Endocrine factors modulating immune responses in pregnancy

Abstract

How the semi-allogeneic fetus is tolerated by the maternal immune system remains a fascinating phenomenon. Despite extensive research activity in this field, the mechanisms underlying fetal tolerance are still not well understood. However, there are growing evidences that immune-immune interactions as well as immune-endocrine interactions build up a complex network of immune regulation that ensures fetal survival within the maternal uterus. In the present review, we aim to summarize emerging research data from our and other laboratories on immune modulating properties of pregnancy hormones with a special focus on progesterone, estradiol, and human chorionic gonadotropin. These pregnancy hormones are critically involved in the successful establishment, maintenance, and termination of pregnancy. They suppress detrimental maternal alloresponses while promoting tolerance pathways. This includes the reduction of the antigen-presenting capacity of dendritic cells (DCs), monocytes, and macrophages as well as the blockage of natural killer cells, T and B cells. Pregnancy hormones also support the proliferation of pregnancy supporting uterine killer cells, retain tolerogenic DCs, and efficiently induce regulatory T (Treg) cells. Furthermore, they are involved in the recruitment of mast cells and Treg cells into the fetal-maternal interface contributing to a local accumulation of pregnancy-protective cells. These findings highlight the importance of endocrine factors for the tolerance induction during pregnancy and encourage further research in the field.

Keywords: alpha-fetoprotein; estradiol; human chorionic gonadotropin; immune regulation; luteinizing hormone; pregnancy; progesterone.

Figure 1

Hypothetical scenario presenting the influence of pregnancy-associated hormones on innate immunity. The scenario suggests several mechanisms by which E2, P4, and hCG influence innate immune cells and thereby support pregnancy success. ER, estrogen receptor; GR, glucocorticoid receptor; IDO, indoleamine 2,3-dioxygenase; IL-1, interleukin-1; IL-10, interleukin-10; LH/CG-R, luteinizing hormone/chorionic gonadotropin receptor; NO, nitric oxide; PIBF, progesterone-induced blocking factor; PR, progesterone receptor; VEGF, vascular endothelial growth factor.

Figure 2

Hypothetical scenario presenting the influence of hormonal changes taking place during the reproductive cycle on the distribution of innate and adaptive immune cell populations in the uterus. The upper part of the scenario displays the accumulation of different immune cell populations in uterine tissue correlated with the different phases of the human menstrual cycle and the murine estrus cycle. The lower part of the scenario displays hormonal changes taking place during the reproductive cycles, both in humans and mice.

Figure 3

Hypothetical scenario presenting the influence of pregnancy-associated hormones on adaptive immunity. The scenario suggests several mechanisms by which E2, P4, and hCG influence adaptive immune cells and thereby support pregnancy success. AABs, asymmetric antibodies; ER, estrogen receptor; IDO, indoleamine 2,3-dioxygenase; IL-10, interleukin-10; LH/CG-R, luteinizing hormone/chorionic gonadotropin receptor; PIBF, progesterone-induced blocking factor; PR, progesterone receptor.