抗リン脂質抗体症候群において補体活性化を惹起する異常機序について

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25461466
• Research Institution: Hokkaido University
• Principal Investigator: 奥 健志 北海道大学, 大学病院, 助教 (70544295)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 抗リン脂質抗体症候群 / 抗C1q抗体 / 補体活性化

Outline of Annual Research Achievements

抗リン脂質抗体症候群(APS)はその半数が全身性エリテマトーデス(SLE)に合併する。SLEは代表的な低補体血症を来す疾患だが、研究者はSLEが合併しない原発性APS患者にも低補体血症及び補体活性化を認めることを報告し、局所の炎症と2次的凝固亢進によってAPSの主症状である血栓症発症に関与すると考えられている。
本研究では、主にAPSにおける補体活性化の起点について検討した。APSでは循環血中の免疫複合体の発現は顕著でなく、抗リン脂質抗体(APL)がその主な対応組織である血管内皮細胞に結合し補体活性化を惹起すると考えられてきた。しかし、APLの主なサブタイプはIgG2であり、その免疫複合体は補体活性化能に乏しい。本研究では昨年迄に①補体第１成分(C1q)に対する自己抗体がAPS患者で高率に認められ、有意に難治性APSにおいて出現する②抗C1q抗体の存在は、補体前期蛋白の活性化断片であるアナフィラトキシンの血中濃度と有意な相関を認める点を解明した。最終年度は本データを投稿した(Oku et al, Rheumatology (Oxford) in press, Oku et al, Autoimmun Rev in press)。また、マウスモノクローナル抗C1q抗体であるJL-1を用いてin vitroでの検討を行った結果、JL-1は濃度異存性にマウス単球細胞株RAW264.7やヒト臍帯静脈内皮細胞(HUVEC)に結合し、凝固外因系のinitiator proteinである組織因子(tissue factor：TF)の発現亢進を促すことを解明した。この時、APLが併存することにより凝固傾向は亢進する。現在、in vitroのデータを投稿準備中であり、また、balb-cマウスにAPLモノクローナル抗体及びJL-1を投与する疾患モデルマウスを作成し、解析中である。

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 Pages: Epub ahead
  • DOI: 10.1093/rheumatology/kew196
  • Peer Reviewed / 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 Pages: 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 Pages: Epub ahead
  • DOI: 10.1016/j.autrev.2016.03.017
  • Peer Reviewed
• [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 Pages: Epub ahead
  • DOI: 10.1177/0961203316638165
  • Peer Reviewed
• [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 T, Otomo K, Kato M, Oku K, Bohgaki T, Horita T, Yasuda S, Maenaka K, Hatakeyama S, Nakayama KI, Atsumi T
  • Journal Title: Rheumatology(Oxford) Volume: Epub ahead Pages: Epub ahead
  • DOI: 10.1093/rheumatology/kew005
  • Peer Reviewed
• [Journal Article] Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systemic 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 Pages: 1135-42
  • DOI: 10.1177/0961203315578765
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An independent validation of the Global Anti-Phospholipid Syndrome Score in a Japanese cohort of patients with autoimmune diseases (2015)
  • Author(s): Oku K, Amengual O, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Journal Title: Lupus Volume: 24 Pages: 774-5
  • DOI: 10.1177/0961203314561284
  • Peer Reviewed / Acknowledgement Compliant
• [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, Amengual O, Horita T, Atsumi T
  • Journal Title: Arthritis and Rheumatolgy Volume: 67 Pages: 396-407
  • DOI: 10.1002/art.38924
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The efficacy of tacrolimus in patients with interstitial lung diseases compacted 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 Pages: 39-44
  • DOI: 10.1093/rheumatology/keu166
• [Journal Article] 完全自動測定器による抗リン脂質抗体測定の意義 (2015)
  • Author(s): 奥健志、アメングアルオルガ、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: 38 Pages: 157-63
  • DOI: 10.2177/jsci.38.157
• [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 – 2016-12-03
  • 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 – 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 – 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 – 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 – 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 – 2015-05-22