (2007)
  • Author(s): Minegishi. Y.
  • Organizer: 9^<th> FIMSA advanced immunology training course and workshop
  • Place of Presentation: Jeju,Kores
• [Remarks] 2007年8月6日、高IgE症候群の原因遺伝子同定のニュースが、NHKテレビ朝日、読売、毎日、日経、産経、東京などの各紙報道された。
• [Remarks] 日本免疫学会主催のアウトリーチ活動、免疫ふしふ未来2008,2009において講師を務めた。