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

Abstract

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.

Figure 1

During the three trimesters of pregnancy, there is a shift in the balance of proinflammatory and anti-inflammatory responses. By the third trimester, anti-inflammatory responses, including the activity of M2 macrophages, Th2 cells, and regulatory T cells, are elevated and inflammatory responses, including the activity of NK cells, M1 macrophages, and Th1 cells, are reduced. Changes in the concentrations of sex steroids, including estradiol, estriol, and progesterone, lead to the immunological shifts during pregnancy.

Figure 2

Hormonal changes and exposure to fetal antigens during pregnancy skew the maternal immune system toward higher anti-inflammatory responses and away from proinflammatory responses, especially during the third trimester. These immunological changes are necessary for successful pregnancy, but also affect the outcome of disease.