Assessment of biomarkers indicating activation of the complement system in pregnant women with fetal growth restriction

Abstract

Aims: To compare serum levels of sC5b-9, C3, C4, C1-INH, and CH50, which are indicators of complement system activation and regulatory processes, in pregnant women with and without fetal growth restriction (FGR). Methods: This study enrolled eighty-six women with gestational age between 24 and 36 weeks. Maternal blood samples were obtained from 43 patients diagnosed with FGR and 43 from healthy pregnancies. Serum complement levels were measured using commercially available ELISA kits according to the manufacturer’s instructions (SunRed, China). Results: When the levels of complement activation biomarkers of pregnancies with FGR were compared with those of healthy pregnancies, the C1est level was significantly higher, C4 and CH50 levels were slightly lower, and Sc5b9 and C3 levels were similar. Conclusion: While the exact role of complement activation in FGR remains fully elucidated, the elevated levels of C1-INH in women with FGR suggest a compensatory mechanism to mitigate thrombus formation and inflammation. This adaptive response may be a potential therapeutic target for improving placental function and pregnancy outcomes.

Keywords

• Complement system
• fetal growth restriction
• pregnancy
• placenta

Etal büyüme kısıtlılığı olan hamile kadınlarda kompleman sisteminin aktivasyonunu gösteren biyobelirteçlerin değerlendirilmesi

Abstract

Amaç Fetal büyüme kısıtlılığı (FGR) olan ve olmayan gebelerde kompleman sistemi aktivasyonu ve düzenleyici süreçlerin göstergeleri olan sC5b-9, C3, C4, C1-INH ve CH50 serum düzeylerini karşılaştırmak. Çalışma Tasarımı. Bu çalışmaya gebelik yaşı 24 ila 36 hafta arasında olan seksen altı kadın dahil edilmiştir. Maternal kan örnekleri, FGR tanısı konmuş 43 hastadan ve 43 sağlıklı gebelikten elde edilmiştir. Serum kompleman düzeyleri ticari olarak temin edilebilen ELISA kitleri kullanılarak üreticinin talimatlarına göre ölçülmüştür (SunRed, Çin). Sonuçlar. FGR'li gebelerin kompleman aktivasyon biyobelirteçlerinin seviyeleri sağlıklı gebelerinkiyle karşılaştırıldığında, C1est seviyesi anlamlı derecede yüksek, C4 ve CH50 seviyeleri hafif düşük ve Sc5b9 ve C3 seviyeleri benzerdi. Sonuçlar. Sonuç olarak, FGR'de kompleman aktivasyonunun rolü tam olarak aydınlatılamamış olsa da, FGR'li kadınlarda yüksek C1-INH seviyeleri trombüs oluşumunu ve enflamasyonu azaltmak için telafi edici bir mekanizma olduğunu düşündürmektedir. Bu adaptif yanıt, plasental fonksiyonu ve gebelik sonuçlarını iyileştirmek için potansiyel bir terapötik hedef olabilir.

Keywords

• Kompleman sistemi
• Fetal büyüme kısıtlılığı
• Gebelik
• Plasenta

References

1. 1. Holers VM. Complement and its receptors: new insights into human disease. Annu Rev Immunol. 2014;32:433.
2. 2. Derzsy Z, Prohászka Z, Rigó JJ, Füst G, Molvarec A. Activation of the complement system in normal pregnancy and preeclampsia. Mol Immunol. 2010;47(7–8):1500-1506.
3. 3. Romano R, Giardino G, Cirillo E, Prencipe R, Pignata C. Complement system network in cell physiology and in human diseases. Int Rev Immunol. 2021;40(3):159-170.
4. 4. Abu-Raya B, Michalski C, Sadarangani M, Lavoie PM. Maternal immunological adaptation during normal pregnancy. Front Immunol. 2020;11:575197.
5. 5. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010;63(6):425-433.
6. 6. Bulla R, Bossi F, Tedesco F. The complement system at the embryo implantation site: friend or foe? Front Immunol. 2012;3:55.
7. 7. Blakey H, Sun R, Xie L, et al. Pre-eclampsia is associated with complement pathway activation in the maternal and fetal circulation, and placental tissue. Pregnancy Hypertension. 2023;32:43-49.
8. 8. Unterscheider J, O’Donoghue K, Daly S, et al. Fetal growth restriction and the risk of perinatal mortality-case studies from the multicentre PORTO study. BMC Pregnancy Childbirth. 2014;14(1):63.

9. 9. Chauhan SP, Beydoun H, Chang E, et al. Prenatal detection of fetal growth restriction in newborns classified as small for gestational age: correlates and risk of neonatal morbidity. Am J Perinatol. 2014;31(03):187.
10. 10. Leitner Y, Fattal-Valevski A, Geva R, et al. Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study. J Child Neurol. 2007;22(5):580.
11. 11. Pavličev M, Wagner GP, Chavan AR, et al. Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface. Genome Res. 2017;27(3):349-361.
12. 12. Abbas Y, Turco MY, Burton GJ, Moffett A. Investigation of human trophoblast invasion in vitro. Human Reproduct Update. 2020;26(4):501-513.
13. 13. Kingdom J, Huppertz B, Seaward G, Kaufmann P. Development of the placental villous tree and its consequences for fetal growth. Eur J Obstetr Gynecol Reproduct Biol. 2000;92(1):35-43.
14. 14. Girardi G. Complement activation, a threat to pregnancy. Semin Immunopathol. 2018;40(1):103-111.
15. 15. Regal JF, Burwick RM, Fleming SD. The complement system and preeclampsia. Curr Hypertens Rep. 2017;19(11):87.
16. 16. Isaksson GL, Nielsen LH, Palarasah Y, et al. Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes. J Hypertens. 2023;41(2):223-232.
17. 17. Crisafulli F, Andreoli L, Zucchi D, et al. Variations of C3 and C4 before and during pregnancy in systemic lupus erythematosus: association with disease flares and obstetric outcomes. J Rheumatol. 2023;50(10):1296-1301.
18. 18. Hurler L, Toonen EJM, Kajdácsi E, et al. Distinction of early complement classical and lectin pathway activation via quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs. Front Immunol. 2022;13:1039765.
19. 19. Agostinis C, Zito G, Toffoli M, et al. A longitudinal study of C1q and anti-C1q autoantibodies in homologous and heterologous pregnancies for predicting pre-eclampsia. Front Immunol. 2022;13:1037191.
20. 20. Pyo JY, Lee LE, Ahn SS, Song JJ, Park YB, Lee SW. Total haemolytic complement activity at diagnosis as an indicator of the baseline activity of antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumat Dis. 2021;28(2):85-93.
21. 21. American College of Obstetricians and Gynecologists. Intrauterine growth restriction. Practice Bulletin-Clinical Guidance 2020-ACOG No: 12.
22. 22. Karnaukhova, E. C1-inhibitor: structure, functional diversity and therapeutic development. Curr Med Chem 2022;29(3):467-488.
23. 23. Tanaka KA, Buehler P, Stewart KE. High plasma levels of C1-inhibitor are associated with lower risk of future venous thromboembolism”: comment from Tanaka et al. J Thrombos Haemostas. 2023;21(10):2991-2992.
24. 24. Grover SP, Snir O, Hindberg K, et al. High plasma levels of C1-inhibitor are associated with lower risk of future venous thromboembolism. J Thrombos Haemostas. 2023;21(7):1849-1860.
25. 25. Dorresteijn MJ, Visser T, Cox LAE, et al. C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia. Critical Care Medicine, 2010;38(11):2139-2145.
26. 26. Baker JW, Craig TJ, Riedl MA, et al. Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women. Allergy Asthma Proceed. 2013;34(2):162-169.
27. 27. Thomson TM, Toscano-Guerra E, Casis E, Paciucci R. C1 esterase inhibitor and the contact system in COVID-19. Br J Haematol. 2020;190(4):520-524.
28. 28. Blakey H, Sun R, Xie L, et al. Pre-eclampsia is associated with complement pathway activation in the maternal and fetal circulation, and placental tissue. Pregnancy Hypertension. 2023;32:43-49.
29. 29. Girardi G. Guilty as charged: all available evidence implicates complement’s role in fetal demise. Am J Reproduct Immunol. 2008;59(3):183-192.
30. 30. Lynch AM, Gibbs RS, Murphy JR, Giclas PC, Salmon JE, Holers VM. Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obstetr Gynecol. 2011;117(1):75-83.
31. 31. Qu XW, Jilling T, Neerhof MG, Luo K, Hirsch E, Thaete LG. Unilateral uterine ischemia/reperfusion-induced bilateral fetal loss and fetal growth restriction in a murine model require intact complement component 5. J Reproduct Immunol. 2012;95(1-2): 27-35.
32. 32. Burwick RM, Feinberg BB. Eculizumab for the treatment of preeclampsia/HELLP syndrome. Placenta. 2013;34(2):201-203.
33. 33. Girardi G. Complement inhibition keeps mothers calm and avoids fetal rejection. Immunolog Investigat. 2008;37(5):645-659.