title: Preeclampsia is characterized by placental complement dysregulation.
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.
authors.affiliation: Department of Pathology, Leiden University Medical Center, L1 Q, PO Box 9600, P0-107, 2300 RC Leiden, the Netherlands. a.j.buurma@lumc.nl
authors.forename: Aletta
authors.initials: A
authors.lastname: Buurma
authors.forename: Danielle
authors.initials: D
authors.lastname: Cohen
authors.forename: Kimberley
authors.initials: K
authors.lastname: Veraar
authors.forename: Dorrith
authors.initials: D
authors.lastname: Schonkeren
authors.forename: Frans H
authors.initials: FH
authors.lastname: Claas
authors.forename: Jan A
authors.initials: JA
authors.lastname: Bruijn
authors.forename: Kitty W
authors.initials: KW
authors.lastname: Bloemenkamp
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D018958:CD55 Antigens / Q000235:genetics; D018957:CD59 Antigens / Q000235:genetics; D015922:Complement C1q / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000378:metabolism; D037601:Mannose-Binding Lectin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011414:Properdin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D018958:CD55 Antigens; D018957:CD59 Antigens; C507497:KRT7 protein, human; D053552:Keratin-7; D037601:Mannose-Binding Lectin; D010446:Peptide Fragments; D011414:Properdin; D015922:Complement C1q; D015935:Complement C4b; C032261:complement C4d; D003165:Complement System Proteins