Fas and Fas Ligand Expression in Maternal Blood and in Umbilical Cord Blood in Preeclampsia

Abstract

The Fas-Fas ligand (FasL) pathway of apoptosis is abnormally activated in diseases associated with impaired immune tolerance or chronic inflammation. Pregnancy-related hypertension is a spectrum of disease that commonly causes significant morbidity in women and in their newborn infants, is associated with generalized inflammation, and may be causally related to impaired maternal-fetal tolerance. Our recent observation of enhanced trophoblast expression of FasL in one form of pregnancy-related hypertension led us to hypothesize that this group of disorders might be associated with abnormal activation of the Fas-FasL pathway. To test this hypothesis, we prospectively quantified soluble and leukocyte-associated Fas receptor and FasL in the maternal and umbilical cord blood (CB) sera of 20 gestations complicated by preeclampsia and of 18 normal control gestations, using ELISA and flow cytometric analyses. We determined higher soluble FasL levels in paired maternal and CB sera of hypertensive gestations compared with control gestations (p Ͻ 0.01); in contrast, soluble Fas levels were similar between groups. Surface expression of FasL was lower on maternal (p Ͻ 0.01) and CB (p Ͻ 0.05) neutrophils from affected gestations, whereas surface Fas expression was lower on maternal (p Ͻ 0.02), but not CB, neutrophils and lymphocytes. We conclude that expression of Fas and FasL in sera and on leukocytes is altered in gestations complicated by preeclampsia, and speculate that activation of the Fas-FasL pathway mediates associated pathologic processes in affected women and in their neonates. Activation of the Fas-Fas Ligand pathway involves cellular interactions between the Fas receptor and FasL, and can result in apoptosis or in an inflammatory response (1). The Fas receptor (CD95, Apo-1, FasR), a type I integral membrane protein belonging to the tumor necrosis factor receptor family, is expressed on numerous cell types including hematopoietic cells, and its expression increases during inflammation (1). In contrast, expression of FasL (CD95L), a type II transmembrane molecule belonging to the tumor necrosis factor receptor superfamily, is limited to certain leukocytes and tissues with immune privilege (2). Fas-FasL interactions leading to clonal deletion of antigen-presenting cells have been implicated in the establishment of graft tolerance (3), and provide one explanation for the immune privilege status of certain tissues, including the placenta, cornea, and testis (2). In contrast, abnormal function of the Fas-FasL pathway is involved in the pathogenesis of a variety of disorders, including cytopenias, autoimmune diseases, graft-versus-host disease, and graft rejection (1,(3)(4)(5)(6).Mice with the gld mutation are deficient in FasL function and have smaller litters with decreased viability (7). Studies in these mice suggest that the Fas-FasL pathway contributes to preservation of the fetal allograft by preventing the trafficking of activated leukocytes between the mother and fetus during normal gestation, observations also ...

The CD95/CD95L pathway is involved in phagocytosis-induced cell death of monocytes and may account for sustained inflammation in neonates

“…Former reports on serum sCD95L predominantly revealed decreased levels in cord blood and during the neonatal period as compared with adults and pregnant women (29,30). In view of balancing inflammatory reactions in neonates, we therefore speculate that reduced levels of external death ligands such as CD95L might shift the balance toward prolonged inflammation by insufficient downregulation of immune effector cells, possibly leading to tissue destruction.…”

Soluble Fas and Fas Ligand in Pregnancy

“…[7][8][9] Nevertheless, there is evidence of changes in Fas and FasL that imply a role in preeclampsia. [9][10][11] Furthermore, Fas and FasL may also be involved in the hypertension of pregnancy as Koenig and Chegini reported differential expression of Fas and FasL in fetal membranes, decidua, and placentas from gestations with hypertension than in normal controls. 12 Matrix metalloproteinases are able to cleave FasL, leading to a soluble form measurable in plasma, as reported in preeclampsia, pregnancy, and in the syndrome of hemolysis, elevated liver enzymes, and low platelets.…”

Dissociation between increased apoptosis and expression of the tumor necrosis factor-alpha system in term placental villi with preeclampsia

“…Previous reports have suggested an association between increased placental apoptosis and preeclampsia [10,26]. Increased trophoblast apoptosis reported in preeclampsia may be due to specific mechanisms, including TNF-α and TNF receptor superfamilies [28,29], inasmuch levels of TNF/ TNFR superfamily ligands and receptors [30][31][32] and other cytokines [30,33] stimulating apoptosis have been shown to be increased in preeclampsia. Our results showed an exaggeration of apoptosis in preeclamptic cytotrophoblasts and syncytiotrophoblasts and this is consistent with the findings of Cocker et al [27], who showed differences in apoptotic susceptibility of isolated cytotrophoblasts and syncytiotrophoblasts in pregnancy complicated with preeclampsia [27].…”