Aberrant complement activation in pathological pregnancy
A number of pregnancy complications including recurrent abortion7, premature delivery 8, fetal intrauterine growth restriction (IUGR) 9, hypertensive disorders, preeclampsia (PE) 10, HELLP syndrome11 are associated with aberrant complement activation. And women with inherited or acquired complement system dysfunction is a risk factor of suffering from these pregnancy disorders. Some complement activation products are potential serum and urine biomarkers to predict adverse pregnancy outcomes 12.
Preeclamptic (PE) is a severe and worldwide pregnancy associated disease13, leading to multi-organ dysfunction and sometimes is life-threatening. C5a and membrane attack complex (MAC, sC5b-9) are two strong pro-inflammatory products in complement activation cascade, they significantly elevated in severe PE patients. C5a acts as chemotactic factors to recruit leukocytes 14 and induce proteases, free oxygen radicals and pro-inflammatory cytokines15-17. C5a/C5aR interaction can induce trophoblasts to an anti-angiogenic phenotype. And it inhibits the tube formation and migration 18. MAC can not only mediate lysis and apoptosis of trophoblasts but also induce NOD-like receptor family, pyrin domain containing 3 (NLRP3) activation and then secretion of pro-inflammatory cytokines 19 . An in vivo experiment reinforced this conclusion that C6 knock down can significantly reduce inflammatory processes 20. (Figure 1) Data shew that urinary sC5b-9 level was finely correlated with decreased placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) and increased Soluble fms-like tyrosine kinase-1 (sFlt-1, sVEGFR-1) 21, which forms an anti-angiogenic status and impairs placenta blood vessel formation. Now, C5-C5a axis is a promising target for drug development in complement related pregnancy disorder. It can not only inhibit C5a but also the subsequent generation of MAC.