Complement activation and regulation in preeclamptic placenta

Abstract

† Anna Inkeri Lokki and Jenni Heikkinen-Eloranta have contributed equally to this work.Preeclampsia (PE) is a common disorder of pregnancy originating in the placenta. We examined whether excessive activation or poor regulation of the complement system at the maternal-fetal interface could contribute to the development of PE. Location and occurrence of complement components and regulators in placentae were analyzed. Cryostat sections of placentae were processed from 7 early-onset PE (diagnosis <34 weeks of gestation), 5 late-onset PE, 10 control pregnancies, and immunostained for 6 complement activators and 6 inhibitors. Fluorescence was quantified and compared between PE and control placentae. Gene copy numbers of complement components C4A and C4B were assessed by a quantitative PCR method. Maternal C4 deficiencies (≥1 missing or nonfunctional C4) were most common in the early-onset PE group (71%), and more frequent in late-onset PE compared to healthy controls (60 vs. 38%). Complement C1q deposition differed significantly between control and patient groups: controls and early-onset PE patients had more C1q than late-onset PE patients (mean p = 0.01 and p = 0.005, respectively). C3 activation was analyzed by staining for C3b/iC3b and C3d. C3d was mostly specific to the basal syncytium and C3b/iC3b diffuse in other structures, but there were no clear differences between the study groups. Activated C4 and membrane-bound regulators CD55, CD46, and CD59 were observed abundantly in the syncytiotrophoblast. Syncytial knots, structures enriched in PE, stained specifically for the classical pathway inhibitor C4bp, whereas the key regulator alternative pathway, factor H (FH) showed a wider distribution in the placenta. Differences in C1q deposition between late-and early-onset PE groups may be indicative of the different etiology of PE symptoms in these patients. Irregular distribution of the complement regulators C4bp and FH in the PE placenta and a higher frequency of C4A deficiencies suggest a disturbed balance between complement activation and regulation in PE.

The complement system and adverse pregnancy outcomes

“…Most studies have examined term placenta available after normal birth or early placenta obtained at abortion. Lokki et al (Lokki et al, 2014) probed for plasma regulators of complement activation in term placenta and demonstrated C4BP evident in syncytial bodies or areas of damaged syncytiotrophoblasts and Factor H in tissue stroma. Buurma (Buurma et al, 2012) clearly documented message for CD46, CD55 and CD59 in placenta during normal pregnancy.…”

Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat

“…Multiple studies demonstrated significantly enhanced systemic complement system activation in preeclamptic pregnancies compared to normal pregnancies (Derzsy et al, 2010; Regal et al, 2015a). Both the placenta and kidney also showed evidence of increased local complement activation in preeclampsia, coincident with up-regulation of message for complement regulators but no evidence of changes in regulator expression using immunohistochemistry have been reported (Burwick et al, 2014; Buurma et al, 2012; Lokki et al, 2014; Penning et al, 2015). However, the event or events that initiate complement activation in preeclampsia are unknown.…”

Nefropatía C1q, Reporte de caso

“…En pacientes trasplantados se ha documentado depósitos de C1q en aloinjerto renal, aunque su prevalencia es baja 0.4%, el papel pronóstico en el paciente transplantado aún no está muy claro [7] En una revisión de Inkeri y cols se menciona que la excesiva activación del complemento y depósitos de C1q en placenta se relacionan con preeclampsia y abortos, a pesar de una evidencia pobre, no descartamos que en la paciente las perdidas recurrentes del embarazo pudieran estar en relación con esta patología [8].…”