Dual Positive Regulation of Embryo Implantation by Endocrine and Immune Systems – Step‐by‐Step Maternal Recognition of the Developing Embryo

Abstract

In humans, HCG secreted from the implanting embryo stimulates progesterone production of the corpus luteum to maintain embryo implantation. Along with this endocrine system, current evidence suggests that the maternal immune system positively contributes to the embryo implantation. In mice, immune cells that have been sensitized with seminal fluid and then the developing embryo induce endometrial differentiation and promote embryo implantation. After hatching, HCG activates regulatory T and B cells through LH/HCG receptors and then stimulates uterine NK cells and monocytes through sugar chain receptors, to promote and maintain pregnancy. In accordance with the above, the intrauterine administration of HCG-treated PBMC was demonstrated to improve implantation rates in women with repeated implantation failures. These findings suggest that the maternal immune system undergoes functional changes by recognizing the developing embryos in a stepwise manner even from a pre-fertilization stage and facilitates embryo implantation in cooperation with the endocrine system.

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

“…Activation and expansion of Tregs which, in turn, creates a uterine microenvironment favorable for embryo implantation and enhances maternal tolerance towards paternal MHC antigens [21,54,[65][66][67] Induction and expansion of tolerogenic DCs phenotype Involved in the control and activation of Tregs [33,54,68,69] Reduced production of IL-12 by DCs Priming of decidual CD4+ cells into a Th2 phenotype [70,71] EVT cells express HLA-C, HLA-E, and HLA-G but not HLA-A and HLA-B Lack of expression of MHC molecules by syncytiotrophoblasts Inhibition of cytolytic activity of dNK cells against the trophoblasts Induction of NK senscence-Enhanced apoptosis of activated CD8+ cells [70,[72][73][74][75] Trophoblast production of exosomes Downregulation of maternal immunity towards the trophoblast [76] Development of a specific cytokine and chemokine network in the endometrium and decidua Achievement of a correct immune cell recruitment and dialogue favoring embryo implantation and proper pregnancy evolution [77] Presence of asymmetric maternal Abs against paternal antigens Bind trophoblast but are unable to trigger destructive immune response [78] Increased production of PIBF Upregulation of Th2 cytokines production. Downregulation of dNK activity.…”

“…Increase the production of Glycodelin A which induces apoptosis in T cells. These effects can contribute to trophoblast immune protection [66,79] Increased progesterone production in LP and in pregnancy Expansion of Tregs and enhancement of their immunosuppressive actions [33,78] hCG production by syncytiotrophoblast Recruitment of Tregs at the maternal-fetal interface [80] EVT: extravillous trophoblast; HLA: human leukocyte antigen; MHC: major histocompatibility complex; Mϕ: macrophages; DC: dendritic cells; PIBF: progesterone induced blocking factor; LP: luteal phase; hCG: human chorionic gonadotropin; Abs: asymmetric antibodies.…”

Continuous model of conceptus implantation to the maternal endometrium

“…It should be noted, however, that CG in humans (hCG) may not be the only factor maintaining P4 production because the administration of hCG alone does not prevent CL regression in non-pregnant women (Quagliarello et al 1980). Evidence accumulated suggests that endocrine as well as immune systems control CL function in humans and possibly other mammalian species (Fujiwara et al 2016).…”

Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells

“…17 Accumulating evidence supports the involvement of human chorionic gonadotropin (hCG) in the function and differentiation of immune cells; in turn, the tissue-resident immune cells, along with hormones, positively regulate the uterine microenvironment and embryo implantation. 18 Upon stimulation with hCG, the AKT and ERK pathways induce the luteinizing hormone/choriogonadotropin receptor (LH/CG-R)-mediated proliferation, differentiation, and survival of target cells. 19,20 Intriguingly, hCG promotes uterine NK cell proliferation through mannose receptors but not through LH/ CG-R because NK cells do not express LH/CG-R.…”