Preeclampsia Is Characterized by Placental Complement Dysregulation

Abstract

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.

Complement Activation and Kidney Injury Molecule-1–Associated Proximal Tubule Injury in Severe Preeclampsia

“…Complement activation likely begins early in pregnancy with local effects at the placental interface, 60,61 but may ultimately become a systemic process 62 because of shedding of apoptotic or aponecrotic fetoplacental debris into the maternal circulation 63,64 with resulting systemic inflammation and endothelial activation. 14,15,17,18 Complement proteins may be filtered through an injured glomerulus and basement membrane 65 or may propagate terminal complement activation locally at the proximal tubule, 66 contributing directly to tubular inflammation (C3a, C5a) and cell death (C5b-9).…”

Urinary Excretion of C5b-9 in Severe Preeclampsia

“…4 Under normal pregnancy conditions, the fetus is protected from maternal immune responses through an array of mechanisms, including trophoblast expression of complement regulatory proteins that inhibit complement at different steps of the activation cascade. 5 However, in women who develop preeclampsia, early placental aberrations affect blood flow and oxygenation to the placenta, thereby predisposing to necrotic shedding of syncitiotrophoblast. 6 The burden of fetoplacental debris becomes exaggerated in severe preeclampsia, [7][8][9][10] propagating a systemic inflammatory response and placing strain on both classical and alternative complement signaling pathways ( Figure 1) as early as the first trimester.…”

Atypical hemolytic-uremic syndrome in obstetric practice: The first Russian experience of diagnosis and treatment

“…В последнее время в литературе начала обсуждаться связь преэклампсии и HELLP-синдрома с генетически обусловленной дисрегуляцией АПК. Было установлено, что при преэклампсии и HELLP-синдроме в большей сте-пени, чем при нормальной беременности, выражена акти-вация как классического пути активации комплемента, так и альтернативного пути, что подтверждается повы-шенным содержанием компонентов С4d и С3а компле-мента в плазме крови, а также мембраноатакующего ком-плекса (МАК) в крови и его депозитов в ткани трофобла-ста [12][13][14][15]. Дальнейшие исследования показали, что при преэклампсии активация АПК предшествует клиниче-ской манифестации данного осложнения.…”