Increased C4d and Bb immunoreactivity and decreased MBL immunoreactivity characterise first-time pathologic first-trimester miscarriage: a case-control study

Abstract

The role of the complement system in first-time pathologic first-trimester miscarriage was investigated. In this case-control study, tissue samples of 126 women with pathologic miscarriage and termination of normal pregnancies were assessed. The pathologic pregnancy group consisted of 40 women with missed miscarriage, 13 women with incomplete miscarriage and 10 women with a blighted ovum. The control group consisted of 63 normal-appearing pregnancies. Immunoreactivity for C4d, Bb and MBL was evaluated in the deciduas and villous trophoblasts separately using a semi-quantitative histological scoring system (H-score). C4d and Bb H-scores were higher and MBL H-score was reduced in the deciduas and villous tissues from pathologic miscarriage compared to termination of pregnancies (p = .003 and p = .001; p = .011 and p < .001; p < .001 and p < .001, respectively). C4d and Bb activities were increased and MBL activity was decreased in human first-time pathologic first-trimester miscarriage. We suggest that three complement pathways may play a role in human first-time pathologic first-trimester miscarriage. Impact statement Previous studies focussed on complement proteins related to a single complement pathway in cases often associated with antiphospholipid syndrome (APS) or recurrent miscarriage. In APS-related cases, the classical pathway is activated. In antibody-dependent and in antibody-independent mouse models of foetal loss, classical and alternative pathways are activated, respectively. Lectin pathway deficiency has been reported in some recurrent miscarriage. The complement pathway or pathways, which have a role in human pathologic miscarriage was the starting point of this study. There has been no study done till now reporting the role of the three complement pathways in human pathologic miscarriage. In this study, we found increased classical and alternative complement pathway activities and decreased lectin pathway activity in tissues from first-time pathologic human miscarriage.

Serum mannose–binding lectin (MBL) concentrations are reduced in non‐pregnant women with previous adverse pregnancy outcomes

“…MBL seems to play different roles in various pregnancy pathologies. MBL deficiency increases the susceptibility to microbial infections, and it has been reported in first‐time miscarriage, 19 recurrent miscarriage, 20,21 preterm birth, premature rupture of membranes and histological chorioamnionitis, 21 and pre‐eclampsia 21,22 . In contrast, several studies report increased maternal serum levels of MBL in women with pre‐eclampsia and HELLP syndrome, 4,49 which is in agreement with studies describing an active pro‐inflammatory role of high serum MBL concentrations in chronic diseases, such hypoxia ⁄reperfusion injury and microvascular complications in diabetes 50‐53 .…”

“…3 The interaction of EVTs with C1q is strongly inhibited by mannose-binding lectin (MBL), one of the factors increased in pre-eclamptic patient sera. 4 In addition, complement activation is required basis of their history of pregnancy complications, including control patients who had uncomplicated pregnancies and term deliveries (control, n = 33), and three groups of patients with a history of pregnancy complications, including preterm labour (n = 29), recurrent miscarriage (n = 19) or unexplained intrauterine foetal death (IUFD; n = 17). All women enrolled in the study had an interval of three to six months following their previous pregnancy, and they agreed to have a blood sample taken.…”

“…The serum concentrations of MBL increase during pregnancy, and they subsequently fall following delivery. 18 MBL deficiency is associated with various complications of pregnancy, including first-time miscarriage, 19 recurrent miscarriage, 20,21 preterm birth, premature rupture of membranes, and histological chorioamnionitis, 21 and pre-eclampsia. 21,22 We have previously shown that reduced serum MBL levels correlated with the incidence of preterm birth and low birthweight.…”

Clinical and immunological aspects on recurrent pregnancy loss

“…Indeed, it has been shown that trophoblast dysfunction, due to compromised trophoblast infiltration and apoptosis, as well as multiple aberrant signal transduction pathways (64), could lead to adverse pregnancy outcomes, including uRPL (65). In detail, all the impaired pathways previously investigated in RPL trophoblast cells functions (including kisspeptin/GPR54 and PIBF/PR pathways, C4d and Bb, MBL, NOD1 and NOD2 via MAPK/p38 pathway, miR-27a-3p/USP25 axis, Fas and FasL, PKC protein, CCNA2, TWIST, Prototype and Chimera-Type Galectins, miR-520 and PARP1, BMAL1 via SP1-DNMT1/DAB2IP pathway, EIF5A1 via ARAF-mediated activation of integrin/ERK signaling pathway, Stathmin-1, peroxiredoxin2are) are linked to trophoblast migration, proliferation, invasion and apoptosis processes potentially relevant for RPL pathogenesis (64,(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78). Less is known about potential immunological impaired processes induced by trophoblast dysfunction.…”

First‐trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss

“…However, it is not known whether these properties are maintained when using placental tissue from ongoing pregnancies, and whether the properties may be altered in a pathological condition. In uRPL, a compromised trophoblast function has been suggested, 7,8 mainly involving multiple aberrant signal transduction pathways, 7,[9][10][11][12][13][14][15][16][17][18][19][20][21] while their potential immunological dysfunction in uRPL has not been explored.…”