Villitis of Unknown Etiology Is Associated with a Distinct Pattern of Chemokine Up-Regulation in the Feto-Maternal and Placental Compartments: Implications for Conjoint Maternal Allograft Rejection and Maternal Anti-Fetal Graft-versus-Host Disease

Abstract

The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.

CXC Ligand 9 Response to Malaria during Pregnancy Is Associated with Low-Birth-Weight Deliveries

“…During pregnancy, the placenta can be a source of CXCL9 (12). Changes in the levels of CXCL9, CXCL10, CXCL11, and CXCL13 have been previously associated with villitis of unknown etiology (VUE) (12). In immunofluorescence studies, expression of these chemokines in placental tissue is higher during VUE and localizes to Hofbauer cells, stromal cells, and endothelial cells (12).…”

“…Changes in the levels of CXCL9, CXCL10, CXCL11, and CXCL13 have been previously associated with villitis of unknown etiology (VUE) (12). In immunofluorescence studies, expression of these chemokines in placental tissue is higher during VUE and localizes to Hofbauer cells, stromal cells, and endothelial cells (12). Secretion of CXCL9 by macrophages and other cells reflects biologically active IFN-␥, and CXCL9 has been described as a sensitive measure of IFN-␥ activity (2).…”

“…During pregnancy, the placenta can be a source of CXCL9 (12). Changes in the levels of CXCL9, CXCL10, CXCL11, and CXCL13 have been previously associated with villitis of unknown etiology (VUE) (12).…”

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

“…Previously, we demonstrated that the chorioamniotic membranes can recruit T cells, which are implicated in the physiological [14][15][16] and pathological [51][52][53][54][55] processes of labor. Indeed, in vivo activation of T cells through the CD3 complex induces premature labor and delivery [56].…”

VIP contribution to the decidualization program: regulatory T cell recruitment

“…Therefore, the ability of the human endometrium to generate an adequate decidual response based on successive inflammatory events might contribute to the sensitization of the uterine tissues. Under this hypothesis of repeated inflammatory events, it is conceivable that tight immune homeostatic control prior to implantation is required (Kim et al 2009, Weiss et al 2009. In this context, the ability of HESCs to selectively recruit iTregs might contribute to maintenance of immune homeostasis at early stages of implantation.…”