The complement system in preeclampsia-complicated pregnancy

DOI

https://dx.doi.org/10.18565/aig.2021.8.5-12

Sidorova I.S., Nikitina N.A., Unanyan A.L., Ageev M.B., Kokin A.A.
1) Obstetrics and Gynecology Department One, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of the Russian Federation, Moscow, Russia; 2) Anesthesiology and Intensive Care Unit, Maternity Hospital, Branch, V.V. Veresaev Moscow City Clinical Hospital, Moscow Healthcare Department, Moscow, Russia

The paper analyzes the results of studies published in recent years on the complement system in preeclampsia and other pregnancy complications. It presents data on changes in complement factors and its regulatory proteins in placental disorders. The results of the studies suggest that uncontrolled complement activation leads to impaired placentation, affects fetal development, and is an important component of the pathogenesis of complications, such as preeclampsia, HELLP syndrome, spontaneous miscarriage, and premature birth. Dysregulation of the alternative complement pathway in the presence of mutations in the genes of regulatory factors H and I, CD46, factor B. and others is known to be associated with atypical hemolytic uremic syndrome, less often with membranoproliferative glomerulonephritis. The similar mutations have been found in patients with severe preeclampsia and HELLP syndrome. Recent studies have shown a pronounced activation of the complement system in 100% of patients with HELLP syndrome and in 90% of those with severe preeclampsia with the formation of the C5b-9 membrane-attack complex and its deposits on activated endothelial cells. C5b-9 transmembrane integrates into the target cell, forming an asymmetric cylindrical channel, through which water molecules and electrolytes freely penetrate the cell, which causes its osmotic lysis. This is one of the most important mechanisms of endothelial damage in preeclampsia. The paper also presents modern therapeutic strategies for blocking excessive activity of the complement system. It is concluded that serious studies are needed to predict pregnancy complications caused by the imbalanced complement system, pharmacological correction, and safety and efficacy of the drugs used.
Conclusion. In addition to the above-mentioned problems, the most important question of what exactly the direct inducer of excessive complement activation is in preeclampsia needs to be solved.

complement system

complement activation

pregnancy

preeclampsia

HELLP-syndrome

eculizumab

Full text (in Russian)

Girardi G., Lingo J.J., Fleming S.D., Regal J.F. Essential role of complement in pregnancy: from implantation to parturition and beyond. Front. Immunol. 2020; 11: 1681. https://dx.doi.org/10.3389/fimmu.2020.01681.
Denny K.J., Woodruff T.M., Taylor S.M., Callaway L.K. Complement in pregnancy: a delicate balance. Am. J. Reprod. Immunol. 2013; 69(1): 3-11. https://dx.doi.org/10.1111/aji.12000.
Lokki A.I., Heikkinen-Eloranta J., Jarva H., Saisto T., Lokki M.L, Laivuori H, Meri S. Complement activation and regulation in preeclamptic placenta. Front. Immunol. 2014; 5: 312. https://dx.doi.org/10.3389/fimmu.2014.00312.
Pierik E., Prins J.R., van Goor H., Dekker G.A., Daha M.R., Seelen M.A.J., Scherjon S.A. Dysregulation of complement activation and placental dysfunction: a potential target to treat preeclampsia? Front. Immunol. 2020; 10: 3098. https://dx.doi.org/10.3389/fimmu.2019.03098.
Regal J.F., Gilbert J.S., Burwick R.M. The complement system and adverse pregnancy outcomes. Mol. Immunol. 2015; 67(1): 56-70. https://dx.doi.org/10.1016/j.molimm.2015.02.030.
Burwick R.M., Feinberg B.B. Complement activation and regulation in preeclampsia and HELLP syndrome. Am. J. Obstet. Gynecol. 2020 Sep 25: S0002-9378(20)31129-7. https://dx.doi.org/10.1016/j.ajog.2020.09.038.
Contro E., Bernabini D., Farina A. Cell-free fetal DNA for the prediction of pre-eclampsia at the first and second trimesters: a systematic review and meta-analysis. Mol. Diagn. Ther. 201; 21(2): 125-35. https://dx.doi.org/10.1007/s40291-016-0245-9.
Tempfer C.B., Bancher-Todesca D., Zeisler H., Schatten C., Husslein P., Gregg A.R. Placental expression and serum concentrations of cytokeratin 19 in preeclampsia. Obstet. Gynecol. 2000; 95(5): 677-82. https://dx.doi.org/10.1016/s0029-7844(00)00797-3.
Derzsy Z., Prohászka Z., Rigó J. Jr., Füst G., Molvarec A. Activation of the complement system in normal pregnancy and preeclampsia. Mol. Immunol. 2010; 47(7-8): 1500-6. https://dx.doi.org/10.1016/j.molimm.2010.01.021.
Girardi G. Complement activation, a threat to pregnancy. Semin. Immunopathol. 2018; 40(1): 103-11. https://dx.doi.org/10.1007/s00281-017-0645-x.
Lokki A.I., Kaartokallio T., Holmberg V., Onkamo P., Koskinen L.L.E., Saavalainen P. et al. Analysis of Complement C3 gene reveals susceptibility to severe preeclampsia. Front. Immunol. 2017; 8: 589. https://dx.doi.org/10.3389/fimmu.2017.00589.
Regal J.F., Burwick R.M., Fleming S.D. The complement system and preeclampsia. Curr. Hypertens. Rep. 2017; 19(11): 87. https://dx.doi.org/10.1007/s11906-017-0784-4.
Grumach A.S., Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol. Immunol. 2014; 61(2): 110-7. https://dx.doi.org/10.1016/j.molimm.2014.06.030.
Alper C.A. Inherited deficiencies of complement components in man. Immunol. Lett. 1987; 14(3): 175-81. https://dx.doi.org/10.1016/0165-2478(87)90098-8.
Salmon J.E., Heuser C., Triebwasser M., Liszewski M.K., Kavanagh D., Roumenina L. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011; 8(3): e1001013. https://dx.doi.org/10.1371/journal.pmed.1001013.
Mohlin F.C., Mercier E., Fremeaux-Bacchi V., Liszewski M.K., Atkinson J.P., Gris J.C., Blom A.M. Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss. Eur. J. Immunol. 2013; 43(6): 1617-29. https://dx.doi.org/10.1002/eji.201243196.
Wu W., Yang H., Feng Y., Zhang P., Li S., Wang X. et al. Polymorphisms in complement genes and risk of preeclampsia in Taiyuan, China. Inflamm. Res. 2016; 65(10): 837-45. https://dx.doi.org/10.1007/s00011-016-0968-4.
Tedesco F., Radillo O., Candussi G., Nazzaro A., Mollnes T.E., Pecorari D. Immunohistochemical detection of terminal complement complex and S protein in normal and pre-eclamptic placentae. Clin. Exp. Immunol. 1990; 80(2): 236-40. https://dx.doi.org/10.1111/j.1365-2249.1990.tb05240.x.
Sinha D., Wells M., Faulk W.P. Immunological studies of human placentae: complement components in pre-eclamptic chorionic villi. Clin. Exp. Immunol. 1984; 56(1): 175-84.
Buurma A., Cohen D., Veraar K., Schonkeren D., Claas F.H., Bruijn J.A. et al. Preeclampsia is characterized by placental complement dysregulation. Hypertension. 2012; 60(5): 1332-7. https://dx.doi.org/10.1161/HYPERTENSIONAHA.112.194324.
Agostinis C., Stampalija T., Tannetta D., Loganes C., Vecchi Brumatti L, De Seta F. et al. Complement component C1q as potential diagnostic but not predictive marker of preeclampsia. Am. J. Reprod. Immunol. 2016; 76(6): 475-81. https://dx.doi.org/10.1111/aji.12586.
Hering L., Herse F., Verlohren S., Park J.K., Wellner M., Qadri F. et al. Trophoblasts reduce the vascular smooth muscle cell proatherogenic response. Hypertension. 2008; 51(2): 554-9. https://dx.doi.org/ 10.1161/HYPERTENSIONAHA.107.102905.
Wang W., Irani R.A., Zhang Y., Ramin S.M., Blackwell S.C., Tao L. et al. Autoantibody-mediated complement C3a receptor activation contributes to the pathogenesis of preeclampsia. Hypertension. 2012; 60(3): 712-21. https://dx.doi.org/10.1161/HYPERTENSIONAHA.112.191817.
Sarween N., Drayson M.T., Hodson J., Knox E.M., Plant T., Day C.J., Lipkin G.W. Humoral immunity in late-onset Pre-eclampsia and linkage with angiogenic and inflammatory markers. Am. J. Reprod. Immunol. 2018; 80(5): e13041. https://dx.doi.org/10.1111/aji.13041.
Boij R., Svensson J., Nilsson-Ekdahl K., Sandholm K., Lindahl T.L., Palonek E. et al. Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. Am. J. Reprod. Immunol. 2012; 68(3): 258-70. https://dx.doi.org/10.1111/j.1600-0897.2012.01158.x.
Hoffman M.C., Rumer K.K., Kramer A., Lynch A.M., Winn V.D. Maternal and fetal alternative complement pathway activation in early severe preeclampsia. Am. J. Reprod. Immunol. 2014; 71(1): 55-60. https://dx.doi.org/10.1111/aji.12162.
Lynch A.M., Murphy J.R., Byers T., Gibbs R.S., Neville M.C., Giclas P.C. et al. Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am. J. Obstet. Gynecol. 2008; 198(4): 385. e1-9. https:/dx.doi.org/10.1016/j.ajog.2007.10.793.
Kestlerová A., Feyereisl J., Frisová V., Měchurová A., Šůla K., Zima T. et al. Immunological and biochemical markers in preeclampsia. J. Reprod. Immunol. 2012; 96(1-2): 90-4. https://dx.doi.org/10.1016/j.jri.2012.10.002.
Kim E.N., Yoon B.H., Lee J.Y., Hwang D., Kim K.C., Lee J. et al. Placental C4d deposition is a feature of defective placentation: observations in cases of preeclampsia and miscarriage. Virchows Arch. 2015; 466(6): 717-25. https://dx.doi.org/10.1007/s00428-015-1759-y.
Lashley L.E., Buurma A., Swings G.M., Eikmans M., Anholts J.D., Bakker J.A., Claas F.H. Preeclampsia in autologous and oocyte donation pregnancy: is there a different pathophysiology? J. Reprod. Immunol. 2015; 109: 17-23. https://dx.doi.org/10.1016/j.jri.2015.03.004.
Halmos A., Rigó J. Jr., Szijártó J., Füst G., Prohászka Z., Molvarec A. Circulating ficolin-2 and ficolin-3 in normal pregnancy and pre-eclampsia. Clin. Exp. Immunol. 2012; 169(1): 49-56. https://dx.doi.org/10.1111/j.1365-2249.2012.04590.x.
Wang C.C., Yim K.W., Poon T.C., Choy K.W., Chu C.Y., Lui W.T. et al. Innate immune response by ficolin binding in apoptotic placenta is associated with the clinical syndrome of preeclampsia. Clin. Chem. 2007; 53(1): 42-52. https://dx.doi.org/10.1373/clinchem.2007.074401.
Than N.G., Romero R., Erez O., Kusanovic J.P., Tarca A.L., Edwin S.S. et al. A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia. Am. J. Reprod. Immunol. 2008; 60(4): 333-45. https://dx.doi.org/10.1111/j.1600-0897.2008.00631.x.
Csuka D., Molvarec A., Derzsy Z., Varga L., Füst G., Rigó J. Jr., Prohászka Z. Functional analysis of the mannose-binding lectin complement pathway in normal pregnancy and preeclampsia. J. Reprod. Immunol. 2010; 87(1-2): 90-6. https://dx.doi.org/10.1016/j.jri.2010.07.004.
Cohen D., Buurma A., Goemaere N.N., Girardi G., le Cessie S., Scherjon S. et al. Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. J. Pathol. 2011; 225(4): 502-11. https://dx.doi.org/10.1002/path.2893.
Lynch A.M., Murphy J.R., Gibbs R.S., Levine R.J., Giclas P.C., Salmon J.E., Holers V.M. The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia. BJOG. 2010; 117(4): 456-62. https://dx.doi.org/10.1111/j.1471-0528.2009.02473.x.
Agostinis C., Bulla R., Tripodo C., Gismondi A., Stabile H., Bossi F. et al. An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development. J. Immunol. 2010; 185(7): 4420-9. https://dx.doi.org/10.4049/jimmunol.0903215.
Singh J., Ahmed A., Girardi G. Role of complement component C1q in the onset of preeclampsia in mice. Hypertension. 2011; 58(4): 716-24. https://dx.doi.org/10.1161/HYPERTENSIONAHA.111.175919.
Burwick R.M., Fichorova R.N., Dawood H.Y., Yamamoto H.S., Feinberg B.B. Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension. 2013; 62(6): 1040-5. https://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01420.
Burwick R.M., Easter S.R., Dawood H.Y., Yamamoto H.S., Fichorova R.N., Feinberg B.B. Complement activation and kidney injury molecule-1-associated proximal tubule injury in severe preeclampsia. Hypertension. 2014; 64(4): 833-8. https://dx.doi.org/10.1161/HYPERTENSIONAHA.114.03456.
Jia K., Ma L., Wu S., Yang W. Serum levels of complement factors C1q, Bb, and H in normal pregnancy and severe pre-eclampsia. Med. Sci. Monit. 2019; 25: 7087-93. https://dx.doi.org/10.12659/MSM.915777.
He Y., Xu B., Song D., Yu F., Chen Q., Zhao M. Expression of the complement system's activation factors in plasma of patients with early/late-onset severe pre-eclampsia. Am. J. Reprod. Immunol. 2016; 76(3): 205-11. https://dx.doi.org/10.1111/aji.12541.
Palomo M., Blasco M., Molina P., Lozano M., Praga M., Torramade-Moix S. et al. Complement activation and thrombotic microangiopathies. Clin. J. Am. Soc. Nephrol. 2019; 14(12): 1719-32. https://dx.doi.org/10.2215/CJN.05830519.
Denny K.J., Coulthard L.G., Finnell R.H., Callaway L.K., Taylor S.M., Woodruff T.M. Elevated complement factor C5a in maternal and umbilical cord plasma in preeclampsia. J. Reprod. Immunol. 2013; 97(2): 211-6. https://dx.doi.org/10.1016/j.jri.2012.11.006.
Ma Y., Kong L.R., Ge Q., Lu Y.Y., Hong M.N., Zhang Y. et al. Complement 5a-mediated trophoblasts dysfunction is involved in the development of pre-eclampsia. J. Cell. Mol. Med. 2018; 22(2): 1034-46. https://dx.doi.org/10.1111/jcmm.13466.
Lynch A.M., Eckel R.H., Murphy J.R., Gibbs R.S., West N.A., Giclas P.C. et al. Prepregnancy obesity and complement system activation in early pregnancy and the subsequent development of preeclampsia. Am. J. Obstet. Gynecol. 2012; 206(5): 428. e1-8. https://dx.doi.org/10.1016/j.ajog.2012.02.035.
Collier A.-R.Y., Zsengeller Z., Pernicone E., Salahuddin S., Khankin E.V., Karumanchi S.A. Placental sFLT1 is associated with complement activation and syncytiotrophoblast damage in preeclampsia. Hypertens. Pregnancy. 2019; 38(3): 193-9. https://dx.doi.org/10.1080/10641955.2019.1640725.
Miller E.C. Preeclampsia and cerebrovascular disease. Hypertension. 2019; 74(1): 5-13. https://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11513.
Basit S., Wohlfahrt J., Boyd H.A. Pre-eclampsia and risk of dementia later in life: nationwide cohort study. BMJ. 2018; 363: k4109. https://dx.doi.org/10.1136/bmj.k4109.
Lahti-Pulkkinen M., Girchenko P., Tuovinen S., Sammallahti S., Reynolds R.M., Lahti J. et al. Maternal hypertensive pregnancy disorders and mental disorders in children. Hypertension. 2020; 75(6): 1429-38. https://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14140.
Hellerud B.C., Aase A., Herstad T.K., Naess L.M., Kristiansen L.H., Trøseid A.M. et al. Critical roles of complement and antibodies in host defense mechanisms against Neisseria meningitidis as revealed by human complement genetic deficiencies. Infect. Immun. 2010; 78(2): 802-9. https://dx.doi.org/10.1128/IAI.01044-09.
Cohn A.C., MacNeil J.R., Clark T.A., Ortega-Sanchez I.R., Briere E.Z., Meissner H.C. et al. Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm. Rep. 2013; 62(RR-2): 1-28.
Hallstensen R.F., Bergseth G., Foss S., Jæger S., Gedde-Dahl T., Holt J. et al. Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology. 2015; 220(4): 452-9. https://dx.doi.org/10.1016/j.imbio.2014.11.003.
Burwick R.M., Burwick N.R., Feinberg B.B. Eculizumab fails to inhibit generation of C5a in vivo. Blood. 2014; 124(23): 3502-3. https://dx.doi.org/10.1182/blood-2014-07-589366.
Risitano A.M., Ricklin D., Huang Y., Reis E.S., Chen H., Ricci P. et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood. 2014; 123(13):2094-101. https://dx.doi.org/10.1182/blood-2013-11-536573.
Weisman H.F., Bartow T., Leppo M.K., Boyle M.P., Marsh H.C. Jr., Carson G.R. et al. Recombinant soluble CR1 suppressed complement activation, inflammation, and necrosis associated with reperfusion of ischemic myocardium. Trans. Assoc. Am. Physicians. 1990; 103: 64-72.
Martel C., Granger C.B., Ghitescu M., Stebbins A., Fortier A., Armstrong P.W. et al. Pexelizumab fails to inhibit assembly of the terminal complement complex in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Insight from a substudy of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Am. Heart J. 2012; 164(1): 43-51. https://dx.doi.org/10.1016/j.ahj.2012.04.007.
Lillegard K.E., Loeks-Johnson A.C., Opacich J.W., Peterson J.M., Bauer A.J., Elmquist B.J. et al. Differential effects of complement activation products c3a and c5a on cardiovascular function in hypertensive pregnant rats. J. Pharmacol. Exp. Ther. 2014; 351(2): 344-51. https://dx.doi.org/10.1124/jpet.114.218123.
Vogel C.W., Finnegan P.W., Fritzinger D.C. Humanized cobra venom factor: structure, activity, and therapeutic efficacy in preclinical disease models. Mol. Immunol. 2014; 61(2): 191-203. https://dx.doi.org/10.1016/j.molimm.2014.06.035.
Pouw R.B., Brouwer M.C., de Gast M.., van Beek A.E., van den Heuvel L.P., Schmidt C.Q. et al. Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera. Blood Adv. 2019; 3(4): 621-32. https://dx.doi.org/10.1182/bloodadvances.2018025692.
Oberkersch R., Attorresi A.I., Calabrese G.C. Low-molecular-weight heparin inhibition in classical complement activation pathway during pregnancy. Thromb. Res. 2010; 125(5): e240-5. https://dx.doi.org/10.1016/j.thromres.2009.11.030.
Ducat A., Vargas A., Doridot L., Bagattin A., Lerner J., Vilotte J.L. et al. Low-dose aspirin protective effects are correlated with deregulation of HNF factor expression in the preeclamptic placentas from mice and humans. Cell Death Discov. 2019; 5: 94. https://dx.doi.org/10.1038/s41420-019-0170-x.
Gonzalez J.M., Pedroni S.M., Girardi G. Statins prevent cervical remodeling, myometrial contractions and preterm labor through a mechanism that involves hemoxygenase-1 and complement inhibition. Mol. Hum. Reprod. 2014; 20(6): 579-89. https://dx.doi.org/10.1093/molehr/gau019.
Reijnders D., Liu C.C., Xu X., Zhao A.M., Olson K.N., Butler S.D. et al. Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia. Physiol. Genomics. 2018; 50(5): 385-92. https://dx.doi.org/10.1152/physiolgenomics.00115.2017.

Received 18.03.2021

Accepted 02.04.2021

Iraida S. Sidorova, Dr. Med. Sci., Professor, Academician of the RAS, Merited Scholar of the Russian Federation, Department of Obstetrics and Gynecology No. 1,
N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: sidorovais@yandex.ru.
ORCID: 0000-0003-2209-8662. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Natalya A. Nikitina, Dr. Med. Sci., Professor at the Department of Obstetrics and Gynecology No. 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: natnikitina@list.ru. ORCID: 0000-0001-8659-9963. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Ara L. Unanyan, Dr. Med. Sci., Professor at the Department of Obstetrics and Gynaecology No. 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: 9603526@mail.ru. ORCID: 0000-0002-2283-2356. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Mikhail B. Ageev, Ph.D., Teaching Assistant at the Department of Obstetrics and Gynecology No. 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University). E-mail: mikhaageev@yandex.ru. 119991, Russia, Moscow, Trubetskaya str., 8-2.
Albert A. Kokin, Head of the Department of Anesthesiology and Intensive Care, Maternity Hospital affiliated to the V.V. Veresaev Clinical Hospital of Moscow City Health Department. E-mail: Alberkokin@yandex.ru. 127247, Russia, Moscow, 800th anniversary of Moscow str., 22.

For citation: Sidorova I.S., Nikitina N.A., Unanyan A.L., Ageev M.B., Kokin A.A. The complement system in preeclampsia-complicated pregnancy.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 8: 5-12 (in Russian)
https://dx.doi.org/10.18565/aig.2021.8.5-12

The complement system in preeclampsia-complicated pregnancy

Sidorova I.S., Nikitina N.A., Unanyan A.L., Ageev M.B., Kokin A.A.

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