抗リン脂質抗体症候群 : 病因の解明と新たなる治療ターゲット

2008 Fiscal Year Annual Research Report

• Project/Area Number: 19390269
• Research Institution: Hokkaido University
• Principal Investigator: 小池 隆夫 Hokkaido University, 大学院・医学研究科, 教授 (80146795)
• Keywords: 免疫学 / プロテオーム / バイオテクノロジー

Research Abstract

(1) 代表的な抗リン脂質抗体である抗β2グリコプロテインI抗体(抗β2GPI抗体)の血栓原性を明らかにする目的で、単球やマクロファージ細胞株に抗β2GPI抗体を作用させ、抗β2GPI抗体と結合ないし相互作用する細胞表面分子について、免疫沈降法により共沈させ、ウエスタンブロット法あるいは質量分析法などを用いて同定を試みた。質量分析法で同定された複数の候補細胞質蛋白の中でゲルゾリンがβ2GPIと結合していることがウエスタンブロット法で確認された。ゲルゾリンはインテグリンα5β1と共役し、抗β2GPI抗体による細胞刺激に関与する可能性が示唆された。細胞表面分子のみならず抗β2GPI抗体と結合ないし相互作用する流血中の可溶型分子についても検索中である。
(2) 抗β2GPI抗体の血栓原性の機序として、抗体による単球や血管内皮細胞の活性化の結果組織因子の発現の亢進が誘導されることが挙げられる。単球や血管内皮細胞では抗β2GPI抗体による刺激によりMyD88を介し、p38MAPキナーゼ(p38MAPK)のリン酸化が起こることが明らかとなった。また、もう一つの代表的な抗リン脂質抗体であるホスファチジルセリン依存性抗プロトロンビン抗体(抗PS/PT抗体)も単球や血管内皮細胞を活性化し、その結果組織因子の発現亢進が認められるが、抗β2GPI抗体同様にp38MAPKの活性化が関与し、p38MAPK阻害剤で組織因子の発現亢進が抑制されることを明らかにした。異なる抗リン脂質抗体がシグナル伝達経路を共有している可能性が示唆された。

Research Products

• [Journal Article] Exchange of information in Rheumatology between East and West : From Man'yo-shu to the Future (2008)
  • Author(s): Atsumi T, Horita T, Minori T, Koike T
  • Journal Title: Arthritis Rheum 58(2) Pages: 140-142
  • Peer Reviewed
• [Journal Article] Polymyalgia rheumatica as the manifestation of unclassified aortitis (2008)
  • Author(s): Kataoka H, Atsumi T, Hashimoto T, Horita T, Yasuda S, Koike T.
  • Journal Title: Mod Rheumatol 18(1) Pages: 105-108
  • Peer Reviewed
• [Journal Article] Reversible cardiomyopathy due to secondary hemochromatosis with multitransfusions for severe aplastic anemia after successful non-myeloablative stem cell transplantation (2008)
  • Author(s): Nishio M, Endo T, Nakao S, Sato N, Koike T.
  • Journal Title: Int J Cardiol 127 Pages: 400-401
  • Peer Reviewed
• [Journal Article] Autoimmune disease after autologous hematopoietic stem cell transplantation (2008)
  • Author(s): Bohgaki T, Atsumi T, Koike T
  • Journal Title: Autoimmun Rev 7(3) Pages: 198-203
  • Peer Reviewed
• [Journal Article] Thrombotic microangiopathy in patients with phosphatidylserine dependent antiprothrombin antibodies and antiphospholipid syndrome (2008)
  • Author(s): Kon Y, Atsumi T, Hagiwara H, Furusaki A, Kataoka H, Horita T, Yasuda S, Amengua I O, Koike T
  • Journal Title: Clin Exp Rheumatol 26(1) Pages: 129-132
  • Peer Reviewed
• [Journal Article] Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases : analysis of 30 cases (2008)
  • Author(s): Fukaya S, Yasuda S, Hashimoto T, Oku K, Kataoka H, Horita T, Atsumi T, Koike T
  • Journal Title: Rheumatology. 47(11) Pages: 1686-1691
  • Peer Reviewed
• [Journal Article] Involvement of Ymer in suppression of NF-kappaB activation by regulated interaction with lysine-63-linked polyubiquitin chain (2008)
  • Author(s): Bohgaki M, Tsukiyama T, Nakajima A, Maruyama S, Watanabe M, Koike T, Hatakevama S.
  • Journal Title: Biochim Biophys Acta. 1783(5) Pages: 826-837
  • Peer Reviewed
• [Journal Article] Antiprothrombin antibody testing : detection and clinical utility (2008)
  • Author(s): Oku K, Atsumi T, Amengual O. Koike T
  • Journal Title: Semin Thromb Hemost. 34(4) Pages: 335-339
  • Peer Reviewed
• [Journal Article] FCGR3A-158V / F polymorphism may correlate with the levels of immunoglobulin in patients with non-Hodgkin's lymphoma after rituximab treatment as an adjuvant to autologous stem cell transplantation (2008)
  • Author(s): Nishio M, Endo T, Fujimoto K, Yamamoto S, Obara M, Yamaguchi K, Takeda Y, Goto H, Kasahara I, Sato N, Koike T
  • Journal Title: Eur J Haematol 82(2) Pages: 143-147
  • Peer Reviewed
• [Journal Article] Discrepancy between disease activity and levels of vascular endothelial growth factor in a patient with POEMS syndrome successfully treated with autoloaous stem-cell transplantation (2008)
  • Author(s): Goto H, Nishio M, Kumano K, Fujimoto K, Yamaguchi K, Koike T.
  • Journal Title: Bone Marrow Transplant 42(9) Pages: 627-629
  • Peer Reviewed
• [Journal Article] A retrospective analysis of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia / lymphoma (ATL) : clinical impact of graft-versus-leukemia / lymphoma effect (2008)
  • Author(s): Shiratori S, Yasumoto A, Tanaka J, Shigematsu A, Yamamoto S, Nishio M, Hashino S, Morita R, Takahata M, Onozawa M, Kahata K, Kondo T, Ota S, Wakasa K, Sugita J, Koike T, Asaka M, Kasai M, Imamura M.
  • Journal Title: Biol Blood Marrow Transplant. 14 Pages: 817-823
  • Peer Reviewed
• [Journal Article] Excellent outcome of allogeneic hematopoietic stem cell transplantation using a conditioning regimen with medium-dose VP-16, cyclophosphamide and total-body irradiation for adult patients with acute lymphoblastic leukemia (2008)
  • Author(s): Shigematsu A, Kondo T, Yamamoto S, Sugita J, Onozawa M, Kahata K, Endo T, Shiratori S, Ota S, Obara M, Wakasa K, Takahata M, Takeda Y, Tanaka J, Hashino S, Nishio M, Koike T, Asaka M, Imamura M.
  • Journal Title: Biol Blood Marrow Transplant 14(5) Pages: 568-575
  • Peer Reviewed
• [Journal Article] The potential role of macrophage migration inhibitory factor on the migration of vascular smooth muscle cells (2008)
  • Author(s): Okamoto T, Atsumi T, Shimizu C, Yoshioka N, Koike T
  • Journal Title: J Atheroscler Thromb 15(1) Pages: 13-19
  • Peer Reviewed
• [Journal Article] Complement activation in patients with primary antiphospholipid syndrome
  • Author(s): Oku K, Atsumi T, Bohgaki M, Kataoka H, Horita T, Yasuda S, Koike T.
  • Journal Title: Ann Rheum Dis (In press)
  • Peer Reviewed
• [Journal Article] STAT4 single nucleotide polymorphism, rs7574865 G /T, as a risk for antiphospholipid syndrome
  • Author(s): Horita T, Atsumi T, Yoshida N, Nakagawa H, Kataoka H, Yasuda S. Koike T.
  • Journal Title: Ann Rheum Dis (In press)
  • Peer Reviewed
• [Journal Article] Immunological reconstitution after autologous hematopoietic stem cell transplantation in patients with systemic sclerosis : relationship between clinical benefits and intensity of immunosuppression
  • Author(s): Bohgaki T, Atsumi T, Bohgaki M, Furusaki A, Kondo M, Sato-MatsumuraK, Abe R, Kataoka H, Horita T, Yasuda S, Amasaki Y, Nishio M, Sawada K, Shimizu H, Koike T.
  • Journal Title: J Rheumatol (In press)
  • Peer Reviewed
• [Presentation] Development of Autoimmune Diseases : A Lesson from Stem Cell Transplantation (2008)
  • Author(s): Koike, T
  • Organizer: 6^<th> International Congress on Autoimmunity
  • Place of Presentation: コングレスセンター, Porto, Portugal
  • Year and Date: 2008-09-13
• [Book] Recent Advances in Thrombosis and Haemostasis 2008 (2008)
  • Author(s): Atsumi T, Amengual O, Koike T
  • Total Pages: 643
  • Publisher: Springer