Abstract-Increasing evidence suggests that preeclampsia is associated with complement dysregulation. The origin of complement dysregulation in preeclampsia is unknown, and further unraveling this mechanism could provide both diagnostic tools and therapeutic targets. Because the placenta is believed to play a crucial role in the pathogenesis of preeclampsia, we investigated placentas from preeclamptic women (n=28) and controls (n=44) for the presence of complement activation products. Immunohistochemistry was performed for C1q, mannose-binding lectin, properdin, and C4d. Staining patterns were related to pregnancy outcome. Possible causes of complement activation were investigated, including the presence of immune deposits at the syncytiotrophoblast and changes in the placental mRNA expression of complement regulatory proteins. C4d was rarely present in placentas from healthy controls (3%), whereas it was observed in 50% of placentas obtained from preeclamptic women (P=0.001). In these placentas, C4d was observed in a focal (9/14) or diffuse (5/14) staining pattern at the syncytiotrophoblast. With respect to C1q, mannose-binding lectin, and properdin, no differences were observed between cases and controls. In preeclamptic women, diffuse placental C4d was associated with a significantly lower gestational age at delivery. Furthermore, the mRNA expression of the complement regulatory proteins CD55 and CD59 was significantly upregulated in preeclampsia. In conclusion, there is evidence for increased classical pathway activation and altered complement regulation in preeclampsia. The relation between C4d and lower gestational age at birth suggests that the extent of complement dysregulation is associated with the severity of preeclampsia. Inhibiting excessive complement activation may be a promising therapeutic approach in the management of preeclampsia.
Recurrent miscarriage, fetal growth restriction and intrauterine fetal death are frequently occurring complications of pregnancy in patients with systemic lupus erythaematosus (SLE) and antiphospholipid syndrome (APS). Murine models show that complement activation plays a pivotal role in antiphospholipid antibody-mediated pregnancy morbidity, but the exact pathways of complement activation and their potential role in human pregnancy are insufficiently understood. We hypothesized that the classical pathway would play a major role in inducing fetal loss. Pregnant C57BL/6 mice and mice deficient in C1q and factor D were injected with antiphospholipid antibodies or normal human IgG. Mouse placentas were subsequently stained with an anti-C4 antibody and anti-normal human IgG to determine the presence of classical complement activation and IgG binding. Findings in mice were validated in 88 human placentae from 83 women (SLE and APS cases versus controls), which were immunohistochemically stained for C4d, C1q, properdin and MBL. Staining patterns were compared to pregnancy outcome. In murine placentae of mice pretreated with antiphospholipid antibodies, increased C4 deposition was observed, which was associated with adverse fetal outcome but not with IgG binding. In humans, diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS (p < 0.001) and was related to intrauterine fetal death (p = 0.03). Our data show that presence of C4d in murine and human placentae is strongly related to adverse fetal outcome in the setting of SLE and APS. The excessive deposition of C4d supports the concept of severe autoantibody-mediated injury at the fetal-maternal interface. We suggest C4d as a potential biomarker of autoantibody-mediated fetal loss in SLE and APS.
BACKGROUND Pre-eclampsia has a clear familial component, suggesting that the condition may be partly attributable to genetic susceptibility. The search for susceptibility genes has led to a drastic increase in the number of published studies associating genetic factors with pre-eclampsia. However, attempts to replicate these findings have yielded inconsistent results. This meta-analysis assessed the pooled effect of each genetic variant that is reproducibly associated with pre-eclampsia. METHODS Studies that assessed the association between genes and pre-eclampsia were searched in PubMed, Embase and Web of Science. We selected all genetic variants that were significantly associated with pre-eclampsia in an initial study and were subsequently independently reproduced in at least one additional study. All studies that assessed these reproduced variants were then included. The association between genetic variants and pre-eclampsia was calculated at the allele level, and the main measure of effect was a pooled odds ratio in a random-effects model. RESULTS The literature search yielded 2965 articles, of which 542 investigated genetic associations in pre-eclampsia. We identified 22 replicated genetic variants, of which 7 remained significantly associated with pre-eclampsia following meta-analysis. These variants were in or near the following genes: ACE, CTLA4, F2, FV, LPL and SERPINE1. CONCLUSIONS This meta-analysis identified seven genetic variants associated with pre-eclampsia. Importantly, many of these variants are also risk factors for developing cardiovascular disease, revealing that pre-eclampsia and cardiovascular disease have shared genetic risk factors. The contribution of the identified genetic variants in the pathogenesis of pre-eclampsia should be the focus of future studies.
A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 non-pregnant controls with hypertension. The samples were immunostained for C4d, C1q, MBL, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d—a stable marker of complement activation—and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 (sFlt-1) mouse model of preeclampsia. The kidneys in the sFlt-1–injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that sFlt-1–injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia.
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