Do antiphospholipid antibodies have direct pathologic effects upon endometrial and trophoblast cells?

Current Rheumatology Reviews

Volumn 5, Issue 2, 2009, Pages 83-97

  Pericleous, Charis ^a,b   Rahman, Anisur ^a,b   Giles, Ian ^a,b  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Antiphospholipid antibodies; Endometrium; Trophoblast

Indexed keywords

ABETIMUS; ACETYLSALICYLIC ACID; BETA2 GLYCOPROTEIN 1; BETA2 GLYCOPROTEIN 1 ANTIBODY; BLOOD CLOTTING FACTOR 12; CELL ADHESION MOLECULE; CHORIONIC GONADOTROPIN; CLASSICAL COMPLEMENT PATHWAY C3 C5 CONVERTASE; COMPLEMENT COMPONENT C3B RECEPTOR; DECAY ACCELERATING FACTOR; GAMMA INTERFERON; HEPARIN; IMMUNOGLOBULIN G1 ANTIBODY; LJP 1082; MONOCLONAL ANTIBODY; PHOSPHATIDYLSERINE; PHOSPHOLIPASE A; PHOSPHOLIPID ANTIBODY; PROLACTIN; PROSTAGLANDIN; PROTEIN C; PROTEIN S; PROTHROMBIN; STAT5 PROTEIN; THROMBOPLASTIN; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA ANTIBODY;

ABSENCE OF SIDE EFFECTS; ANTIGEN ANTIBODY REACTION; ANTIPHOSPHOLIPID SYNDROME; APOPTOSIS; CELL ADHESION; CLINICAL TRIAL; COMPLEMENT ACTIVATION; DECIDUA; DOSE RESPONSE; DRUG BINDING; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; DRUG SYNTHESIS; ENDOMETRIUM CELL; ENZYME LINKED IMMUNOSORBENT ASSAY; HISTOLOGY; HUMAN; NEUTROPHIL; NIDATION; NONHUMAN; PATHOPHYSIOLOGY; PERINATAL MORBIDITY; PLACENTAL THROMBOSIS; PRIORITY JOURNAL; PROSTAGLANDIN SYNTHESIS; PROTEIN DOMAIN; REVIEW; THROMBOSIS; TROPHOBLAST; VEIN THROMBOSIS;

EID: 71849118565     PISSN: 15733971     EISSN: None     Source Type: Journal    
DOI: 10.2174/157339709788298455     Document Type: Review

References (113)

1. Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13(3): 486-489
2. nd ed. Amsterdam: Elsevier Science B.V. 2002. pp. 11-20.
3. Rai RS. Antiphospholipid syndrome and recurrent miscarriage. J Postgrad Med 2002; 48(1): 3-4.
4. Backos M, Rai R, Baxter N, Chilcott IT, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynaecol 1999; 106(2): 102-107 (Pubitemid 29065223)
5. Shah NM, Khamashta MA, Atsumi T, Hughes GR. Outcome of patients with anticardiolipin antibodies: a 10 year follow- up of 52 patients. Lupus 1998; 7(1): 3-6. (Pubitemid 28052654)
6. Shoenfeld Y, Gerli R, Doria A, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005; 112(21): 3337-3347 (Pubitemid 43739380)
7. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332(15): 993-997
8. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174(5): 1584-1589 (Pubitemid 26165282)
9. Sebire NJ, Fox H, Backos M, Rai R, Paterson C, Regan L. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod 2002; 17(4): 1067-1071 (Pubitemid 34411147)
10. Jankowski M, Vreys I, Wittevrongel C, et al. Thrmobogenicity of beta2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood 2003; 101: 157-162 (Pubitemid 36025902)
11. Pierangeli SS, Harris EN. Antiphospholipid antibodies in an in vivo thrombosis model in mice. Lupus 1994; 3(4): 247-251
12. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci USA 1991; 88(8): 3069-3073 (Pubitemid 21916560)
13. Ikematsu W, Luan FL, La Rosa L, et al. Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice. Arthritis Rheum 1998; 41(6): 1026-1039 (Pubitemid 28265405)
14. Fischetti F, Durigutto P, Pellis V, et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complementing dependent and requires a priming factor. Blood 2005; 106: 2340-2346 (Pubitemid 41510805)
15. Holers VM, Girardi G, Mo L, et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002; 195(2): 211-220 (Pubitemid 34461265)
16. Branch DW, Dudley DJ, Mitchell MD, et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am J Obstet Gynecol 1990; 163(1): 210-216
17. Lynch A, Marlar R, Murphy J, et al. Antiphospholipid antibodies in predicting adverse pregnancy outcome. A prospective study. Ann Intern Med 1994; 120(6): 470-475
18. Vaarala O, Manttari M, Manninen V, et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91(1): 23-27
19. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following antico-agulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998; 104(4): 332-338 (Pubitemid 28211022)
20. Greaves M, Cohen H, MacHin SJ, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome. Br J Haematol 2000; 109(4): 704-715 (Pubitemid 30609746)
21. Loizou S, Mackworth-Young CG, Cofiner C, Walport MJ. Heterogeneity of binding reactivity to different phospholipids of antibodies from patients with systemic lupus erythematosus (SLE) and with syphilis. Clin Exp Immunol 1990; 80(2): 171-176 (Pubitemid 20147710)
22. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2- glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87(11): 4120-4124 (Pubitemid 20217993)
23. Tsutsumi A, Matsuura E, Ichikawa K, et al. Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus. Arthritis Rheum 1996; 39(9): 1466-1474 (Pubitemid 26314979)
24. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4(2): 295-306.
25. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46(4): 1019-1027 (Pubitemid 34303815)
26. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42(7): 1309-1311 (Pubitemid 30265586)
27. Galli M, Borrelli G, Jacobsen EM, et al. Clinical significance of different antiphospholipid antibodies in the WAPS (Warfarin in the Anti- Phospholipid Syndrome) study. Blood 2007; 110(4): 1178-1183 (Pubitemid 47281414)
28. Bertolaccini ML, Mepani K, Sanna G, Hughes GRV, Khamashta MA. Factor XII autoantibodies as a novel marker for thrombosis and adverse obstetric history in patients with systemic lupus erythematosus. Ann Rheum Dis 2007; 66(4): 533-537 (Pubitemid 46580477)
29. Wu S, Stephenson MD. Obstetrical antiphospholipid syndrome. Semin Reprod Med 2006; 24(1): 40-53.
30. Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum 2001; 44(6): 1466-1467 (Pubitemid 32537548)
31. Quenby S, Farquharson RG, Dawood F, Hughes AM, Topping J. Recurrent miscarriage and long-term thrombosis risk: a casecontrol study. Hum Reprod 2005; 20(6): 1729-1732 (Pubitemid 40852272)
32. Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA 2006; 295(9): 1050-1057 (Pubitemid 43313721)
33. Derksen RH, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 2004; 50(4): 1028-1039
34. Derksen RH, de Groot PG. The obstetric antiphospholipid syndrome. J Reprod Immunol 2008; 77(1): 41-50.
35. Spitzer KA, Murphy K, Crowther M, Clark CA, Laskin CA. Postpartum management of women at increased risk of thrombosis- -results of a Canadian pilot survey. J Rheumatol 2006; 33(11): 2222-2226 (Pubitemid 44749781)
36. Stone S, Hunt BJ, Seed PT, Parmar K, Khamashta MA, Poston L. Longitudinal evaluation of markers of endothelial cell dysfunction and hemostasis in treated antiphospholipid syndrome and in healthy pregnancy. Am J Obstet Gynecol 2003; 188: 454-460 (Pubitemid 36249985)
37. Branch DW, Dudley DJ, Scott JR, Silver RM. Antiphospholipid antibodies and fetal loss. N Engl J Med 1992; 326: 952.
38. Chaddha V, Viero S, Huppertz B, Kingdom J. Developmental biology of the placenta and the origins of placental insufficiency. Semin Fetal Neonatal Med 2004; 9(5): 357-369
39. Hustin J, Schaaps J. Echographic and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy. Am J Obstet Gynecol 1987; 157: 162-168 (Pubitemid 17099909)
40. Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol 2000; 157: 2111-2122
41. Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab 2002; 87: 2954-2959 (Pubitemid 34655369)
42. Genbacev O, Jensen KD, Powlin SS, Miller RK. In vitro differentiation and ultrastructure of human extravillous trophoblast (EVT) cells. Placenta 1993; 14(4): 463-475
43. De Wolf F, Carreras LO, Moerman P, Vermylen J, Van Assche A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol 1982; 142(7): 829-834
44. Out HJ, Kooijman CD, Bruinse HW, Derksen RH. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Rreprod Biol 1991; 41(3): 179-186
45. Sebire NJ, Backos M, El Gaddal S, Goldin RD, Regan L. Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients. Obstet Gynecol 2003; 101(2): 258-263 (Pubitemid 36170126)
46. Van Horn JT, Craven C, Ward K, Branch DW, Silver RM. Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndrome. Placenta 2004; 25: 642-648 (Pubitemid 38950318)
47. Francis J, Rai R, Sebire NJ, et al. Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome. Mol Hum Reprod 2006; 12(7): 435-442 (Pubitemid 44288202)
48. Mak IY, Brosens JJ, Christian M, et al. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab 2002; 87(6): 2581-2588 (Pubitemid 34655317)
49. Pierro E, Cirino G, Bucci MR, et al. Antiphospholipid antibodies inhibit prostaglandin release by decidual cells of early pregnancy: possible involvement of extracellular secretory phospholipase A2. Fertil Steril 1999; 71(2): 342-346 (Pubitemid 29069915)
50. Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112(11): 1644-1654 (Pubitemid 38063722)
51. Salmon JE, Girardi G, Holers VM. Complement activation as a mediator of antiphospholipid antibody induced pregnancy loss and thrombosis. Ann Rheum Dis 2002; 61(Suppl 2): ii46-50.
52. Redecha P, Tilley R, Tencati M, et al. Tissue factor: a link betwen C5a and neutrophil activation in antiphospholipid antibody-induced fetal loss. Blood 2007; 110(7): 2423-2431 (Pubitemid 47523163)
53. Higure A, Okamoto K, Hirata K, et al. Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis. Thromb Haemost 1996; 75: 791-795 (Pubitemid 26181552)
54. Todoroki H, Nakamura S, Higure A, et al. Neutrophils express tissue factor in a monkey model of sepsis. Surgery 2000; 127: 209-216 (Pubitemid 30091268)
55. Osterud B. Tissue factor in neutrophils: no. J Thromb Haemost 2004; 2: 218-20.
56. Shamonki JM, Salmon JE, Hyjek E, Baergen RN. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies. Am J Obstet Gynecol 2007; 196: 167.e1-167.e5. (Pubitemid 46239993)
57. Salmon JE, Girardi G, Holers VM. Activation of complement mediates antiphospholipid antibody-induced pregnancy loss. Lupus 2003; 12(7): 535-538 (Pubitemid 36890146)
58. Ilaria C, Nebuloni M, Cetin I, et al. Complement activation in antiphospholipid syndrome: a clue for an inflammatory process? J Autoimmun 2007; 28: 160-164
59. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10(11): 1222-1226 (Pubitemid 39540439)
60. Schwartz N, Shoenfeld Y, Barzilai O, et al. Reduced placental growth and hCG secretion in vitro induced by antiphospholipid antibodies but not by anti-Ro or anti-La: studies form women with SLE/PAPS. Lupus 2007; 16(2): 110-120
61. Bose P, Kadyrov M, Goldin R, et al. Abberations of early trophoblast differentiation predispose to pregnancy failure: lessons from the antiphospholipid syndrome. Placenta 2006; 27: 869-875 (Pubitemid 43905927)
62. Quenby S, Mountfield S, Cartwright JE, Whitley GS, Chamley L, Vince G. Antiphospholipid antibodies prevent extravillous trophoblast differentiation. Fertil Steril 2005; 83(3): 691-698 (Pubitemid 40348582)
63. Stone S, Pijnenborg R, Vercruysse L, et al. The placental bed in pregnancies complicated by primary antiphospholipid syndrome. Placenta 2006; 27: 457-467
64. Girardi G, Salmon JB. The role of complement in pregnancy and fetal loss. Autoimmunity 2003; 36(1): 19-26. (Pubitemid 36321904)
65. Lambropoulou M, Tamionakis D, Venizelos J, et al. Imbalance of mononuclear cell infiltrates in the placental tissue from foetuses after spontaneous abortion versus therapeutic termination from 8th to 12th weeks of gestational age. Clin Exp Med 2006; 6: 171-176 (Pubitemid 46028479)
66. Katsuragawa H, Kanzaki H, Inoue T, Hirano T, Mori T, Rote NS. Monolconal antibody against phopshatidylserine inhibits in vitro human trophoblastic hormone production and invasion. Biol Reprod 1997; 56: 50-58.
67. Di Simone N, Raschi E, Testoni C, et al. Pathogenic role of anti-beta2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of beta2-glycoprotein I binding to trophoblast cells and functional effects of anti-beta2-glycoprotein I antibodies in vitro. Ann Rheum Dis 2005; 64: 462-467 (Pubitemid 40283060)
68. Di Simone N, Castellani R, Raschi E, Orietta Borghi M, Meroni PL, Caruso A. Anti-beta-2 glycoprotein I antibodies affect Bcl-2 and Bax trophoblast expression without evidence of apoptosis. Ann NY Acad Sci 2006; 1069: 364-376 (Pubitemid 43989879)
69. Meroni PL, Borghi MO, Raschi E, et al. Inflammatory response and the endothelium. Thromb Res 2004; 114(5-6): 329-334
70. Di Simone N, Meroni PL, D'Asta MD, Di Nicuolo F, D'Alessio MC, Caruso A. Pathogenic role of anti-beta2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin. Hum Reprod 2007; 13(2): 189-196 (Pubitemid 46323195)
71. Lyden TW, Vogt E, Ng AK, Johnson PM, Rote NS. Monoclonal antiphospholipid antibody reactivity against human placental trophoblast. J Reprod Immunol 1992; 22(1): 1-14.
72. Di Simone N, Meroni PL, de Papa N, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion 27 and invasiveness by binding directly and through adhered beta2- glycoprotein I. Arthritis Rheum 2000; 43(1): 140-150 (Pubitemid 30368223)
73. Pierangeli SS, Colden-Stanfield M, Liu X, Barker JH, Anderson GL, Harris EN. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 1999; 99(15): 1997-2002. (Pubitemid 29183897)
74. Pierangeli SS, Liu X, Espinola R, et al. Functional analyses of patient-derived IgG monoclonal anticardiolipin antibodies using in vivo thrombosis and in vivo microcirculation models. Thromb Haemost 2000; 84(3): 388-395
75. Raschi E, Testoni C, Bosisio D, et al. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 2003; 101(9): 3495-3500 (Pubitemid 36857933)
76. Simoncini S, Sapet C, Camoin-Jau L, et al. Role of reactive oxygen species and p38MAPK in the induction of the proadhesive endothelial state mediated by IgG from patients with antiphospholipid syndrome. Int Immunol 2005; 17(4): 489-500. (Pubitemid 40568124)
77. Pierangeli SS, Vega-Ostertag ME, Raschi E, et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis 2007; 66(10): 1327-1333
78. Satta N, Dunoyer-Geindre S, Reber G, et al. The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies. Blood 2007; 109(4): 1507-1514 (Pubitemid 46239583)
79. Sorice M, Longo A, Capozzi A, et al. Anti-beta2-glycoprotein I antibodies induce monocyte release of tumour necrosis factor alpha and tissue factor by signal transduction pathways involving lipid rafts. Arthritis Rheum 2007; 56(8): 2687-2697 (Pubitemid 47237287)
80. Abrahams VM, Mor G. Toll-like receptors and their role in the trophoblast. Placenta 2005; 26(7): 540-547 (Pubitemid 40916306)
81. Krikun G, Lockwood CJ, Abrahams VM, Mor G, Paidas M, Guller S. Expression of toll-like receptors in the human decidua. Histol Histopathol 2007; 22: 847-854 (Pubitemid 47034150)
82. Rand JH, Wu XX. Antibody-mediated interference with annexins in the antiphospholipid syndrome. Thromb Res 2004; 114: 383-389 (Pubitemid 39422570)
83. Chamley LW, Pattison NS, McKay JE. The effect of human anticardiolipin antibodies on murine pregnancy. J Reprod Immunol 1994; 27(2): 123-134 (Pubitemid 24344571)
84. Silver RM, Smith LA, Edwin SS, Oshiro BT, Scott JR, Branch DW. Variable effects on murine pregnancy od immunoglobulin G fractions from women with antiphospholipid antibodies. Am J Obstet Gynecol 1997; 177(1): 229-233
85. Giles I, Haley J, Nagl S, et al. Relative importance of different human aPL derived heavy and light chains in the binding of aPL to cardiolipin. Mol Immunol 2003; 40: 49-60. (Pubitemid 36937060)
86. Giles I, Lambrianedes N, Latchman D, et al. The critical role of arginine residues in the binding of human antiphospholipid antibodies to cardiolipin. Arthritis Res Ther 2005; 7(1): R47-R56.
87. Giles I, Lambrianides N, Pattni N, et al. Arginine residues are important in determining the binding of human monoclonal antiphospholipid antibodies to clinically relevant antigens. J Immunol 2006; 177(3): 1729-1736 (Pubitemid 44092509)
88. Blank M, Anafi L, Zandman-Goddard G, et al. The efficacy of specific IVIG anti-idiotypic antibodies in antiphospholipid syndrome (APS): trophoblast invasiveness and APS animal model. Int Immunol 2007; 19(7): 857-865 (Pubitemid 47241894)
89. Zhou H, Wolberg AS, Roubey RA. Characterisation of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood 2004; 104(8): 2353-2358 (Pubitemid 39331833)
90. Kornberg A, Renaudineau Y, Blank M, Youinou P, Shoenfeld Y. Anti-beta 2-Glycoprotein I antibodies and anti-endothelial cells antibodies induce tissue factor in endothelial cells. Isr Med Assoc J 2000; 2(Suppl): 27-31. (Pubitemid 30614258)
91. Vega-Ostertag M, Harris EN, Pierangeli SS. Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin. Arthritis Rheum 2004; 50(9): 2911-2919 (Pubitemid 39209530)
92. Bose P, Black S, Kadyrov M, et al. Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro. Am J Obstet Gynecol 2004; 191: 2125-2131 (Pubitemid 39601524)
93. Di Simone N, Caliandro D, Castellani R, Ferrazzani S, De Carolis S, Caruso A. Low-molecular weight heparin restores in vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. Hum Reprod 1999; 14(2): 489-495
94. Hills F, Abrahams VM, Gonzalez-Timon B, et al. Heparin prevents programmed cell death in human trophoblast. Mol Hum Reprod 2006; 12(4): 237-243 (Pubitemid 43779075)
95. Steinkasserer A, Barlow PN, Willis AC, et al. Activity, disulphide mapping and structural modelling of the fifth domain of human beta 2-glycoprotein I. FEBS Lett 1992; 313(2): 193-197
96. Hunt J, Krilis S. The fifth domain of beta 2-glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies. J Immunol 1994; 152(2): 653-659 (Pubitemid 2048581)
97. Sheng Y, Sali A, Herzog H, Lahnstein J, Krilis SA. Site-directed mutagenesis of recombinant human beta 2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity. J Immunol 1996; 157(8): 3744-3751 (Pubitemid 126449192)
98. Iverson GM, Victoria EJ, Marquis DM. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Proc Natl Acad Sci USA 1998; 95(26): 15542-15546
99. De Laat B, Derksen RH, van Lummel M, Pennings MT, de Groot PG. Pathogenic anti-beta2-glycoprotein I antibodies recognise domain I of beta2-glycoprotein I only after a conformational change. Blood 2005; 107(5): 1916-1924
100. Guerin J, Sheng Y, Reddel S, Iverson GM, Chapman MG, Krilis SA. Heparin inhibits the binding of beta2-glycoprotein I to phospholipids and promotes the plasmin-mediated inactivation of this blood protein. J Biol Chem 2002; 277(4): 2644-2649
101. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signalling. Cell Death Differ 2003; 10: 45-65.
102. Mellor AL, Munn DH. Immunology at the maternal-fetal interface: Lessons for T cell tolerance and suppression. Ann Rev Immunol 2000; 18: 367-391
103. Anim-Nyame N, Gamble J, Sooranna SR, Johnson MR, Steer PJ. Microvascular permeability is related to circulating levels of tumour necrosis factor-a in pre-eclampsia. Cardiovasc Res 2003; 58(1): 162-169 (Pubitemid 36351634)
104. Babbage SJ, Arkwright PD, Vince GS, et al. Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss. J Reprod Immunol 2000; 51(1): 21-27.
105. Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005; 174(1): 485-490 (Pubitemid 40007438)
106. Ostensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006; 8(3): 209.
107. Iverson GM, Reddel S, Victoria EJ, et al. Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies. J Immunol 2002; 169(12): 7097-7103 (Pubitemid 36899298)
108. Ioannou Y, Pericleous C, Giles I, Latchman DS, Isenberg DA, Rahman A. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human beta(2)-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum 2007; 56(1): 280-290
109. Horizon A, Weisman M, Wallace DJ, et al. Results of a randomised, placebo controlled, double blind phase 1/2 clinical trial (RCT) to assess the safety and tolerability of LJP 1082 in patients with antiphospholipid syndrome. Arthritis Rheum 2003; 48 (Suppl 9): S364.
110. Merrill JT. LJP 1082: a toleragen for Hughes syndrome. Lupus 2004; 13(5): 335-338
111. Alarcon-Segovia D, Tumlin JA, Furie RA, et al. LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebocontrolled study. Arthritis Rheum 2003; 48(2): 442-454 (Pubitemid 36278013)
112. Linnik MD, HU JZ, Heilbrunn KR, et al. Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis Rheum 2005; 52(4): 1129-1137 (Pubitemid 40530120)
113. Ioannou J, Harper T, Romay-Penabad Z, et al. Domain I of beta2-glycoprotein I ameliorates thrombosis induced by antiphospholipid antibodies in mice. Arthritis Rheum 2006; 54: S559.