Immune Modifications in Fetal Membranes Overlying the Cervix Precede Parturition in Humans

Abstract

In humans, parturition is currently viewed as an intrauterine outbreak of inflammation, accompanied by a massive release of proinflammatory cytokines at the maternal-fetal interface that comprises the maternal decidua, placenta, and fetal membranes. At term, fetal membranes overlying the cervix, the future site of rupture, show altered morphology and are termed the zone of altered morphology (ZAM). These alterations occur in normal fetal membranes during late pregnancy, in preparation for labor. In this study, transcriptome, flow cytometry, electron microscopy, and immunohistochemistry analyses collectively highlight a local shift in gene expression and lymphocyte activation in the ZAM. Just before labor, we show that highly polymorphic HLA-A, -B, and -C determinants of fetal origin are selectively exposed in the ZAM to the maternal immune system. A graft rejection-like program occurs in the ZAM, which involves 1) the activation of cytotoxic decidual NK cells, and 2) the decline of decidual immunotolerant M2-like macrophages. Comparison with a prior cohort of fetal membranes shows that acute inflammation only takes place after these first steps of immune modifications. Our results therefore strongly argue in favor of local immune remodeling at the onset of parturition.

Changes in fetal membrane histology with cervical insufficiency and transabdominal cerclage

“…In addition, the membrane immune pathway also participates in the onset of labor . Innate immune cells mediate the activation of labor by releasing proinflammatory cytokines .…”

Immunobiology of Cervix Ripening

“…This perspective needs to be expanded to understand phenotypic activities by macrophages and other immune cells of lymphoid lineage in the cervix. Moreover, the time course of critical cellular and biomolecular processes in fetal membranes of the so-called zone of altered morphology that overlays the internal os of the cervix (176), as well as within the internal fetal-maternal interface must be integrated to develop a unified mechanism for parturition. Hypotheses generated and tested in various animal models described in this review would help identify the chronology of relevant biomarkers for translational studies and with clinical relevance.…”

Amnion epithelial cell–derived exosomes induce inflammatory changes in uterine cells

“…1–4 Clinical and animal (mainly mouse) studies have identified key roles of specific cytokines, chemokines and immune cell types in the parturition process. 5–15 Endocrine signals arising from the fetus, such as corticotropin-releasing hormone and adrenocorticotropic hormone, are postulated to function as a biologic clock translating organ maturation and triggering labor at term. These hormones are known to have pro-inflammatory effects on various tissues in vitro.…”