NK cell frequency and cytotoxicity in correlation to pregnancy outcome and response to IVIG therapy among women with recurrent pregnancy loss

Abstract

Background Recurrent miscarriage (RM) has a multifactorial etiology mainly due to chromosomal abnormalities and immunological factors. Treating RM has remained to be a challenging issue and the role of intravenous immunoglobulin (IVIG) in treating RM is still controversial. Materials and Methods This study aimed to evaluate the changes in natural killer (NK) cells’ frequency and cytotoxicity in patients with RM who received the IVIG therapy. A total of 78 women with a history of three or more recurrent miscarriages were included and their peripheral blood was drawn in case of positive pregnancy test. On the same date, 400 mg/kg of IVIG was administrated intravenously in 38 women and it continued every four weeks through weeks 30–32 of gestation. The remaining 40 patients with RM were included to be the untreated control group. Then, the effects of IVIG on NK cell frequency, cytotoxic activity, and the expression of inhibitory and activating receptors in the patients with RM, pre and posttreatment were assessed. Results NK cells percentage and cytotoxicity were significantly reduced in the IVIG‐treated patients after 32 weeks of gestation (p < 0.0001). Expression levels of inhibitory receptors was increased, however, the expression levels of activating receptors were significantly decreased after the IVIG therapy. Pregnancy outcome after the treatment was significantly higher (86.8%) in the IVIG‐treated patients than controls (45%; p = 0.0006). Conclusion Our results suggested that women with RM may benefit from IVIG as a therapeutic approach and the frequency and functional status of peripheral NK cells may serve as a valuable predictive factor of therapy response.

The exploration of Hashimoto's Thyroiditis related miscarriage for better treatment modalities

“…However, instead of dNK cells, the high levels of CD16 + CD56 dim NK cells derived from other body parts through blood circulation can impair maternal tolerance to the fetus. As shown in most recent studies, the percentage of peripheral CD3 − CD56 + CD16 + NK dim cells in women with RM is higher than that in healthy controls (p< 0.0001) [75]. Thus, altogether, these results imply that the abnormal activation of CD56 dim NK cells under HT conditions may share the same cytotoxic effects on the fetus during gestation and lead to early miscarriage in women.…”

“…Additionally, the birth rate in the IVIG group was significantly higher than that in the control group (87.5% vs. 41.6%, p<0.0001). Furthermore, in another study [75], the authors demonstrated that IVIG could decrease the number of NK cells and the activating receptors KIR2DS1, KIR2DS4, and NKG2D in women with RM. As some research concluded, low-dose (0.2 g/kg) IVIG therapy can significantly increase the live birth rate in women with HT by rebalancing the functions of the immune system [142,143].…”

Natural Killer cells role in embryonic implantion

“…After implantation T and B cells become sporadic (10%), mast cells and eosinophils become rare and there is a predominance of NK and macrophages (10 to 15%). 10,20,21 Because they are located in different body regions, NK does not exhibit the same receptor parameters. In view of this, when present in uterus are named uterine NK (uNK) and blood NK when found in peripheral blood.…”

“…In view of this, when present in uterus are named uterine NK (uNK) and blood NK when found in peripheral blood. 21,22 Uterine natural killer cells More than 100 years ago, literature describes the presence of granular cells in uterine mucosa of pregnant women. In vitro studies have determined that these cells belong to NK lineage.…”

The role of lymphocytes in fetal development and recurrent pregnancy loss

“…IVIG treatment significantly lowered peripheral NK cell cytotoxicity and frequency. Investigators did not asses uterine NK population [24].…”