Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Abstract

ProblemPreeclampsia affects 3–17% of pregnancies worldwide and has serious consequences for both the mother and the fetus. As maternal–fetal immune tolerance is bidirectional, fetal immunopathology may play a significant role in the pathogenesis of pregnancy disorders. Nevertheless, the impact of preeclampsia on the fetal immune system is unclear.Method of studyIn this case–control study, we examined the phenotype of innate and adaptive immune cells from the cord blood of 3rd trimester babies born to healthy mothers and compared them to cord blood from 3rd trimester babies born to mothers with symptomatic preeclampsia.ResultsThe ratio of CD56hi CD16− non‐activated/regulatory NK cells to CD56lo CD16+ activated/effector NK cells as well as the proportion of CD4+ T cells was significantly decreased in the cord blood of babies born to preeclamptic mothers. The percentage of FoxP3+ Treg, especially the FoxP3lo populations (resting Treg and cytokine Treg), were significantly reduced. Importantly, this reduction in FoxP3+ Treg affected the ratio of CD8+ effector T cells per FoxP3+ Treg in the cord blood of babies born to preeclamptic mothers.ConclusionThese observations indicate that there are significant fetal immune system derangements during preeclampsia.

Placental implantation over prior cesarean scar causes activation of fetal regulatory T cells

“…The complexity of in utero antigen exposure and its subsequent effects are reflected in the fact that the cord blood of only a portion of children whose placentae presented with evidence of Plasmodium infection in the study by Malhotra et al displayed a tolerogenic response, or in fact any response, toward Plasmodium antigens indicating that not all exposures result in fetal immune recognition [19,21]. Further, other maternal disease states such as type 1 diabetes and preeclampsia can also alter the fetal immune system [22,23]. The question raised by our study pertains to mothers infected or possibly even vaccinated during pregnancy who have a uterine scar from either a prior c-section or other surgical intervention: if the placenta abuts the uterine scar, that situation may chronically expose fetuses to infectious agent-or vaccine antigens, an important topic of future research as such exposure may lead to a fetal Treg response with vaccine antigen specificity, that is likely to persist into childhood, and could therefore contribute to subsequent vaccine failure.…”

Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

“…93 However, modification and regulation of NK cells adjusting to an appropriate status are essential to protect pregnant women from any complication. 13,94 Abnormalities in number and activation of NK cells have been related to RSA suggesting a possible pathogenic role of these cells in this condition. 90,[94][95][96] Inhibitory and activating receptors such as killer-cell immunoglobulin-like receptors (KIRs), C-type lectin and natural cytotoxicity receptors appear to be involved in placentation as well as in pregnancy outcome.…”

Abnormal lymphatic vessel development is associated with decreased decidual regulatory T cells in severe preeclampsia

“…18 Tregs are then activated by the MHC/TCR interaction and the CD28-B7 costimulatory system. 21,42,43 Similarly, the distribution of Tregs in the decidua has been reported to be reduced in PE. 13,14 When Tregs fail to function properly, immune homeostasis is disrupted and elicits unnecessary immune responses.…”

“…18 Several groups have investigated the alteration of circulating and decidual Tregs in PE. [19][20][21][22] However, the relationship between lymphangiogenesis and regulatory T cells at the maternal-fetal interface has not been investigated.…”

“…16,17 Tregs must migrate to lymph nodes draining both the uterus and maternal-fetal interface via the lymphatics and must also be activated to promote immune tolerance to an allogeneic fetus. [19][20][21][22] However, the relationship between lymphangiogenesis and regulatory T cells at the maternal-fetal interface has not been investigated. [19][20][21][22] However, the relationship between lymphangiogenesis and regulatory T cells at the maternal-fetal interface has not been investigated.…”