The immune system destroys infected cells and rebuilds tissue.71 Similar processes are driven by hormones. In women, during the 9 days preceding ovulation (the proliferative phase) the endometrium becomes built up, highly vascularized and infiltrated with small NK cells.72,73 Ovulation defines the beginning of the 14-day secretory phase during which NK cells proliferate and differentiate. In the secretory phase, an embryo can implant or die off, in the presence or absence of NK cells, respectively. Upon implantation of an embryo, the menstrual cycle is broken and pregnancy starts.
Whereas NK cells represent approximately 10% of cells in peripheral blood, uterine NK cells constitute 60% to 90% of the leukocytes in the decidua, a tissue in which B lymphocytes and T lymphocytes are rare. Two types of NK cells are distinguished, those expressing low levels of CD56 and specialized in cytolysis, and those expressing high levels of CD56 and involved in cytokine secretion.74 Uterine NK cells express the highest amount of CD56.75
Cortisol, an adrenocortical hormone in humans suppresses the immune system and directly inhibits NK cell activity.76–78 Conversely, prolactin, a 24 kDa single chain hormone secreted by the anterior pituitary gland, is an immunostimulatory “cytokine”79,80 that directly affects NK cell function.81
NK cell cytolytic activity decreases significantly during pregnancy and NK cytotoxic activity defect has been reported in pregnant women.82,83 We measured NK cell cytotoxicity in peripheral venous blood samples obtained from pregnant Gabonese women at the time of delivery. The NK cell-mediated cytotoxicity against P. falciparum-infected erythrocytes in vitro was lower in samples obtained from primiparous women than in multiparous ones.84 However, these findings were discussed and contested by Pearson.85 He supported the “prolactin hypothesis” and pointed out that labor was not an appropriate time to assay for prolactin levels because they naturally fall 24 hours preceding the onset of delivery. Nevertheless, we and others have demonstrated that the surface expression and function of the triggering receptors responsible for NK-mediated recognition and killing of tumor cells is regulated by hormones.85,86 Prolactin selectively upregulates the surface expression of NKp46 and NKp30. In contrast, cortisol downregulates the expression of NKp30.86 Our data are interesting because NKp30 acts together with NKp46 to induce cytotoxic activity against a variety of target cells. These results have important implications for the understanding of the involvement of NK cells in the susceptibility of pregnant women to P. falciparum malaria. Pregnant women living in endemic areas are most susceptible to malaria between the second trimester and the early postpartum period.87
We recently reported that cortisol and prolactin concentrations increase during pregnancy, regardless of parity. We found that cortisol concentrations were higher in primigravidae than in multigravidae, and also higher in P. falciparum-infected primigravidae than in uninfected primigravidae throughout pregnancy and at the time of delivery.88 We showed that prolactin concentration did not differ according to P. falciparum status. The low NK cell cytotoxic activity we found was correlated with high cortisol concentrations. Some studies have found that exogenous cortisol suppresses NK cell cytotoxicity89 and that subphysiological concentration of cortisol results in direct functional inactivation.74,75 Moreover, the surface density of natural cytotoxicity receptors is directly correlated with the magnitude of NK cell cytolytic activity against several target cell types.90 We, therefore, hypothesize that the difference in NK cell cytotoxic activity against P. falciparum-infected erythrocytes observed between primiparous and multiparous women can be partially explained by the difference in cortisol concentrations found in these two groups of pregnant women.