The mechanisms of triggering complement activation in patients with antiphospholipid syndrome

• Project/Area Number: 25461466
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Hokkaido University
• Principal Investigator: OKU KENJI 北海道大学, 大学病院, 助教 (70544295)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 抗リン脂質抗体症候群 / 補体古典経路 / 抗C1q抗体 / C1q / 補体活性化 / 抗リン脂質症候群 / 補体 / 血栓症 / モデルマウス / 難治性抗リン脂質抗体症候群

Outline of Final Research Achievements

Antiphospholipid syndrome(APS)is an autoimmune disease that is characterized with the arterial/venous thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibody(aPL). Complement activation is one of the major pathogenesis besides procoagulant activity of the aPL. We have investigated the origination of the complement activation and clarified that the 1) autoantibodies against the 1st component(C1q) of the complement system is frequently observed in the sera of patients with APS and the high titer of the autoantibodies significantly observed in the refractory APS 2) The presence of the anti-C1q antibodies is related with the activation of early components of the complement system 3) monoclonal anti-C1q antibodies activated monocytes or endothelial cells and induced procoagulant activities in vitro. As anti-C1q antibodies are readily inhibited with the immunosuppressants, there is a possibility that the refractory APS patients may effectively be treated.

Research Products

• [Journal Article] Autoantibodies against a complement component 1 q subcomponent contribute to complement activation and recurrent thrombosis/pregnancy morbidity in anti-phospholipid syndrome (2016)
  • Author(s): Oku K, Amengual O, Hisada R, Ohmura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Journal Title: Rheumatology(Oxford) Volume: Epub ahead Issue: 8 Pages: 1403-1411
  • DOI: 10.1093/rheumatology/kew196
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Complement and thrombosis in the antiphospholipid syndrome (2016)
  • Author(s): Oku K, Nakamura H, Kono M, Ohmura K, Kato M, Bohgaki T, Horita T, Yasuda S, Amengual O, Atsumi T
  • Journal Title: Autoimmunity Reviews Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Post-steroid neuropsychiatric manifestations are significantly more frequent in SLE compared with other systemic autoimmune diseases and predict better prognosis compared with de novo neuropsychiatric SLE (2016)
  • Author(s): Shimizu Y, Yasuda S, Kato Y, Nakagawa S, Kanda M, Hisada R, Ohmura K, Shimamura S, Shida H, Fujieda Y, Kato M, Oku K, Bohgaki T, Horita T, Kusumi I, Atsumi T
  • Journal Title: Autoimmunity Reviews Volume: Epub ahead Issue: 8 Pages: 786-794
  • DOI: 10.1016/j.autrev.2016.03.017
  • Peer Reviewed / Open Access
• [Journal Article] Role of apolipoprotein B100 and oxidized low-density lipoprotein in the monocyte tissue factor induction mediated by anti-b2 glycoprotein I antibodies. (2016)
  • Author(s): Otomo K, Amengual O, Fujieda Y, Nakagawa H, Kato M, Oku K, Horita T, Yasuda S, Matsumoto M, Nakayama KI, Hatakeyama S, Koike T, Atsumi T
  • Journal Title: Lupus Volume: Epub ahead Issue: 12 Pages: 1288-1298
  • DOI: 10.1177/0961203316638165
  • Peer Reviewed / Open Access
• [Journal Article] Ribophorin II is involved in the tissue factor expression mediated by phosphatidylserine-dependent antiprothrombin antibody on monocytes (2016)
  • Author(s): Fujieda Y., Amengual O., Matsumoto M., Kuroki K., Takahashi H., Kono M., Kurita Y., Otomo K., Kato M., Oku K., Bohgaki T., Horita T., Yasuda S., Maenaka K., Hatakeyama S., Nakayama K.I. and Atsumi T. et al.
  • Journal Title: Rheumatology Volume: 印刷中 Issue: 6 Pages: 1117-1126
  • DOI: 10.1093/rheumatology/kew005
  • Peer Reviewed / Open Access
• [Journal Article] Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review. (2015)
  • Author(s): Amengual O, Fujita D, Ota E, Carmona L, Oku K, Sugiura-Ogasawara M, Murashima A, Atsumi T.
  • Journal Title: Lupus Volume: 24 Issue: 11 Pages: 1135-1142
  • DOI: 10.1177/0961203315578765
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An independent validation of the global anti-phospholipid syndrome score in Japanese cohort of patients with antoimmune diseases (2015)
  • Author(s): Oku K, Amengual O, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Journal Title: Lupus Volume: 24 Issue: 7 Pages: 774-775
  • DOI: 10.1177/0961203314561284
  • Peer Reviewed / Open Access
• [Journal Article] Ras guanine nucleotide-releasing protein 4 is aberrantly expressed in the fibroblast-like synoviocytes of patients with rheumatoid arthritis and controls their proliferation. (2015)
  • Author(s): Kono M, Yasuda S, Stevens RL, Koide H, Kurita T, Shimizu Y, Kanetsuka Y, Oku K, Bohgaki T, Amengual O, Horita T, Shimizu T, Majima T, Koike T, Atsumi T.
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 2 Pages: 396-407
  • DOI: 10.1002/art.38924
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. (2015)
  • Author(s): Kurita T, Yasuda S, Oba K, Odani T, Kono M, Otomo K, Fujieda Y, Oku K, Bohgaki T, Amengual O, Horita T, Atsumi T.
  • Journal Title: Rheumatology (Oxford) Volume: 54 Issue: 1 Pages: 39-44
  • DOI: 10.1093/rheumatology/keu166
  • Peer Reviewed / Open Access
• [Journal Article] The function and the significance of full-automated tests for detecting antiphospholipid antibodies (2015)
  • Author(s): Oku K, Amengual O, Hisada R, Oomura K, Nakagawa N, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T.
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 38 Issue: 3 Pages: 157-163
  • DOI: 10.2177/jsci.38.157
  • NAID: 130005089221
  • ISSN: 0911-4300, 1349-7413
  • Peer Reviewed / Open Access
• [Journal Article] Decreased expression of Runx1 and lowered proportion of Foxp3+CD25+CD4+ regulatory T cells in systemic sclerosis. (2015)
  • Author(s): Kataoka H, Yasuda S, Fukaya S, Oku K, Horita T, Atsumi T, Koike T
  • Journal Title: Mod Rheumatol. Volume: 25 Issue: 1 Pages: 90-95
  • DOI: 10.3109/14397595.2014.899736
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications. (2015)
  • Author(s): Matsuki Y, Atsumi T, Yamaguchi K, Hisano M, Arata N, Oku K, Watanabe N, Sago H, Takasaki Y, Murashima A
  • Journal Title: Modern Rheumatology Volume: 25(2) Issue: 2 Pages: 215-218
  • DOI: 10.3109/14397595.2014.942503
  • Peer Reviewed / Open Access
• [Journal Article] 完全自動化測定器による抗リン脂質抗体測定の意義 (2015)
  • Author(s): 奥健志、オルガアメングアル、久田諒、大村一将、中川育麿、渡邊俊之、坊垣暁之、堀田哲也、保田晋助、渥美達也
  • Journal Title: 日本臨床免疫学会会誌 Volume: 不明
  • NAID: 130005089221
  • Peer Reviewed
• [Journal Article] Clinical significance of antiphospholipid antibody measured by EliA anticardiolipin antibodies and anti-β2Glycoprotein I antibodies in antiphospholipid syndrome (2014)
  • Author(s): Fujieda Y, Shida H, Oku K, Bohgaki T, Amengual O, Horita T, Yasuda S, Atsumi T.
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 37 Issue: 5 Pages: 430-436
  • DOI: 10.2177/jsci.37.430
  • NAID: 130004875940
  • ISSN: 0911-4300, 1349-7413
  • Peer Reviewed / Open Access
• [Journal Article] Comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies. (2014)
  • Author(s): Amengual O, Horita T, Binder W, Norman GL, Shums Z, Kato M, Otomo K, Fujieda Y, Oku K, Bohgaki T, Yasuda S, Atsumi T
  • Journal Title: Rheumatol Int. Volume: 34 Issue: 9 Pages: 1225-1230
  • DOI: 10.1007/s00296-014-2951-0
  • NAID: 120005656328
  • Peer Reviewed / Open Access
• [Journal Article] Antiphospholipid Scoring: significance in diagnosis and prognosis. (2014)
  • Author(s): Oku K, Amengual O, Atsumi T
  • Journal Title: Lupus Volume: 23 Issue: 12 Pages: 1269-1272
  • DOI: 10.1177/0961203314537361
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 抗リン脂質抗体症候群と補体活性化（仮題） (2016)
  • Author(s): 奥健志
  • Organizer: 第31回日本生殖免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2016-12-02
  • Invited
• [Presentation] Complement and thrombosis in the antiphospholipid syndrome (2016)
  • Author(s): Tatsuya Atsumi, Kenji Oku
  • Organizer: 10th International congress on autoimmunity
  • Place of Presentation: Leizpig, Germany
  • Year and Date: 2016-04-09
  • Int'l Joint Research / Invited
• [Presentation] 抗リン脂質抗体検査と抗リン脂質抗体症候群の診断：抗リン脂質抗体スコアを中心に (2016)
  • Author(s): 奥健志
  • Organizer: 第10回日本血栓止血学会学術標準化委員会(SSC)シンポジウム
  • Place of Presentation: 野村コンファレンスプラザ日本橋（東京都中野区）
  • Year and Date: 2016-02-20
  • Invited
• [Presentation] rocoagulant property of a novel patient-derived autoimmune IgG type monoclonal anticardiolipin antibody that binds to beta 2 glycoprotein I domain I but not to total beta 2 glycoprotein I molecule. (2015)
  • Author(s): Kenji Oku, Yuusaku Kanetsuka, Olga Amengual, Hiroyuki Nakamura, Kazumasa Ohmura, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Bas deLaat, Tatsuya Atsumi
  • Organizer: Annual meeting of the American College of Rheumatology
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] Predictive markers for thrombotic events in autoimmune diseases: comparison of Antiphospholipid Score (APL-S) and GLOBAL ANTI-PHOSPHOLIPID SYNDROME (2015)
  • Author(s): Kenji Oku, Olga Amengual, Kazumasa Ohmura, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
  • Organizer: XXVth Annual Congress of the International Society of Thrombosis and Haemostasis
  • Place of Presentation: Tronto, Canada
  • Year and Date: 2015-06-23
  • Int'l Joint Research
• [Presentation] 定量マーカーとしての抗リン脂質抗体 抗リン脂質抗体とGAPSSの比較 (2015)
  • Author(s): １．奥健志、アメングアルオルガ、大村一将、中川育麿、渡邊俊之、坊垣暁之、堀田哲也、保田晋助、渥美達也
  • Organizer: 第37回日本血栓止血学会
  • Place of Presentation: 甲府市総合市民会館（山梨県甲府市）
  • Year and Date: 2015-05-22
• [Presentation] Markers of thrombotic events in autoimmune diseases: comparison of Antiphospholipid Score (aPL-S) and Global Anti-phospholipid Syndrome Score(GAPSS) (2014)
  • Author(s): Oku K, Amengual O, Hisada R, Oomura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] The protective effects of statins for thrombosis in patients with systemic lupus erythematosus positive for antiphospholipid antibodies (2014)
  • Author(s): Watanabe T, Oku K, Amengual O, Sugawara E, Hisada R, Oomura K, Shimamura S, Nakagawa I, Noguchi A, Fukui T, Shida H, Kono M, Shimizu Y, Kurita T, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] Thrombocytopenia in primary antiphospholipid syndrome is related to arterial thrombosis (2014)
  • Author(s): Nakagawa I , Oku K, Amengual O, , Hisada R, Oomura K, Watanabe T Bohgaki T, Horita T, Yasuda S and Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] Decreased levels of SF2/ASF ( Serin Arginine-Rich splicing Factor 1) induced lower levels of the RasGRP1 T Cells from patients with systemic lupus erythematosus (2014)
  • Author(s): 5Kurita T, Yasuda S, Moulton VR, Kono M1, Koide H, Oku K, Bohgaki T, Amengual O, Horita T, Tsokos GC and Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] Upregulation of Mx1( Myxovirus Resitence Protein 1) in patients with neuropsychiatric systemic lupus erythematosus (2014)
  • Author(s): Shimizu Y, Yasuda S, Kurita T, Shimamura S, Nakagawa I, Noguchi A, Shida H, Watanabe T, Kono M, Oku K, Bohgaki T, Amengual O, Horita T and Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] Efficacy of tocilizumab in patients with rheumatoid arthritis: sequential evaluation using whole-body Magnetic Resonance Imaging (2014)
  • Author(s): 7Kono M, Yasuda S, Fukui T, , Shimamura S, Nakagawa I, Noguchi A, Shida H, Watanabe T, Shimizu Y, Kurita T, Oku K, Bohgaki T, Amengual O, Horita T, Sakamoto K, Kamishima T and Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] Antiphospholipid-associated nephrotay is a risk for developing atherial thrombosis in patietns with systemic lupus erythematosus (2014)
  • Author(s): Tomita T, Yasuda, Watanabe T, Omura K, Shimamura S, Nakagawa I, Noguchi A, Shida H, , Kono M, Shimizu Y, Kurita T, Oku K, Bohgaki T, Amengual O, Horita T, Sakamoto K, Kamishima T and Atsumi T
  • Organizer: American College of Rheumatology, National Scientific Meeting
  • Place of Presentation: Boston Convention and Exhibiton Center (Boston, USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] 抗リン脂質抗体症候群の発症機序 (2014)
  • Author(s): 奥健志
  • Organizer: 千里ライフサイエンスセミナー
  • Place of Presentation: 千里ライフサイエンスセンター（豊中市）
  • Year and Date: 2014-11-06
  • Invited
• [Presentation] Risk factor for developing thrombosis in patients with antineutrophil cytoplasmic antibody-associated vasculitis. (2014)
  • Author(s): Nakagawa I , Oku K, Amengual O, , Hisada R, Oomura K, Watananbe T Bohgaki T, Horita T, Yasuda S and Atsumi T
  • Organizer: The 8th meeting of the Asia Pacific Society on Thrombosis and Haemostasis (APSTH)
  • Place of Presentation: Keangnam Landmark 72 (Hanoi, Vietnam)
  • Year and Date: 2014-10-08 – 2014-10-11
• [Presentation] International multi center study to evaluate the clinical significance of phosphatidylserine-dependent antiprothrombin antibodies for the diagnosis of antiphospholipid syndrome. (2014)
  • Author(s): Amengual O, Forastiero R, Sugiura-Ogasawara M, Oku K, Otomo K, Alves J, C.Favas C, Zigon P, Ambrozic A, Tomsic M, Ruiz=Irastorza G, Ruiz-Arruza I, Bertolaccini ML, Norman GL, Shums Z, Arai J, Atsumi T
  • Organizer: European League Against Rheumatism
  • Place of Presentation: Le Palais des Congres de Paris (Paris, France)
  • Year and Date: 2014-06-11 – 2014-06-14
• [Presentation] 抗 C1q 抗体は抗リン脂質抗体症候群における補体活性化及び予防治療下の再発に関与 する (2014)
  • Author(s): 奥健志
  • Organizer: 第３６回日本血栓止血学会総会
  • Place of Presentation: 大阪国際交流センター（大阪市）
  • Year and Date: 2014-05-30 – 2014-05-31
• [Presentation] Features and risk factor for atherosclerosis in systemic lupus erythematosus (2014)
  • Author(s): Watanabe T, Oku K, Amengual O, Akita K, , Ohmura K, Kanda M, Nakagawa I, Noguchi A, Fukui T, Shida H, Kono M, Shimizu Y, Kurita T, Bohgaki T, Horita T, Yasuda S and Atsumi T
  • Organizer: The 58th Annual General Assembly and Scientific Meeting of Japan College of Rheumatology
  • Place of Presentation: グランドプリンスホテル新高輪 国際館パミール（東京都）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Thrombocytopenia in primary antiphospholipid syndrome is related to thrombotic risk (2014)
  • Author(s): Nakagawa I , Oku K, Amengual O, Akita K, Oomura K, Kanda M, Fukui T, Shida H, Watanabe T, Kono M, Takahashi K, Bohgaki T, Horita T, Yasuda S and Atsumi T
  • Organizer: The 58th Annual General Assembly and Scientific Meeting of Japan College of Rheumatology
  • Place of Presentation: ホテル新高輪 国際館パミール（東京都）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] The synovial proliferative effect of RasGRP4 (Ras guanine nucleotide-releasing protein 4) in fibroblast-like synoviocytes from patients with rheumatoid arthritis (2014)
  • Author(s): Kono M, Yasuda S, Kurita T Oku K, Bohgaki T, Amengual O, Horita T, Sakamoto K, Kamishima T and Atsumi T
  • Organizer: The 58th Annual General Assembly and Scientific Meeting of Japan College of Rheumatology
  • Place of Presentation: ホテル新高輪 国際館パミール（東京都）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Decreased expression of SF2 in T cells from patients with systemic lupus erythematosus (2014)
  • Author(s): Kurita T, Yasuda S, Noguchi A, Shimizu Y, Kono, Oku K, Bohgaki T, Amengual O, Horita T and Atsumi T
  • Organizer: The 58th Annual General Assembly and Scientific Meeting of Japan College of Rheumatology
  • Place of Presentation: ホテル新高輪 国際館パミール（東京都）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Autoantibodies against component of complement 1: Possible mechanism for complement activation and manifestations of refractory antiphospholipid syndrome (APS) (2013)
  • Author(s): Kenji Oku, Olga Amengual, Ikuma Nakagawa, Toshiyuki Watanabe, Yuusaku Kanetsuka, Yuuichiro Fujieda, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda and Tatsuya Atsumi
  • Organizer: 14th International Congress on Antiphospholipid Antibodies and 4th Latin American Congress on Autoimmunity
  • Place of Presentation: Sofitel Rio de Janeiro Copacapana (Rio de Janeiro, Brazil)
• [Presentation] Autoantibodies against component of complement one contribute to the complement activation and clinical manifestation of antiphospholipid syndrome (APS) especially in refractory cases (2013)
  • Author(s): Kenji Oku, Olga Amengual, Ikuma Nakagawa, Toshiyuki Watanabe, Yuusaku Kanetsuka, Yuuichiro Fujieda, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
  • Organizer: 77th Annual Meeting of the American College of Rheumatology
  • Place of Presentation: San Diego Convention Center (San Diego, USA)
• [Presentation] Antibodies against component of complement 1 contribute to the complement activation and to the manifestations of refractory antiphospholipid syndrome (APS) (2013)
  • Author(s): Kenji Oku, Olga Amengual, Toshiyuki Watanabe, Yuusaku Kanetsuka, Yuuichiro Fujieda, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
  • Organizer: XXIV Congress of the International Society of Thrombosis and Haemostasis
  • Place of Presentation: RIA Amsterdam Congress Centre (Amsterdam, Netherlands)