Decidual Lymphocytes of Human Spontaneous Abortions Induce Apoptosis but Not Necrosis in JEG-3 Extravillous Trophoblast Cells1

Abstract

The human decidua contains an unusually high proportion of lymphocytes, mainly NK and T cells, which are potentially cytotoxic to the trophoblast when they are stimulated with certain cytokines. Given the high incidence of spontaneous abortion in humans and other species, our working hypothesis is that decidual lymphocytes are involved in immunological mechanisms that attack the trophoblast and induce abortion when any gestational problem arises. To test this hypothesis, flow cytometry was used to compare decidual lymphocyte populations in first-trimester spontaneous abortions and elective terminations of first-trimester pregnancy. We found significantly higher proportions of decidual lymphocytes that expressed activation markers, and of T cells (mainly T helper cells) in spontaneous abortions than in elective terminations of pregnancy. Decidual lymphocytes from spontaneous abortion, like decidual lymphocytes from elective termination of pregnancy and peripheral blood lymphocytes, were however, unable to lyse the JEG-3 extravillous cytotrophoblast cell line in a (51)Cr-release assay. Nevertheless, decidual lymphocytes from spontaneous abortion, unlike decidual lymphocytes from elective termination of pregnancy and peripheral blood lymphocytes, induced apoptosis in JEG-3 cells as determined by DNA fragment-release assay. Hematoxylin and eosin staining showed a significantly higher proportion of apoptotic JEG-3 cells when these cells were treated with decidual lymphocytes from spontaneous abortion than when JEG-3 cells were cultured with decidual lymphocytes from elective termination of pregnancy. The ultrastructural signs of apoptosis were confirmed by electron microscopy. These data support the hypothesis that activated decidual lymphocytes participate in human spontaneous abortion by inducing apoptosis but not necrosis of the trophoblast.

Embryonic Resorption and Polycyclic Aromatic Hydrocarbons: Putative Immune-mediated Mechanisms

“…High peripheral NK activity [Matsubayashi et al 2005] and elevated IFNg secretion from peripheral blood mononuclear cells [Lee et al 2005] have been reported to be associated with recurrent pregnancy loss. In addition, decidual lymphocytes collected from early miscarriages exhibited a significantly greater capacity to kill cultured trophoblast cell lines in comparison to decidual lymphocytes from age-matched, elective abortions [Olivares et al 2002]. In humans, CD56 bright CD16…”

Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4

“…Thus, the accurate function of trophoblasts is crucial to normal pregnancy. It has been demonstrated that an insufficient proliferation or increased apoptosis of trophoblasts is highly linked with both murine and human pregnancy failure (Qumsiyeh et al 2000, Olivares et al 2002, Greer 2003, Burdon et al 2007. The interesting point is that our work showed that the expression of PCNA of ectoplacental-derived trophoblastic cells increased and the level of Annexin V in these cells decreased after CsA treatment at the window of murine implantation, compared with the non-treated abortion-prone matings, suggesting that this drug presents a favorable effect on murine trophoblasts via promoting proliferation and suppressing apoptosis of these cells.…”

“…Therefore, CsA may present different effects on different cells via different signaling pathways, and the pharmacological action of this drug is far from being completely understood and deserves further investigation. It is evident that the decidual local and peripheral lymphocytes are overactivated and produce aberrant Th1-related cytokines in spontaneous abortion, leading to extensive destruction of the trophoblast by inducing apoptosis (Hill et al 1995, Abadia-Molina et al 1996, Bates et al 2002, Olivares et al 2002. Thus, it is proposed that CsA might modulate the biological function of trophoblast cells in vivo in both a direct (MAPK signaling pathway) and an indirect manner suppressing lymphocyte activation by down-regulating co-stimulatory molecules, which are all beneficial to the improvement of trophoblast functions in the abortionprone matings.…”

Granulysin Produced by Uterine Natural Killer Cells Induces Apoptosis of Extravillous Trophoblasts in Spontaneous Abortion

“…1,2 However, direct evidence that cytotoxic T cells or natural killer (NK) cells cause apoptosis in extravillous trophoblasts (EVTs) has not been reported in humans, and little is known about the precise mechanism of apoptosis in EVTs of spontaneous abortion. Namba et al showed that interleukin (IL)-2R␤ (CD122)-overexpressing transgenic mice showed 100% viable fetuses at gestational day 8 but 100% fetal death at gestational day 12, and proposed that excessive activation of uterine NK (uNK) cells can cause abortion.…”

“…6 Once balance is lost, excessive activation signals may induce trophoblast lysis by these activating NK cells. 2,7 Hyperactivated NK cells release cytolytic granules such as granzymes and granulysin through perforin-induced pores. The distribution of perforin-positive uNK cells is essentially the same between normal and abortion model mice, 8 although a slight elevation of perforin-positive uNK cells in human sporadic miscarriage with a normal fetal chromosomal karyotype has been reported.…”