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

2014 Fiscal Year Research-status 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: 抗リン脂質症候群 / 補体 / 抗C1q抗体 / 血栓症 / モデルマウス

Outline of Annual Research Achievements

抗リン脂質抗体症候群（APS）における異常な補体活性化の機序として補体第1成分（C1q）に対する自己抗体（抗C1q抗体）の存在が重要と言う点を明らかにして現在投稿中である。抗C1q抗体はAPSと類縁疾患として認識されている全身性エリテマトーデス（SLE)において高発現していることが報告されているが(Katsumata et al, Arthritis Rheum, 2011)、APSでの報告は未だない。申請者は抗C1q抗体がSLEが合併しない原発性APSにおいて高率に発現しており、この存在が恐らく感染症などのトリガーイベントをきっかけに補体古典経路の活性化を促進し、血栓症の発症や難治化（標準的2次予防下での血栓症再発）に関与することを学会報告している(Oku et al, American College of Rheumatology annual meeting 2013, 日本血栓止血学会総会2014　他)。 また、補体制御因子のうち、血清H因子の発現低下がAPSで高率に認められることを解明し、近日中に投稿予定である。これらはいずれも患者データであり、それを元にin vitroでの検討を進めており、概ね良好な結果を得ている。すなわち、マウスモノクローナル抗C1q抗体を用いて、in vitroで補体系活性化と血栓傾向が再現される。これらから今年度は実際に、マウスモデルの作成を行い、血栓症の発現を評価する

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

これまでのところ、APS患者データから抗C1q抗体が高頻度に存在することと補体制御因子、とりわけH因子の血清蛋白濃度が低下している点を確認しておりデータを投稿している。これを元に、APSモデルマウスを作成するため準備を行っているが、実験申請や予備実験に時間を要しており、近日中にマウスの実験を開始予定である。

Strategy for Future Research Activity

今後は、balb/cもしくは動脈硬化モデルであるApoEKOマウスにマウスモノクローナル抗C1q抗体であるJL-1を投与して、血中の補体蛋白の活性化を確認するとともに、血栓の形成について定量的に評価する。十分なJL-1濃度及び、補体活性化のtrigger（例えばLPSの投与等）を適切に加えても血栓形成が明らかでない際には、共投与するモノクローナル抗リン脂質抗体の濃度を増量する。それでも血栓作成が明らかでない場合には、動脈結紮など従来の血栓症モデルと同様に侵襲的な処置を加え産生される血栓量の変化（血栓サイズの増大など）を確認する。また、H因子欠損マウスを用いて、JL-1、抗リン脂質抗体の共投与を行うモデルについて現在実験計画を申請者の施設において申請中である。

Causes of Carryover

支出削減につとめ、当初予定していた海外学会参加費の科研費からの支出をとりやめたことと、実験計画からの遅れのため、マウスの購入・飼育費や投与する抗体の費用が不要となったため

Expenditure Plan for Carryover Budget

来年度に試薬、マウス購入・試薬費としてあてる

Research Products

• [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] 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: Modern Rheumatology Volume: 25(1) Pages: 90-95
  • DOI: 10.3109/14397595.2014.899736
  • Peer Reviewed
• [Journal Article] The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. (2015)
  • Author(s): Kurita T, Yasuda S, ObaY, Odani T, Kono M, Otomo K,
  • Journal Title: Rheumatology(Oxford) Volume: 54(1) Pages: 39-44
  • DOI: 10.1093/rheumatology/keu166
  • Peer Reviewed
• [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) Pages: 215-218
  • DOI: 10.3109/14397595.2014.942503
  • Peer Reviewed
• [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 Pages: 不明
  • 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: Nihon Rinsho Meneki Gakkai Kaishi Volume: 37(5) Pages: 430-436
  • DOI: 10.2177/jsci.37.430.
  • Peer Reviewed
• [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: Rheumatology International Volume: 34(9) Pages: 1225-1230
  • DOI: 10.1007/s00296-014-2951-0
  • Peer Reviewed
• [Journal Article] Antiphospholipid scoring: significance in diagnosis and prognosis (2014)
  • Author(s): Oku K, Amengual O, Atsumi T
  • Journal Title: Lupus Volume: 23(12) Pages: 1269-1272
  • DOI: 10.1177/0961203314537361
  • Peer Reviewed / Acknowledgement Compliant
• [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 – 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