Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis

Abstract

This article is part of a Special Issue “Neuroendocrine-Immune Axis in Health and Disease.”

During pregnancy, it is evolutionarily advantageous for inflammatory immune responses that might lead to fetal rejection to be reduced and anti-inflammatory responses that promote transfer of maternal antibodies to the fetus to be increased. Hormones modulate the immunological shift that occurs during pregnancy. Estrogens, including estradiol and estriol, progesterone, and glucocorticoids increase over the course of pregnancy and affect transcriptional signaling of inflammatory immune responses at the maternal–fetal interface and systemically. During pregnancy, the reduced activity of natural killer cells, inflammatory macrophages, and helper T cell type 1 (Th1) cells and production of inflammatory cytokines, combined with the higher activity of regulatory T cells and production of anti-inflammatory cytokines, affects disease pathogenesis. The severity of diseases caused by inflammatory responses (e.g., multiple sclerosis) is reduced and the severity of diseases that are mitigated by inflammatory responses (e.g., influenza and malaria) is increased during pregnancy. For some infectious diseases, elevated inflammatory responses that are necessary to control and clear a pathogen have a negative consequence on the outcome of pregnancy. The bidirectional interactions between hormones and the immune system contribute to both the outcome of pregnancy and female susceptibility to disease.

Introduction

The state of pregnancy represents an extreme challenge for the immune system. From the perspective of the pregnant female's immune system, the fetus is an allograft that contains foreign antigens from the father. To support a successful pregnancy, it is evolutionarily advantageous for a pregnant female's immune responses to shift away from inflammatory responses that contribute to fetal rejection and toward anti-inflammatory immune responses that aid in passive transfer of antibodies to the developing fetus (Raghupathy, 1997). Hormones contribute significantly to the shift in immune function that occurs over the three trimesters of pregnancy (Fig. 1). Importantly, pregnant females are not immunosuppressed, but rather their immune responses are biased toward an anti-inflammatory phenotype that influences not only the outcome of pregnancy but disease pathogenesis as well.

The hormonal and immunological changes that occur over the course of pregnancy are necessary to support a healthy pregnancy, but also dramatically affect female susceptibility to autoimmune and infectious diseases. While many studies of autoimmune and infectious disease pathogenesis report changes in immunological factors over the course of pregnancy, few studies consider the role that hormones play in orchestrating these immunological changes. The goals of this review are to: (1) evaluate the immunological shifts that occur during pregnancy; (2) determine the effects of pregnancy-associated hormones, in particular estrogens and progesterone (P4), on innate and adaptive immune responses; (3) provide relevant examples of pregnancy and pregnancy-associated hormones affecting the outcome of diseases caused by pathogens as well as recognition of self-antigens; and (4) identify general principles across diseases that might improve interpretation and treatment for immune-related diseases during pregnancy.