Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Placental complement component C5 levels are elevated in term preeclampsia - its inhibition does not mitigate placental dysfunction (#461)

Natasha de Alwis 1 , Chloe Miles 1 , Anjali Garg 1 , Lydia Baird 1 , Sally Beard 1 , Natalie K Binder 1 , Tu'uhevaha J Kaitu'u-Lino 2 , Stephen Tong 2 , Lisa Hui 3 4 , Natalie J Hannan 1
  1. Department of Obstetrics, Gynaecology & Newborn Health, Therapeutics Discovery and Vascular Function in Pregnancy Group, The University of Melbourne, Melbourne, Victoria, Australia
  2. Department of Obstetrics, Gynaecology & Newborn Health, Translational Obstetrics Group, The University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Obstetrics, Gynaecology & Newborn Health, The University of Melbourne, Melbourne, Victoria, Australia
  4. Northern Health, Epping, Melbourne, Victoria, Australia

The immune complement system is essential for maintaining immunotolerance in pregnancy. However, complement overactivation is implicated in the serious pregnancy complication, preeclampsia - via elevated circulating complement protein levels. Though complement activation is canonically driven by circulating effector proteins, intracellular complement can regulate inflammation independently. As placental dysfunction is central to preeclampsia pathogenesis, here we determine placental levels of key complement effectors C3, C4 and C5, and assess whether inhibiting complement could mitigate placental dysfunction.

C3, C4 and C5 expression was measured in placental tissue collected from first trimester surgical terminations (7-11 weeks; n=11), early preterm (24-30 weeks; n=15), and term caesarean deliveries (38-39 weeks; n=10) (qPCR). Expression was assessed in placentas from preterm (<34 weeks) and term (>37 weeks) cases of preeclampsia, fetal growth restriction (FGR), and gestation-matched controls (n=10-25/group). Term preeclamptic placentas were treated with 125-1000nM eculizumab (biologic C5 inhibitor) for 48h (n=5). Expression and secretion (Luminex/ELISA) of inflammatory and anti-angiogenic markers elevated in preeclampsia were assessed.

Placental C3 and C4 expression were higher in first trimester compared to later gestation. C5 expression was lower in term compared to preterm placentas. Neither C3 nor C4 expression was altered in preterm or term pathological samples compared to gestation-matched controls. C5 expression was decreased in both preterm preeclampsia and FGR placentas, compared to preterm controls. In contrast, C5 expression was elevated in term preeclamptic placenta compared to term controls and FGR placenta. Eculizumab treatment (all doses) did not alter levels of inflammatory interleukin-1β, interleukin-6 or tumor necrosis factor, nor antiangiogenic factor soluble fms-like tyrosine kinase.

These data demonstrate the distinct placental regulation of complement effectors throughout gestation, and in early and late-onset disease. Inhibiting C5 did not reduce inflammatory or anti-angiogenic factors in the preeclamptic placenta, suggesting that targeting C5 is unlikely to mitigate placental dysfunction in preeclampsia.