Pregnancy Induces an Immunological Memory Characterized by Maternal Immune Alterations Through Specific Genes Methylation

Abstract

During pregnancy, the maternal immune system undergoes major adaptive modifications that are necessary for the acceptance and protection of the fetus. It has been postulated that these modifications are temporary and limited to the time of pregnancy. Growing evidence suggests that pregnancy has a long-term impact on maternal health, especially among women with pregnancy complications, such as preeclampsia (PE). In addition, the presence of multiple immunological-associated changes in women that remain long after delivery has been reported. To explain these long-term modifications, we hypothesized that pregnancy induces long-term immunological memory with effects on maternal well-being. To test this hypothesis, we evaluated the immunological phenotype of circulating immune cells in women at least 1 year after a normal pregnancy and after pregnancy complicated by PE. Using multiparameter flow cytometry (FCM) and whole-genome bisulfite sequencing (WGBS), we demonstrate that pregnancy has a long-term effect on the maternal immune cell populations and that this effect differs between normal pregnancy and pregnancy complicated by PE; furthermore, these modifications are due to changes in the maternal methylation status of genes that are associated with T cell and NK cell differentiation and function. We propose the existence of an “immunological memory of pregnancy (IMOP)” as an evolutionary advantage for the success of future pregnancies and the proper adaptation to the microchimeric status established during pregnancy. Our findings demonstrate that the type of immune cell populations modified during pregnancy may have an impact on subsequent pregnancy and future maternal health.

Next generation of immune checkpoint molecules in maternal‐fetal immunity*

“…Kinder et al showed that a group of fetal‐specific CD8 + T cells functionally exhausted with increased PD‐1 and Lag‐3 expression after pregnancy and maintained protection against fetal loss in subsequent pregnancies 58 . A study by our group also found an increased ratio of PD‐1 + Vδ2 + γδT in women who have experienced PE at least 1 year postpartum 59 . More research is needed to determine whether the PD‐1/PD‐L1 pathway is involved in regulating pregnancy memory.…”

“…58 A study by our group also found an increased ratio of PD-1 + Vδ2 + γδT in women who have experienced PE at least 1 year postpartum. 59 More research is needed to determine whether the PD-1/PD-L1 pathway is involved in regulating pregnancy memory. immunoglobulin V domain (Table 1).…”

Introduction to the immunology of pregnancy

“…The placenta, through cytokines and hormones secreted by trophoblast cells, educate uterine maternal immune cells, 31 and determines the immunological environment at the maternal/fetal interface, as well as at the maternal systemic immune system 32–35 . Interestingly, many of the maternal immunological changes that take place during pregnancy remain after the delivery of the fetus, suggesting a long term effect of the pregnancy on the maternal immune system 36 and another major difference from the original conceptualization of pregnancy as a host/graft immunological process.…”

“…Signals form the embryo will inhibit the expression of chemokines and will shift the phenotype of local macrophages leading to tolerance, placentation and fetal growth by trophoblast educate uterine maternal immune cells, 31 and determines the immunological environment at the maternal/fetal interface, as well as at the maternal systemic immune system. [32][33][34][35] Interestingly, many of the maternal immunological changes that take place during pregnancy remain after the delivery of the fetus, suggesting a long term effect of the pregnancy on the maternal immune system 36 and another major difference from the original conceptualization of pregnancy as a host/graft immunological process. The second explanation proposed by Medawar was a generalized maternal immune suppression, similar to what is induced in transplant patients.…”

Role of NLRP7 in Normal and Malignant Trophoblast Cells

“…The placenta is a highly specialized organ that develops during pregnancy to ensure the growth and the normal progress of the pregnancy. This organ also plays an important role in protecting the fetus from environmental harms, including those emanating from the maternal immune system [ 1 ]. Among important cells that form the placenta is the cytotrophoblast, a cell type capable of strong adaptation to its environment, as it expresses both the maternal and paternal antigens.…”