Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction

Abstract

Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly and via mediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine production in vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and anti-trophoblast activities. These cytokine-modulating effects and the PIBF-inducing capabilities of dydrogesterone may contribute to the demonstrated beneficial effects of dydrogesterone in recurrent spontaneous miscarriage and threatened miscarriage. IL-17 and IL-22 produced by T helper cells are involved in allograft rejection, and therefore could account for the rejection of paternal HLA-C-expressing trophoblast. Th17 cells (producing IL-17 and IL-22) and Th22 cells (producing IL-22) exhibit plasticity and could produce IL-22 and IL-17 in association with Th2-type cytokines or with Th1-type cytokines. IL-17 and IL-22 producing Th cells are not harmful for the conceptus, if they also produce IL-4. Another important protective mechanism is connected with the expansion and action of regulatory T cells, which play a major role in the induction of tolerance both in pregnant women and in tumour-bearing patients. Clonally-expanded Treg cells increase at the feto-maternal interface and in tumour-infiltrating regions. While in cancer patients, clonally-expanded Treg cells are present in peripheral blood, they are scarce in pregnancy blood, suggesting that fetal antigen-specific tolerance is restricted to the foeto-maternal interface. The significance of Treg cells in maintaining a normal materno-foetal interaction is underlined by the fact that miscarriage is characterized by a decreased number of total effector Treg cells, and the number of clonally-expanded effector Treg cells is markedly reduced in preeclampsia. In this review we present an overview of the above mechanisms, attempt to show how they are connected, how they operate during normal gestation and how their failure might lead to pregnancy pathologies.

Longitudinal Variations of M. tuberculosis-Induced IFN-γ Responses in HIV-Negative Pregnant Women Exposed to Tuberculosis

“…We observed a decreased IFN-γ production from whole blood T cell ex vivo stimulation with M. tuberculosis -specific antigens in pregnant women independently to their clinical TB groups when compared to their non-pregnant women counterpart with similar childbearing ages. This alteration of the Th1 response in pregnant women is involved in physiological processes known to preserve the fetus ( 4 ). Here the present study showed that the concentrations of IFN-γ produced are lower in pregnant women exposed to M. tuberculosis (latent infection and active TB) compared to those non-pregnant with active TB (ATB) and healthy controls (HC) baseline concentrations.…”

“…The physiological changes during pregnancy result in distinct immune responses that lead to an immunological tolerance toward the fetus characterized by downregulations of both the cell-mediated immunity and the production of Th1 cytokines and an upregulation of both the humoral immunity and the Th2 cytokine productions ( 4 , 5 ). While this maternal immune tolerance protects the fetus from rejection and promote a healthy pregnancy outcome, it may increase the vulnerability against pathogens like TB as the cell-mediated immunity and the Th1 response play key roles in containing the M. tuberculosis infection ( 6 , 7 ).…”

Editorial: Veterinary Reproductive Immunology

“…The proposal of an immunotropic hypothesis ( 51 ) elicited new and exciting concepts to the field of reproductive immunology [( 52 , 53 ), reviewed in ( 54 , 55 )] and elicited controversy ( 56 – 58 ) on the importance of the adaptive immune system in gestation maintenance. The initial concept of a Th1/Th2 balance required for successful gestation further evolved toward the concept of a balance between regulatory T cells (T-reg) ( 59 ) and T-reg/Th17 cells being critical for successful pregnancies ( 60 , 61 ).…”

Learning From Human Responses to Deconditioning Environments: Improved Understanding of the “Use It or Lose It” Principle

“…Thus, the retention of the conditioning imposed by sex hormones likely serve functions regarding reproductive processes. Considerable change occurs during pregnancy, including vascular changes, bone adaptations, and immune/inflammatory responses (discussed in Brislane et al, 2021 ; Capozzi et al, 2021 ; Piccinni et al, 2021 ). For instance, in a rabbit ligament, it has been shown that neurovascular regulation is altered during pregnancy (McDougall et al, 1998 , 2000 ).…”