Ontogeny of Beta 2 Glycoprotein I and Annexin V in Villous Placenta of Normal and Antiphospholipid Syndrome Pregnancies

Summary

β₂-glycoprotein I (β₂GPI) and annexin V (AV) have been implicated in the pathophysiology of the antiphospholipid syndrome (APS). We investigated their placental expression in normal villous tissues throughout gestation; first trimester n = 10, early second trimester; n = 4, preterm; n = 5) and term; n = 7 and in APS (2 first trimester, 1 preterm and 8 term deliveries). β₂GPI and AV were both expressed by the placenta from as early as seven weeks gestation and were colocalised to the syncytiotrophoblast. β₂GPI staining was also observed in stromal cells, being present in phagocytic Hofbauer cells and surrounding newly formed fetal vessels in a perivascular pattern, from seven to seventeen weeks gestation. An abnormal morphological distribution of AV was noted in one first trimester APS placenta, and for β₂GPI in a further first trimester placenta. When placental proteins were extracted from villous tissue, the concentration of AV/mg protein in term APS placentas (median, interquartile range) (aPS; 8.16, 7.87-9.72 µg/mg) was significantly higher (p <0.005) than normal term levels (normal; 2.47, 2.28-2.54 µg/mg). β₂GPI increased with advancing gestation (first trimester; 0.93, 0.64-1.26 µg/mg, term; 3.67, 2.58-4.48 µg/mg) in normal pregnancy. Term APS placentas had a reduced β₂GPI content (2.31, 1.87-2.49 µg/mg), p <0.05. The placental role of these proteins remains to be identified.

Keywords

β₂-glycoprotein-I - annexin V - placenta - antiphospholipid syndrome (APS)

• References

• 1 Levy RA. Clinical manifestations of the aPL syndrome. Lupus 1996; 05: 393-7.
• 2 Salafia CM, Parke AL. Placental pathology in systemic lupus erythematosus and phospholipid antibody syndrome. Rheum Dis Clin North Am 1997; 23: 85-97.
• 3 Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, Harpel PC. Pregnancy loss in the antiphospholipid-antibody syndrome – a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-60.
• 4 Carreras LO, Forastiero RR. Pathogenic role of antiprotein-phospholipid antibodies. Haemostasis 1996; 26 (Suppl. 04) 340-57.
• 5 Sheng Y, Kandiah DA, Krilis SA. Beta2-glycoprotein I: target antigen for ‘antiphospholipid’ antibodies. Immunological and molecular aspects. Lupus 1998; 07 (Suppl. 02) S5-9.
• 6 Nakaya Y, Schaefer EJ, Brewer HBJ. Activation of human post heparin lipoprotein lipase by apolipoprotein H (beta2-glycoprotein I). Biochem Biophys Res Commun 1980; 95: 1168-72.
• 7 Wurm H, Beubler E, Polz E, Holasek A, Kostner G. Studies on the possible function of beta2-glycoprotein I: influence in the triglyceride metabolism in the rat. Metabolism 1982; 31: 484-6.
• 8 Kochl S, Fresser F, Lobentanz E, Baier G, Utermann G. Novel interaction of apolipoprotein (a) with beta2-glycoprotein I mediated by the kringle IV domain. Blood 1997; 90: 1482-9.
• 9 Rojkjaer R, Klaerke DA, Schousboe I. Characterization of the interaction between beta2-glycoprotein I and calmodulin, and identification of a binding sequence in beta2-glycoprotein I. Biochim Biophys Acta 1997; 1339: 217-25.
• 10 McNally T, Purdy G, Mackie IJ, Machin SJ, Isenberg DA. The use of an anti-beta2-glycoprotein I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis. Br J Haematol 1995; 91: 471-3.
• 11 Ogasawara M, Aoki K, Matsuura E, Sasa H, Yagami Y. Anti beta2-glycoprotein I antibodies and lupus anticoagulant in patients with recurrent pregnancy loss: prevalence and clinical significance. Lupus 1996; 05: 587-92.
• 12 Forastiero RR, Martinuzzo ME, Cerrato GS, Kordich LC, Carreras LO. Relationship of anti beta2-glycoprotein I and antiprothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb Haemost 1997; 78: 1008-14.
• 13 Chamley LW, Pattison NS, McKay EJ. Elution of anticardiolipin antibodies and their cofactor beta2-glycoprotein 1 from the placentae of patients with a poor obstetric history. J Reprod Immunol 1993; 25: 209-20.
• 14 La LRosa, Meroni PL, Tincani A, Balestrieri G, Faden D, Lojacono A, Morassi L, Brocchi E, Del Papa N, Gharavi A. Beta2-glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome. J Rheumatol 1994; 21: 1684-93.
• 15 Chamley LW, Allen JL, Johnson PM. Synthesis of beta2-glycoprotein I by the human placenta. Placenta 1997; 18: 403-10.
• 16 Schlaepfer DD, Haigler HT. Expression of annexins as a function of cellular growth state. J Cell Biol 1990; 111: 229-38.
• 17 van Heerde WL, de Groot PG, Reutelingsperger CP. The complexity of the phospholipid binding protein Annexin V. Thromb Haemost 1995; 73: 172-9.
• 18 Kirsch T, Nah HD, Demuth DR, Harrison G, Golub EE, Adams SL, Pacifici M. Annexin V-mediated calcium flux across membranes is dependent on the lipid composition: implications for cartilage mineralization. Biochemistry 1997; 36: 3359-67.
• 19 Krikun G, Lockwood CJ, Wu XX, Zhou XD, Guller S, Calandri C, Guha A, Nemerson Y, Rand JH. The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation. Placenta 1994; 15: 601-12.
• 20 Rambotti MG, Spreca A, Donato R. Immunocytochemical localization of annexins V and VI in human placentae of different gestational ages. Cell Mol Biol Res 1993; 39: 579-88.
• 21 Rand JH, Wu XX, Guller S, Gil J, Guha A, Scher J, Lockwood CJ. Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 1994; 171: 1566-72.
• 22 Redman CW, Jefferies M. Revised definition of pre-eclampsia. Lancet 1988; 01: 809-12.
• 23 McNally T, Mackie IJ, Isenberg DA, Machin SJ. Immunoelectrophoresis and ELISA techniques for assay of plasma beta2-glycoprotein I and the influence of plasma lipids. Thromb Res 1993; 72: 275-86.
• 24 Schousboe I. Beta2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway. Blood 1985; 66: 1086-91.
• 25 Willems GM, Janssen MP, Pelsers MM, Comfurius P, Galli M, Zwaal RF, Bevers EM. Role of divalency in the high-affinity binding of anticardiolipin antibody-beta2-glycoprotein I complexes to lipid membranes. Biochemistry 1996; 35: 13833-42.
• 26 Bonet B, Brunzell JD, Gown AM, Knopp RH. Metabolism of very-lowdensity lipoprotein triglyceride by human placental cells: the role of lipoprotein lipase. Metabolism 1992; 41: 596-603.
• 27 Chonn A, Semple SC, Cullis PR. Beta2-glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of “non-self” particles. J Biol Chem 1995; 270: 25845-9.
• 28 Balasubramanian K, Chandra J, Schroit AJ. Immune clearance of phosphatidylserine-expressing cells by phagocytes The role of beta2-glycoprotein I in macrophage recognition. J Biol Chem 1997; 272: 31113-7.
• 29 Manfredi AA, Rovere P, Heltai S, Galati G, Nebbia G, Tincani A, Balestrieri G, Sabbadini MG. Apoptotic cell clearance in systemic lupus erythematosus II. Role of beta2-glycoprotein I. Arthritis Rheum 1998; 41: 215-23.
• 30 Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T. Involvement of beta2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol 1997; 107: 569-73.
• 31 Lyden TW, Vogt E, Ng AK, Johnson PM, Rote NS. Monoclonal antiphospholipid antibody reactivity against human placental trophoblast. J Reprod Immunol 1992; 22: 1-14.
• 32 Katsuragawa H, Rote NS, Inoue T, Narukawa S, Kanzaki H, Mori T. Monoclonal antiphosphatidylserine antibody reactivity against human first-trimester placental trophoblasts. Am J Obstet Gynecol 1995; 172: 1592-7.
• 33 Huppertz B, Frank HG, Kingdom JC, Reister F, Kaufmann P. Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 1998; 110: 495-508.
• 34 Lakasing L, Campa JS, Poston R, Khamashta MA, Poston L. Normal expression of tissue factor, thrombomodulin, and annexin V in placentas from women with antiphospholipid syndrome. Am J Obstet Gynecol 1999; 181: 180-9.
• 35 Wang X, Campos B, Kaetzel MA, Dedman JR. Annexin V is critical in the maintenance of murine placental integrity. Am J Obstet Gynecol 1999; 180: 1008-16.
• 36 Rand JH, Wu XX, Guller S, Scher J, Andree HA, Lockwood CJ. Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi. Am J Obstet Gynecol 1997; 177: 918-23.
• 37 Vogt E, Ng AK, Rote NS. Antiphosphatidylserine antibody removes annexin-V and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. Am J Obstet Gynecol 1997; 177: 964-72.