The establishment of the novel murine model of the antiphospholipid syndrome

• Project/Area Number: 26293230
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Hokkaido University
• Principal Investigator: Tatsuya Atsumi 北海道大学, 医学(系)研究科(研究院), 教授 (20301905)
• Co-Investigator(Kenkyū-buntansha): 奥 健志 北海道大学, 大学病院, 助教 (70544295)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 内科 / 免疫学 / 脂質 / 生体分子 / 内科学

Outline of Final Research Achievements

We have strived to develop novel APS animal model using arteriosclerotic mouse model with additional monoclonal aPL administration, however, failed to develop the spontaneous thrombosis.
Recently, we have clarified that abnormal acceleration of the complement activation contributes to APS pathogenesis and the autoantibody against first component of the classical pathway (C1q), highly produced in the patients' sera, initiates the activation. Additionally, in APS, primary abnormality of the vascular endothelial cells,especially dysfunction of endothelial NOS(eNOS) secretion is reported.These factors facilitates aPL to bind the cell surfaces of vascular endothelial cells via inducing anionic phospholipids expressions on cell membranes. And these processes result to the up-regulation of pro-thrombotic states of the cells.We are now planning to establish APS model mouse by using eNOS KO mouse with the pathogenic autoantibodies (aPL, anti-C1q antibody) which seems promising

Research Products

• [Journal Article] Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. (2017)
  • Author(s): Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Delgado Alves J, Zigon P, Ambrozic A, Tomsic M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pintó I, Cervera R, Swadzba J, Musial J, Atsumi T.
  • Journal Title: Lupus Volume: 26(3) Issue: 3 Pages: 266-276
  • DOI: 10.1177/0961203316660203
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Acute aortic thrombosis related to antiphospholipid antibodies. (2017)
  • Author(s): Nakamura H, Amengual O, Horita T, Kato M, Oku K, Bohgaki T, Yasuda S, Atsumi T
  • Journal Title: Lupus Volume: 印刷中 Issue: 7 Pages: 783-784
  • DOI: 10.1177/0961203316678672
  • Peer Reviewed
• [Journal Article] The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression (2016)
  • Author(s): Atsumi T, Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, Eguchi K, Watanabe A, Origasa H, Yasuda S, Yamanishi Y, Kita Y, Matsubara T, Iwamoto M, Shoji T, Okada T, van der Heijde D, Miyasaka N, Koike T
  • Journal Title: Annals of the Rheumatic Diseases Volume: 75 Issue: 1 Pages: 75-83
  • DOI: 10.1136/annrheumdis-2015-207511
  • NAID: 120005697202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treatment Patterns, Direct Cost of Biologics, and Direct Medical Costs for Rheumatoid Arthritis Patients: A Real-world Analysis of Nationwide Japanese Claims Data. (2016)
  • Author(s): Sugiyama N, Kawahito Y, Fujii T, Atsumi T, Murata T, Morishima Y, Fukuma Y.
  • Journal Title: Clin Ther Volume: 38(6) Issue: 6 Pages: 1359-1375
  • DOI: 10.1016/j.clinthera.2016.03.022
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Brain MRI abnormalities defined as risks for poor prognosis in lupus patients with acute confusional state: Are they antibody mediated? (2016)
  • Author(s): Yasuda S, Shimizu Y Atsumi T.
  • Journal Title: Mod Rheumatol Volume: 27(2) Issue: 2 Pages: 191-192
  • DOI: 10.1080/14397595.2016.1216262
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Significance of fully automated tests for the diagnosis of antiphospholipid syndrome. (2016)
  • Author(s): Oku K, Amengual O, Kato M, Bohgaki T, Horita T, Yasuda S, Sakamoto N, Ieko M, Norman GL, Atsumi T
  • Journal Title: Thromb Res. Volume: 146 Pages: 1-6
  • DOI: 10.1016/j.thromres.2016.08.018
  • 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: Autoimmun Rev Volume: 15(10) Issue: 10 Pages: 1001-1004
  • DOI: 10.1016/j.autrev.2016.07.020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 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: in press
  • 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,
  • Journal Title: Autoimmune Reviews Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autoantibodies against component 1q subcomponent (C1q), contribute to complement activation an recurrent thrombosis/pregnancy morbidity in antiphospholipid syndrome (APS). (2016)
  • Author(s): Oku K, Amengual O, Hisada R, Ohmura K, Nakagawa I, atanabe T, Bohgaki T, Horita T,Yasuda S, Atsumi T.
  • Journal Title: Rheumatology (Oxford) Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of apolipoprotein B100 and oxidized low-density lipoprotein in the monocyte tissue factor induction mediated by anti-β2 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: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 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: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. (2014)
  • Author(s): Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, de Groot P, Lakos G, Lambert M. Meroni P, Ortel TL Petri M, Rahman A, Roubey R, Sciascia S, Snyder M, Tebo AE, Tincani A and Willis R.
  • Journal Title: Autoimmun Rev. Volume: 13(9) Issue: 9 Pages: 917-930
  • DOI: 10.1016/j.autrev.2014.05.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. (2014)
  • Author(s): Devreese KM, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL
  • Journal Title: J Thromb Haemost Volume: 12(5) Issue: 5 Pages: 792-795
  • DOI: 10.1111/jth.12537
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Cumulative Safety Data for Tocilizumab. (2016)
  • Author(s): Atsumi T.
  • Organizer: 10th International Congress on Autoimmunity
  • Place of Presentation: コングレスセンターライプチヒ（ドイツライプツィヒ）
  • Int'l Joint Research / Invited
• [Presentation] Complement and thrombosis in the antiphospholipid syndrome. (2016)
  • Author(s): Atsumi T and Oku K.
  • Organizer: 10th International Congress on Autoimmunity
  • Place of Presentation: コングレスセンターライプチヒ（ドイツライプツィヒ）
  • Int'l Joint Research / Invited
• [Presentation] Phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome. (2016)
  • Author(s): Atsumi T
  • Organizer: 15th International Congress on Antiphospholipid Antibodies
  • Place of Presentation: ELEXUS HOTEL（キプロス，キレニア）
  • Int'l Joint Research / Invited
• [Presentation] Antiphospholipid Scoring (2016)
  • Author(s): Atsumi T and Oku K.
  • Organizer: 15th International Congress on Antiphospholipid Antibodies
  • Place of Presentation: ELEXUS HOTEL（キプロス，キレニア）
  • Int'l Joint Research / Invited
• [Presentation] How to interpret the antiphospholipid profile. (2016)
  • Author(s): Atsumi T and Oku K.
  • Organizer: The 9th Congress of the Asia-Pacific Society on Thrombosis and Haemostasis
  • Place of Presentation: 台北国際コンベンションセンター（台湾，台北市）
  • Int'l Joint Research / Invited
• [Presentation] A novel patient-derived IgG monoclonal anticardiolipin antibody that specifically binds to domain I of beta 2 glycoprotein. (2016)
  • Author(s): 8.Oku K, Kanetsuka Y, Amengual O, Ohmura K, Kato M, Bohgaki T, Horita T, Yasuda S, Atsumi T.
  • Organizer: The 9th Congress of the Asia-Pacific Society on Thrombosis and Haemostasis
  • Place of Presentation: コンベンションセンター（台湾，台北市）
  • Int'l Joint Research / Invited
• [Presentation] Procoagulant property of a novel patient-derived autoimmune IgG type monoclonal anticardiolipin antibody that binds to beta 2 glycoprotein domain I but tot to total beta 2 glycoprotein I molecule. (2015)
  • Author(s): Oku K, Kanetsuka Y, Amengual O, Nakamura H, Oomura K, Bohgaki T, Horita T,Yasuda S, de Laat B and Atsumi T
  • Organizer: American College of Rheumatology, 79th Annual Scientific Meeting
  • Place of Presentation: San Francisco（USA）
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Reduction of HLA Class II Expression and Beta-2-Glycoprotein I Presentation By Fluvastatin in Vitro and in Vivo: Possible Mechanism of Statin-Induced-Deprocoagulation in the Antiphospholipid Syndrome. (2015)
  • Author(s): Watanabe T, Oku K Amengual O, Hisada R Oomura K, Shida S, Shimizu Y, Kato M, Bohgaki T, Horita T,Yasuda S, Ishizu A, Arase H and Atsumi T.
  • Organizer: American College of Rheumatology, 79th Annual Scientific Meeting
  • Place of Presentation: San Francisco（USA）
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Interpretation of antiphospholipid antibody profile. (2015)
  • Author(s): Atsumi T.
  • Organizer: 17th Asia Pacific League of Associations for Rheumatology Congress.
  • Place of Presentation: Chennai（India）
  • Year and Date: 2015-09-07
  • Int'l Joint Research / Invited
• [Presentation] Antiphospholipid Scoring. (2015)
  • Author(s): Atsumi T.
  • Organizer: 61st Annual Meeting of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH).
  • Place of Presentation: Toronto（Canada）
  • Year and Date: 2015-06-20
  • Int'l Joint Research / Invited
• [Presentation] Predictive markers for thrombotic events in autoimmune diseases: comparison of Antiphospholipid Score (aPL-S) and Global Anti-phospholipid Syndrome Score (GAPSS). (2015)
  • Author(s): Oku K, Amengual O, Hisada R, Oomura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S and Atsumi T.
  • Organizer: International Society on Thrombosis and Haemostasis；ISTH2015.
  • Place of Presentation: Toronto（Canada）
  • Year and Date: 2015-06-20
  • Int'l Joint Research
• [Presentation] Prophylaxis for the prevention of obstetric complications in asymptomatic women with antiphospholipid antibodies. (2015)
  • Author(s): Amengual O, Fujita D, Otta E, Carmona L, Kenji O, Sugiura-Ogasawara M,Murashima A, Atsumi T.
  • Organizer: The Annual European Congress of Rheumatology EULAR
  • Place of Presentation: Rome（Italy）
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] Significance of IgG phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results from the initial and validation studies. (2015)
  • Author(s): Amengual O, Forastiero R, Sugiura-Ogasawara M, Oku K, Otomo K, Alves J, C. Favas C, Zigon P , Ambrozic A, Tomšic M, Ruiz-Irastorza G, Ruiz-Arruza I, Bertolaccini ML, Norman GL, Shums Z, Arai,Atsumi T.
  • Organizer: The Annual European Congress of Rheumatology EULAR
  • Place of Presentation: Rome（Italy）
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] arkers of thrombotic events in autoimmune diseases:comparison of Antiphospholipid Score (aPL-S) and Global Anti-phospholipid Syndrome Score (GAPSS) (2014)
  • Author(s): 1.Oku K, Amengual O, Hisada R, Oomura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T.
  • Organizer: The 78th American College of Rheumatology Annual Meeting
  • Place of Presentation: Boston convention Exhibision 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, Ohmura 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: The 78th Annual Meeting of American College of Rheumatology
  • Place of Presentation: Boston convention Exhibision center(Boston,USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] International multi-centre study in Phosphatidylserine-dependent-antiprothrombin antibodies (aPS/PT) for the diagnosis of antiphospholipid syndrome. (2014)
  • Author(s): Atsumi T.
  • Organizer: 60th Annual Meeting of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH).
  • Place of Presentation: The Wisconsin Center (Milwaukee,USA)
  • Year and Date: 2014-06-23 – 2014-06-26
  • Invited
• [Book] Pathogenesis of Antiphospholipid Syndrome. (2016)
  • Author(s): Amengual O, Atsumi T.
  • Total Pages: 640
  • Publisher: Academic Press
• [Book] Antiphospholipid Syndrome. (2016)
  • Author(s): Amengual O, Bertolaccini ML, Atsumi T.
  • Total Pages: 326
  • Publisher: Academic Press
• [Book] Laboratory Markers with clinical significance in the antiphospholipid Syndrome. (2016)
  • Author(s): Amengual O, Bertolaccini ML and Atsumi T.
  • Publisher: Elsevier Science
• [Book] Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects (2016)
  • Author(s): Amengual O and Atsumi Tatsuya.
  • Total Pages: 571
  • Publisher: Academic Press