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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2017

Open Access 01-12-2017 | Research

Anti-human platelet antigen (HPA)-1a antibodies may affect trophoblast functions crucial for placental development: a laboratory study using an in vitro model

Authors: Mariana Eksteen, Gøril Heide, Heidi Tiller, Yan Zhou, Nora Hersoug Nedberg, Inigo Martinez-Zubiaurre, Anne Husebekk, Bjørn R. Skogen, Tor B. Stuge, Mette Kjær

Published in: Reproductive Biology and Endocrinology | Issue 1/2017

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Abstract

Background

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by maternal antibodies against paternal human platelet antigens (HPAs) on fetal platelets. Antibodies against HPA-1a are accountable for the majority of FNAIT cases. We have previously shown that high levels of maternal anti-HPA-1a antibodies are associated with clinically significant reduced birth weight in newborn boys. Chronic inflammatory placental lesions are associated with increased risk of reduced birth weight and have previously been reported in connection with FNAIT pregnancies. The HPA-1a epitope is located on integrin β3 that is associated with integrin αIIb (the fibrinogen receptor) on platelets and megakaryocytes. Integrin β3 is also associated with integrin αV forming the αVβ3 integrin heterodimer, the vitronectin receptor, which is expressed on various cell types, including trophoblast cells. It is therefore thinkable that maternal anti-HPA-1a antibodies present during early pregnancy may affect placenta function through binding to the HPA-1a antigen epitope on invasive throphoblasts. The aim of the study was to examine whether interaction of a human anti-HPA-1a monoclonal antibody (mAb) with HPA-1a on trophoblast cells affect adhesion, migration and invasion of extravillous trophoblast cells.

Methods

An in vitro model with human anti-HPA-1a mAb, clone 26.4, and the first trimester extravillous trophoblast cell line HTR8/SVneo was employed. The xCELLigence system was utilized to assess the possible effect of anti-HPA-1a mAb on adhesion and migration of HTR8/SVneo cells. Specially designed chambers precoated with Matrigel were used to assess the effect on the invasive capacity of cells.

Results

We found that human anti-HPA-1a mAb 26.4 partially inhibits adhesion and migratory capacity of HTR8/SVneo cells.

Conclusions

Our findings suggest that anti-HPA-1a antibodies may affect trophoblast functions crucial for normal placental development. Future studies including primary throphoblast cells and polyclonal anti-HPA-1a antibodies are needed to confirm these results.
Literature
1.
Winkelhorst D, Kamphuis MM, de Kloet LC, Zwaginga JJ, Oepkes D, Lopriore E. Severe bleeding complications other than intracranial hemorrhage in neonatal alloimmune thrombocytopenia: a case series and review of the literature. Transfusion. 2016;56:1230–5.CrossRefPubMed
2.
Kjeldsen-Kragh J, Killie MK, Tomter G, Golebiowska E, Randen I, Hauge R, Aune B, Øian P, Dahl LB, Pirhonen J, et al. A screening and intervention program aimed to reduce mortality and serious morbidity associated with severe neonatal alloimmune thrombocytopenia. Blood. 2007;110:833–9.CrossRefPubMed
3.
Williamson LM, Hackett G, Rennie J, Palmer CR, Maciver C, Hadfield R, Hughes D, Jobson S, Ouwehand WH. The Natural History of Fetomaternal Alloimmunization to the Platelet-Specific Antigen HPA-1a (PlA1, Zwa) as Determined by Antenatal Screening. Blood. 1998;92:2280–7.PubMed
4.
Tiller H, Killie MK, Husebekk A, Skogen B, Ni H, Kjeldsen-Kragh J, ØIan P. Platelet antibodies and fetal growth: maternal antibodies against fetal platelet antigen 1a are strongly associated with reduced birthweight in boys. Acta Obstet Gynecol Scand. 2012;91:79–86.CrossRefPubMed
5.
Tiller H, Kamphuis MM, Flodmark O, Papadogiannakis N, David AL, Sainio S, Koskinen S, Javela K, Wikman AT, Kekomaki R, et al. Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry. BMJ Open. 2013;3:e002490.CrossRefPubMedPubMedCentral
6.
Dubruc E, Lebreton F, Giannoli C, Rabilloud M, Huissoud C, Devouassoux-Shisheboran M, Allias F. Placental histological lesions in fetal and neonatal alloimmune thrombocytopenia: A retrospective cohort study of 21 cases. Placenta. 2016;48:104–9.CrossRefPubMed
7.
Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11–25.CrossRefPubMed
8.
Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Dejana E, Wheelock M, Damsky CH. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest. 1997;99:2139–51.CrossRefPubMedPubMedCentral
9.
Vanderpuye OA, Labarrere CA, McIntyre JA. A vitronectin-receptor-related molecule in human placental brush border membranes. Biochem J. 1991;280(Pt 1):9–17.CrossRefPubMedPubMedCentral
10.
Pijnenborg R, Bland JM, Robertson WB, Brosens I. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta. 1983;4:397–413.CrossRefPubMed
11.
12.
Brodsky D, Christou H. Current Concepts in Intrauterine Growth Restriction. J Intensive Care Med. 2004;19:307–19.CrossRefPubMed
13.
Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986;93:1049–59.CrossRefPubMed
14.
Damsky CH, Fitzgerald ML, Fisher SJ. Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest. 1992;89:210–22.CrossRefPubMedPubMedCentral
15.
Kabir-Salmani M, Shiokawa S, Akimoto Y, Sakai K, Nagamatsu S, Sakai K, Nakamura Y, Lotfi A, Kawakami H, Iwashita M. Alphavbeta3 integrin signaling pathway is involved in insulin-like growth factor I-stimulated human extravillous trophoblast cell migration. Endocrinology. 2003;144:1620–30.CrossRefPubMed
16.
Eksteen M, Tiller H, Averina M, Heide G, Kjaer M, Ghevaert C, Michaelsen TE, Ihle O, Husebekk A, Skogen B, Stuge TB. Characterization of a human platelet antigen-1a-specific monoclonal antibody derived from a B cell from a woman alloimmunized in pregnancy. J Immunol. 2015;194:5751–60.CrossRefPubMed
17.
Graham CH, Hawley TS, Hawley RG, MacDougall JR, Kerbel RS, Khoo N, Lala PK. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res. 1993;206:204–11.CrossRefPubMed
18.
Weber M, Vasheghani F, Göhner C, Liehr T, Schleussner E, Fitzgerald JS, Markert UR, Weise A. Karyotypes of trophoblastic cell lines. Placenta. 2016;45:108.CrossRef
19.
Weiss EJ, Goldschmidt-Clermont PJ, Grigoryev D, Jin Y, Kickler TS, Bray PF. A monoclonal antibody (SZ21) specific for platelet GPIIIa distinguishes P1 A1 from Pl A2. Tissue Antigens. 1995;46:374–81.CrossRefPubMed
20.
Skogen B, Bellissimo DB, Hessner MJ, Santoso S, Aster RH, Newman PJ, McFarland JG. Rapid determination of platelet alloantigen genotypes by polymerase chain reaction using allele-specific primers. Transfusion. 1994;34:955–60.CrossRefPubMed
21.
Bugert P, McBride S, Smith G, Dugrillon A, Klüter H, Ouwehand WH, Metcalfe P. Microarray-based genotyping for blood groups: comparison of gene array and 5′-nuclease assay techniques with human platelet antigen as a model. Transfusion. 2005;45:654–9.CrossRefPubMed
22.
Dhallan R, Au W, Mattagajasingh S, et al. MEthods to increase the percentage of free fetal dna recovered from the maternal circulation. JAMA. 2004;291:1114–9.CrossRefPubMed
23.
24.
Killie MK, Salma W, Bertelsen E, Skogen B, Husebekk A. Quantitative MAIPA: Comparison of different MAIPA protocols. Transfus Apher Sci. 2010;43:149–54.CrossRefPubMed
25.
Kilburn BA, Wang J, Duniec-Dmuchowski ZM, Leach RE, Romero R, Armant DR. Extracellular matrix composition and hypoxia regulate the expression of HLA-G and integrins in a human trophoblast cell line. Biol Reprod. 2000;62:739–47.CrossRefPubMed
26.
Althaus J, Weir EG, Askin F, Kickler TS, Blakemore K. Chronic villitis in untreated neonatal alloimmune thrombocytopenia: an etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy. Am J Obstet Gynecol. 2005;193:1100–4.CrossRefPubMed
27.
Tchakarov A, Coffey A, Tatevian N. Neonatal Alloimmune Thrombocytopenia Associated with Massive Chronic Intervillositis: A Case Report and Review of the Literature. Pediatr Dev Pathol. 2013;16:32–4.CrossRefPubMed
28.
Tamblyn JA, Lissauer DM, Powell R, Cox P, Kilby MD. The immunological basis of villitis of unknown etiology - Review. Placenta. 2013;34:846–55.CrossRefPubMed
29.
Boyd TK, Redline RW. Chronic histiocytic intervillositis: a placental lesion associated with recurrent reproductive loss. Hum Pathol. 2000;31:1389–96.CrossRefPubMed
30.
Murphy MF, Hambley H, Nicolaides K, Waters AH. Severe fetomaternal alloimmune thrombocytopenia presenting with fetal hydrocephalus. Prenat Diagn. 1996;16:1152–5.CrossRefPubMed
31.
Tiller H, Fedorcsak P, Skogen BR. Old tools revisited give hope - new treatment option for families with a history of severe FNAIT complications. Acta Obstet Gynecol Scand 2016:n/a-n/a.
32.
33.
Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264:569–71.CrossRefPubMed
34.
Drake CJ, Cheresh DA, Little CD. An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci. 1995;108:2655–61.PubMed
35.
Yougbare I, Lang S, Yang H, Chen P, Zhao X, Tai WS, Zdravic D, Vadasz B, Li C, Piran S, et al. Maternal anti-platelet beta3 integrins impair angiogenesis and cause intracranial hemorrhage. J Clin Invest. 2015;125:1545–56.CrossRefPubMedPubMedCentral
36.
Sloan EK, Pouliot N, Stanley KL, Chia J, Moseley JM, Hards DK, Anderson RL. Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res. 2006;8:R20.CrossRefPubMedPubMedCentral
37.
Thirkill TL, Douglas GC. The Vitronectin Receptor Plays a Role in the Adhesion of Human Cytotrophoblast Cells to Endothelial Cells. Endothelium. 1999;6:277–90.CrossRefPubMed
38.
Douglas GC, Thirkill TL, Blankenship TN. Vitronectin receptors are expressed by macaque trophoblast cells and play a role in migration and adhesion to endothelium. BBA-Mol Cell Res. 1999;1452:36–45.
39.
van Gils JM, Stutterheim J, van Duijn TJ, Zwaginga JJ, Porcelijn L, de Haas M, Hordijk PL. HPA-1a alloantibodies reduce endothelial cell spreading and monolayer integrity. Mol Immunol. 2009;46:406–15.CrossRefPubMed
40.
Santoso S, Wihadmadyatami H, Bakchoul T, Werth S, Al-Fakhri N, Bein G, Kiefel V, Zhu J, Newman PJ, Bayat B, Sachs UJ. Antiendothelial αvβ3 Antibodies Are a Major Cause of Intracranial Bleeding in Fetal/Neonatal Alloimmune Thrombocytopenia. Arterioscler Thromb Vasc Biol. 2016;36(8):1517–24.CrossRefPubMed
41.
Abou-Chaker K, Meyer O, Salama A. Rapid typing of the human neutrophil antigen 1a by the particle gel agglutination assay. Tissue Antigens. 2009;73:242–4.CrossRefPubMed
42.
Stafford P, Ghevaert CJG, Campbell K, Proulx C, Smith G, Williamson LM, Ranasinghe E, Watkins NA, Huntington JA, Ouwehand WH. Immunologic and structural analysis of eight novel domain-deletion β 3 integrin peptides designed for detection of HPA-1 antibodies. J Thromb Haemost. 2008;6:366–75.CrossRefPubMed
43.
Socher I, Andrei-Selmer C, Bein G, Kroll H, Santoso S. Low-avidity HPA-1a alloantibodies in severe neonatal alloimmune thrombocytopenia are detectable with surface plasmon resonance technology. Transfusion. 2009;49:943–52.CrossRefPubMed
44.
Bakchoul T, Kubiak S, Krautwurst A, Roderfeld M, Siebert HC, Bein G, Sachs UJ, Santoso S. Low-avidity anti-HPA-1a alloantibodies are capable of antigen-positive platelet destruction in the NOD/SCID mouse model of alloimmune thrombocytopenia. Transfusion. 2011;51:2455–61.CrossRefPubMed
45.
Peterson JA, Kanack A, Nayak D, Bougie DW, McFarland JG, Curtis BR, Aster RH. Prevalence and clinical significance of low-avidity HPA-1a antibodies in women exposed to HPA-1a during pregnancy. Transfusion. 2013;53:1309–18.CrossRefPubMed
46.
Sheiner E, Levy A, Katz M, Hershkovitz R, Leron E, Mazor M. Gender Does Matter in Perinatal Medicine. Fetal Diagn Ther. 2004;19:366–9.CrossRefPubMed
47.
48.
Osei-Kumah A, Smith R, Jurisica I, Caniggia I, Clifton VL. Sex-specific differences in placental global gene expression in pregnancies complicated by asthma. Placenta. 2011;32:570–8.CrossRefPubMed
Metadata
Title
Anti-human platelet antigen (HPA)-1a antibodies may affect trophoblast functions crucial for placental development: a laboratory study using an in vitro model
Authors
Mariana Eksteen
Gøril Heide
Heidi Tiller
Yan Zhou
Nora Hersoug Nedberg
Inigo Martinez-Zubiaurre
Anne Husebekk
Bjørn R. Skogen
Tor B. Stuge
Mette Kjær
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2017
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-017-0245-6

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