Skip to main content
Top
Published in: Reproductive Biology and Endocrinology 1/2019

Open Access 01-12-2019 | Antiphospholipid Syndrome | Research

Amniotic fluid antiphospholipid antibodies: potential role in antiphospholipid syndrome-independent aberrant implantation process

Authors: Valentina Bruno, Marzia Nuccetelli, Carlo Ticconi, Antonella Bruno, Federica Martelli, Maria Vittoria Capogna, Sergio Bernardini, Emilio Piccione, Adalgisa Pietropolli

Published in: Reproductive Biology and Endocrinology | Issue 1/2019

Login to get access

Abstract

Background

The direct role of antiphospholipid antibodies (aPL) at maternal-fetal interface has not been fully investigated, especially whether they are involved in physiological and pathological implantation conditions, in an antiphospholipid syndrome (APS)-independent manner. In fact, trophoblast cells and placental endothelial cells at the implantation site express potential aPL targeted-phospholipid antigens (PL Ags); thus, the local production and presence of their specific antibodies, not related to APS (characterized by aPL presence in the peripheral blood), could be a potential marker of aberrant invasion, implantation and fetal-maternal immune tolerance processes.

Methods

Anti-Beta2glycoprotein I (anti-β2GPI) and anticardiolipin (aCL Ab) antibodies (the most clinically relevant aPL) were detected by immunoenzymatic assay (ELISA), in the amniotic fluid (AF) of 167 women with physiological and complicated common pregnancy conditions, sharing an aberrant implantation process, such as recurrent pregnancy loss (RPL), autoimmune hypothyroidism (ahT) and smoking. All women included in the study were negative to peripheral blood aPL.

Results

aCL and anti-β2GPI antibodies were detectable in all the AF samples. RPL, ahT and smoking patients had higher level of anti-β2GPI Abs (IgM) compared to women with physiological pregnancies (p < 0.0001). Since IgM cannot cross the placenta, their local production in response to maternal-fetal interface stimuli, could be hypothesized.

Conclusions

The presence of aPL in the AF (not related to APS) could reveal a potential clinical significance at maternal-fetal interface in selected pregnancy complications, in which an aberrant implantation process, and in turn an impaired fetal-maternal immune tolerance cross-talk, could occur.
Literature
2.
go back to reference 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.CrossRef 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.CrossRef
3.
go back to reference Wilson WA, Gharavi AE, Koike T, Lockshin MD, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42(7):1309–11.CrossRef Wilson WA, Gharavi AE, Koike T, Lockshin MD, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42(7):1309–11.CrossRef
4.
go back to reference Fischetti F, Durigutto P, Pellis V, et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood. 2005;106(7):2340–6.CrossRef Fischetti F, Durigutto P, Pellis V, et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood. 2005;106(7):2340–6.CrossRef
5.
go back to reference 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):1327–33.CrossRef 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):1327–33.CrossRef
6.
go back to reference Agostinis C, Biffi S, Garrovo C, Durigutto P, Lorenzon A, Bek A, Bulla R, Grossi C, Borghi MO, Meroni PL, Tedesco F. In vivo distribution of b2 glycoprotein I under various pathophysiologic conditions. BLOOD. 2011;118(15):4231–8.CrossRef Agostinis C, Biffi S, Garrovo C, Durigutto P, Lorenzon A, Bek A, Bulla R, Grossi C, Borghi MO, Meroni PL, Tedesco F. In vivo distribution of b2 glycoprotein I under various pathophysiologic conditions. BLOOD. 2011;118(15):4231–8.CrossRef
7.
go back to reference Meroni PL, Borghi OM, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7:330–9.CrossRef Meroni PL, Borghi OM, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7:330–9.CrossRef
8.
go back to reference Robertson SA, Roberts CT, van Beijering E, et al. Effect of beta2-glycoprotein I null mutation on reproductive outcome and antiphospholipid antibody-mediated pregnancy pathology in mice. Mol Hum Reprod. 2004;10:409–16.CrossRef Robertson SA, Roberts CT, van Beijering E, et al. Effect of beta2-glycoprotein I null mutation on reproductive outcome and antiphospholipid antibody-mediated pregnancy pathology in mice. Mol Hum Reprod. 2004;10:409–16.CrossRef
9.
go back to reference Di Simone N, Meroni PL, Del Papa N, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum. 2000;43:140–50.CrossRef Di Simone N, Meroni PL, Del Papa N, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum. 2000;43:140–50.CrossRef
10.
go back to reference Chamley LW, Allen JL, Johnson PM. Synthesis of beta2 glycoprotein 1 by the human placenta. Placenta. 1997;18:403–10.CrossRef Chamley LW, Allen JL, Johnson PM. Synthesis of beta2 glycoprotein 1 by the human placenta. Placenta. 1997;18:403–10.CrossRef
11.
go back to reference Agostinis C, Biffi S, Garrovo C, et al. In vivo distribution of b2 glycoprotein I under various pathophysiological conditions. Blood. 2011;118:4231–8.CrossRef Agostinis C, Biffi S, Garrovo C, et al. In vivo distribution of b2 glycoprotein I under various pathophysiological conditions. Blood. 2011;118:4231–8.CrossRef
12.
go back to reference Di Simone N, Meroni PL, D’Asta M, Di Nicuolo F, D’Alessio MC, Caruso A. Pathogenic role of antibeta2- glycoprotein I antibodies on human placenta:functional effects related to implantation and roles of heparin. Hum Reprod Update. 2007;13(2):189–196. 34.CrossRef Di Simone N, Meroni PL, D’Asta M, Di Nicuolo F, D’Alessio MC, Caruso A. Pathogenic role of antibeta2- glycoprotein I antibodies on human placenta:functional effects related to implantation and roles of heparin. Hum Reprod Update. 2007;13(2):189–196. 34.CrossRef
13.
go back to reference Meroni PL, Tedesco F, Locati M, et al. Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view. Lupus. 2010;19(4):453–6.CrossRef Meroni PL, Tedesco F, Locati M, et al. Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view. Lupus. 2010;19(4):453–6.CrossRef
14.
go back to reference 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;14:489–95.CrossRef 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;14:489–95.CrossRef
15.
go back to reference Jovanović M, Bozić M, Kovacević T, Radojcić L, Petronijević M, Vićovac L. Effects of anti-phospholipid antibodies on a human trophoblast cell line (HTR-8/ SVneo). Acta Histochem. 2010;112:34–41.CrossRef Jovanović M, Bozić M, Kovacević T, Radojcić L, Petronijević M, Vićovac L. Effects of anti-phospholipid antibodies on a human trophoblast cell line (HTR-8/ SVneo). Acta Histochem. 2010;112:34–41.CrossRef
16.
go back to reference Di Simone N, Castellani R, Caliandro D, Caruso A. Antiphospholipid antibodies regulate the expression of trophoblast cell adhesion molecules. Fertil Steril. 2002;77:805–11.CrossRef Di Simone N, Castellani R, Caliandro D, Caruso A. Antiphospholipid antibodies regulate the expression of trophoblast cell adhesion molecules. Fertil Steril. 2002;77:805–11.CrossRef
17.
go back to reference Staun-Ram E, Shlomit G, Gabarin D, Shalev E. Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion. Reprod Biol Endocrinol. 2004;4(2):59.CrossRef Staun-Ram E, Shlomit G, Gabarin D, Shalev E. Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion. Reprod Biol Endocrinol. 2004;4(2):59.CrossRef
18.
go back to reference Di Simone N, Marana R, Castellani R, et al. Decreased expression of heparin binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation. Arthritis Rheum. 2010;62:1504–12.CrossRef Di Simone N, Marana R, Castellani R, et al. Decreased expression of heparin binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation. Arthritis Rheum. 2010;62:1504–12.CrossRef
19.
go back to reference Kovačević TM, Radojčić L, Tošić NM, Pavlović ST, Vićovac LM. Monoclonal antibody 26 cross-reactive with b2-glycoprotein I affects human trophoblast invasion in vitro. Eur J Obstet Gynecol Reprod Biol. 2013;171:23–2924.CrossRef Kovačević TM, Radojčić L, Tošić NM, Pavlović ST, Vićovac LM. Monoclonal antibody 26 cross-reactive with b2-glycoprotein I affects human trophoblast invasion in vitro. Eur J Obstet Gynecol Reprod Biol. 2013;171:23–2924.CrossRef
20.
go back to reference Blois SM, Ilarregui JM, Tometten M, et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med. 2007;13:1450–7.CrossRef Blois SM, Ilarregui JM, Tometten M, et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med. 2007;13:1450–7.CrossRef
21.
go back to reference Cohen SB, Goldenberg M, Rabinovici J, Lidor AL, Dulitzky M, Gilburd B, Shoenfeld Y, Schiff E. Anti-cardiolipin antibodies in fetal blood and amniotic fluid derived from patients with the anti-phospholipid syndrome. Hum Reprod. 2000;15(5):1170–2.CrossRef Cohen SB, Goldenberg M, Rabinovici J, Lidor AL, Dulitzky M, Gilburd B, Shoenfeld Y, Schiff E. Anti-cardiolipin antibodies in fetal blood and amniotic fluid derived from patients with the anti-phospholipid syndrome. Hum Reprod. 2000;15(5):1170–2.CrossRef
22.
go back to reference RECURRENT PREGNANCY LOSS. Guideline of the European society of human reproduction and embryology. ESHRE Early Pregnancy Guideline Development Group. NOVEMBER 2017. RECURRENT PREGNANCY LOSS. Guideline of the European society of human reproduction and embryology. ESHRE Early Pregnancy Guideline Development Group. NOVEMBER 2017.
23.
go back to reference Gärtner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002;87(4):1687–91.CrossRef Gärtner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002;87(4):1687–91.CrossRef
24.
go back to reference Christiansen OB, Steffenson R, Nielsen H, Varming K. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol Obstet Invest. 2008;66:257–67.CrossRef Christiansen OB, Steffenson R, Nielsen H, Varming K. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol Obstet Invest. 2008;66:257–67.CrossRef
25.
go back to reference Pietropolli A, Giuliani E, Bruno V, Patrizi L, Piccione E, Ticconi C. Plasminogen activator inhibitor-1, factor V, factor II and methylenetetrahydrofolate reductase polymorphisms in women with recurrent miscarriage. J Obstet Gynaecol. 2014;34(3):229–34.CrossRef Pietropolli A, Giuliani E, Bruno V, Patrizi L, Piccione E, Ticconi C. Plasminogen activator inhibitor-1, factor V, factor II and methylenetetrahydrofolate reductase polymorphisms in women with recurrent miscarriage. J Obstet Gynaecol. 2014;34(3):229–34.CrossRef
26.
go back to reference Pietropolli A, Bruno V, Capogna MV, Bernardini S, Piccione E, Ticconi C. Uterine blood flow indices, antinuclear autoantibodies and unexplained recurrent miscarriage. Obstet Gynecol Sci. 2015;58(6):453–60.CrossRef Pietropolli A, Bruno V, Capogna MV, Bernardini S, Piccione E, Ticconi C. Uterine blood flow indices, antinuclear autoantibodies and unexplained recurrent miscarriage. Obstet Gynecol Sci. 2015;58(6):453–60.CrossRef
27.
go back to reference Ticconi C, Pietropolli A, Borelli B, Bruno V, Piccione E, Bernardini S, Di Simone N. Antinuclear autoantibodies and pregnancy outcome in women with unexplained recurrent miscarriage. Am J Reprod Immunol. 2016;76(5):396–9.CrossRef Ticconi C, Pietropolli A, Borelli B, Bruno V, Piccione E, Bernardini S, Di Simone N. Antinuclear autoantibodies and pregnancy outcome in women with unexplained recurrent miscarriage. Am J Reprod Immunol. 2016;76(5):396–9.CrossRef
28.
go back to reference National Institute for Health and Clinical Excellence (NICE): Antenatal care for uncomplicated pregnancies. Clinical Guideline CG62. March 2008. National Institute for Health and Clinical Excellence (NICE): Antenatal care for uncomplicated pregnancies. Clinical Guideline CG62. March 2008.
29.
go back to reference Pietropolli A, Martelli F, Vicario R, Montagnoli C, Ticconi C, Piccione E. Evaluation of fetal heart rate variation during amniocentesis: correlation with fetal karyotype. J Matern Fetal Neonatal Med. 2011;24(4):587–9.CrossRef Pietropolli A, Martelli F, Vicario R, Montagnoli C, Ticconi C, Piccione E. Evaluation of fetal heart rate variation during amniocentesis: correlation with fetal karyotype. J Matern Fetal Neonatal Med. 2011;24(4):587–9.CrossRef
30.
go back to reference van Furth R, Schuit HR, Hijmans W. The immunological development of the human fetus. J Exp Med. 1965;122(6):1173–88.CrossRef van Furth R, Schuit HR, Hijmans W. The immunological development of the human fetus. J Exp Med. 1965;122(6):1173–88.CrossRef
31.
go back to reference Gu J, Lei Y, Huang Y, Zhao Y, Li J, Huang T, Zhang J, Wang J, Deng X, Chen Z, Korteweg C, Deng R, Yan M, Xu Q, Dong S, Cai M, Luo L, Huang G, Wang Y, Li Q, Lin C, Su M, Yang C, Zhuang Z. Fab fragment glycosylated IgG may play a central role in placental immune evasion. Hum Reprod. 2015;30(2):380–91.CrossRef Gu J, Lei Y, Huang Y, Zhao Y, Li J, Huang T, Zhang J, Wang J, Deng X, Chen Z, Korteweg C, Deng R, Yan M, Xu Q, Dong S, Cai M, Luo L, Huang G, Wang Y, Li Q, Lin C, Su M, Yang C, Zhuang Z. Fab fragment glycosylated IgG may play a central role in placental immune evasion. Hum Reprod. 2015;30(2):380–91.CrossRef
32.
go back to reference Matthiesen L, Kalkunte S, Sharma S. Multiple pregnancy failures: an immunological paradigm. Am J Reprod Immunol. 2012;67:334–40.CrossRef Matthiesen L, Kalkunte S, Sharma S. Multiple pregnancy failures: an immunological paradigm. Am J Reprod Immunol. 2012;67:334–40.CrossRef
33.
go back to reference Ticconi C, Giuliani E, Veglia M, Pietropolli A, Piccione E, Di Simone N. Thyroid autoimmunity and recurrent miscarriage. Am J Reprod Immunol. 2011;66:452–9.CrossRef Ticconi C, Giuliani E, Veglia M, Pietropolli A, Piccione E, Di Simone N. Thyroid autoimmunity and recurrent miscarriage. Am J Reprod Immunol. 2011;66:452–9.CrossRef
34.
go back to reference Valentina B, Barbara R, Adalgisa P, Vittoria CM, Renato M, Carlo T, Emilio P, Claudio C, Giuseppe N, Francesca A. OLR1 and Loxin expression in PBMCs of women with a history of unexplained recurrent miscarriage: a pilot study. Genet Test Mol Biomarkers. 2017;21(6):363–72.CrossRef Valentina B, Barbara R, Adalgisa P, Vittoria CM, Renato M, Carlo T, Emilio P, Claudio C, Giuseppe N, Francesca A. OLR1 and Loxin expression in PBMCs of women with a history of unexplained recurrent miscarriage: a pilot study. Genet Test Mol Biomarkers. 2017;21(6):363–72.CrossRef
35.
go back to reference Dechanet C, Brunet C, Anahory T, Hamamah S, Hedon B, Dechaud H. Effects of cigarette smoking on embryo implantation and placentation and analysis of factors interfering with cigarette smoke effects (part II). Gynecol Obstet Fertil. 2011;39(10):567–74.CrossRef Dechanet C, Brunet C, Anahory T, Hamamah S, Hedon B, Dechaud H. Effects of cigarette smoking on embryo implantation and placentation and analysis of factors interfering with cigarette smoke effects (part II). Gynecol Obstet Fertil. 2011;39(10):567–74.CrossRef
Metadata
Title
Amniotic fluid antiphospholipid antibodies: potential role in antiphospholipid syndrome-independent aberrant implantation process
Authors
Valentina Bruno
Marzia Nuccetelli
Carlo Ticconi
Antonella Bruno
Federica Martelli
Maria Vittoria Capogna
Sergio Bernardini
Emilio Piccione
Adalgisa Pietropolli
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2019
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-019-0527-2

Other articles of this Issue 1/2019

Reproductive Biology and Endocrinology 1/2019 Go to the issue