Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia

Abstract

Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE.

Identification of complement factor H variants that predispose to pre‐eclampsia: A genetic and functional study

“…Four of these variants resulted in a dysfunctional FH, which in turn led to a dysregulated complement system 38 . This is in line with recent findings of decreased serum levels of FH in PE in comparison with healthy pregnancy and 1.2% prevalence of CFH variants in PE or HELLP syndrome 39,40 . We describe four missense variants within CFH gene that cause either a quantitative defect (decreased secretion as in R127H and C1077S) or a qualitative defect (normal secretion but defective function, as in R166Q and N1176K).…”

“…38 This is in line with recent findings of decreased serum levels of FH in PE in comparison with healthy pregnancy and 1.2% prevalence of CFH variants in PE or HELLP syndrome. 39,40 We describe four missense variants within CFH gene that cause either a quantitative defect (decreased secretion as in R127H and C1077S) or a qualitative defect (normal secretion but defective function, as in R166Q and N1176K). Of note, the variant R127H has also been described in kidney and eye diseases (aHUS and AMD, respectively) known to be associated with complement overactivation.…”

A longitudinal study of C1q and anti-C1q autoantibodies in homologous and heterologous pregnancies for predicting pre-eclampsia

“…Similar to C1q level, but in contrast to CIC, we found a significantly lower concentration of anti-C1q in PE pregnancies as compared to CTRL (p = 0.0013), especially in the more severe disease (EO). Our results partly contradict a recent study published by Jan Dijkstra and colleagues ( 30 ) that evaluated anti-C1q in maternal sera from women with PE and normal pregnancies using samples from 3 cohorts of patients, collected in the Netherlands, Finland and Norway. Their results showed lower anti-C1q levels only in the Netherlands cohort.…”

Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities

“…Conversely, herein reported results about C1q levels were inconclusive. Dijkstra and colleagues observed no significant differences in serum C1q between PE and control pregnancies in three different cohorts (76),while Agostinis et al reported a decrease in PE patients, both in serum and plasma samples, maybe due to C1q binding to circulating immunocomplexes or to syncytiotrophoblast extracellular vesicles derived from PE placentas (71, 77, 78). C1q reduction is also supported by the findings of Jia et al, both in EOPE and LOPE (29).…”