Relationship between Maternal Immunological Response during Pregnancy and Onset of Preeclampsia
Placentation is defined as 'any intimate apposition or fusion of the fetal organs to the maternal or paternal tissues for physiological exchange'1. It is widespread. material from its father, the fetoplacental unit is not rejected by the maternal immune system because of a unique immunological relationship with the mother. The immunological relationship between the mother and the fetus is a bi- directional communication determined on the one hand by fetal antigen presentation.
Fertility and Sterility 83 3: Human Reproduction 26 American Journal of Reproductive Immunology 63 6: Matzinger P Tolerance, danger, and the extended family. Annual Review of Immunology Medawar PB Some immunological and endocrinological problems raised by the evolution of viviparity invertebrates.
Symposia of the Society for Experimental Biology 7: Human Reproduction 24 8: Nature Reviews Immunology 6: Annals of the New York Academy of Sciences Petroff MG and Perchellet A B7 family molecules as regulators of the maternal immune system in pregnancy. Journal of Embryology and Experimental Morphology A possible role in transfer of immunoglobulin G to the foetus. Trends in Endocrinology and Metabolism 23 1: Voisin G and Chaouat GA Demonstration, nature and properties of antibodies eluted from the placenta and directed against paternal antigens.
Journal of Reproduction and Fertility Voisin GA Immunological facilitation. A broadening of the concept of the enhancement phenomenon. Progress in Allergy Wegmann TG Foetal protection against abortion: Annales d'Immunologie de l'Institut Pasteur American Journal of Reproductive Immunology 30 Jul Epub ahead of print.
Bentham Press, in press. Cell Biology and Immunology. Mor G Immunology of Pregnancy. Simmon C and Pellicer A eds Regulators of human implantation. These investigators demonstrated that uNK cells isolated from first-trimester human decidua express the chemokines IL-8 and IFN-inducible protein IPand that purified human invasive trophoblasts express the chemokine receptors for these ligands: The ability of uNK cells, but not peripheral blood NK cells, to induce trophoblast migration in an in vitro trophoblast migration assay was significantly reduced in the presence of neutralizing antibodies to IL-8 and IP These investigators subsequently performed in vivo studies in which NK cell subsets embedded in Matrigel were injected into the subcutaneous tissues of nude mice, and human trophoblast cells were injected around the Matrigel plug.
These in vivo experiments further demonstrated that uterine, but not peripheral, NK cells promoted trophoblast invasion, and that migration of trophoblast cells into the Matrigel plug was significantly reduced in the presence of IL and IPneutralizing antibodies.
Overall, these studies demonstrated the ability of uNK cells to positively regulate invasion of trophoblast, mediated by the uNK-derived cytokines IL-8 and IP The balance of factors involved in regulation of invasion is not yet precisely determined. Excessive invasion predisposes to placenta accreta, a potentially life-threatening obstetrical condition in which the placenta attaches abnormally to the uterine myometrium.
Role of uNK cells in angiogenesis and vascular remodeling in early pregnancy In humans, extensive vascular remodeling must occur to allow for placentation and establishment of early pregnancy, as well as to support the demands of a growing fetus.
The decidual spiral arteries must be transformed into larger-diameter vessels with low resistance and high flow, capable of transporting nutrients and oxygen to the fetus.
However, it is important to note significant differences among species in terms of strategies to increase blood flow to the site of maternal—placental exchange. In humans, extensive invasion and destruction of preexisting arteries by trophoblast occurs. In nonhuman primates such as rhesus macaques, trophoblastic invasion and modification of uterine arteries occurs, but unlike in humans, invasion of decidual stroma by trophoblast in the rhesus monkey occurs only to a minimal extent.
Nevertheless, there are in vivo studies performed in mice that cannot be performed in humans, and the availability of nonhuman primates for such in vivo studies in early pregnancy is limited. Therefore, much of the existing data on uNK cell functions in vascular remodeling are derived from murine studies.
Multiple murine in vivo studies demonstrate that uNK cells play a critical role in the remodeling of endometrial spiral arteries both prior to and during pregnancy. Multiple vascular abnormalities associated with implantation sites, including thickening of the media and adventitia, endothelial damage, reduction in placental size, and onset of fetal loss at Day 10 of gestation, were demonstrated in NK-cell-deficient mice. Subsequent studies from the same laboratory 38 demonstrated that bone marrow transplantation from severe combined immunodeficient mice which lack T- and B- lymphocytes but not NK cells to NK-cell-deficient mice led to restoration of the uNK cell population in recipients, reduced anomalies in decidual blood vessels, increased placental size, and restored fetal viability.
Overall, these studies provide strong support for a critical role of murine uNK cells in decidualization, placentation, and the appropriate vascularization of implantation sites. Rather, the finding that human uNK cells isolated from first-trimester decidua are a potent source of the angiogenic factors angiopoietin Ang 1, Ang2, VEGF, and PLGF 1633 supports an important role for these cells in the vascular remodeling required for successful human pregnancy.
Supernatants derived from human uterine but not peripheral NK cells promoted in vitro angiogenesis, as demonstrated by an increased ability of human umbilical vascular endothelial cells to form network-like structures, a process inhibited in the presence of VEGF- and PLGF-neutralizing proteins. In addition, these investigators 33 demonstrated the in vivo ability of human uNK cells to promote angiogenesis and growth of human trophoblast choriocarcinoma JEG-3 tumor cells when injected subcutaneously into nude mice.
Influence of maternal immune response on development of the fetal immune system Compelling clinical data demonstrate that children of mothers exposed to certain infectious organisms during pregnancy have significantly higher frequencies of neurological disorders, 44 — 53 including schizophrenia and autism spectrum disorders.
Immunological relationship between the mother and the fetus.
Rodent studies in which the maternal immune system is activated during pregnancy replicate these clinical findings and provide validated mouse models of these disorders. The underlying mechanisms of these phenomena have been studied primarily in prenatal rodent models, in which pregnant dams are injected with either infectious pathogens or synthetic agents that mimic viral or bacterial infections namely, lipopolysaccharides and polyinosinic: Offspring of such immunostimulated pregnant dams exhibit immune dysregulation and behavioral abnormalities, as well as chemical and structural anomalies of the brain, which are similar to those seen in individuals with schizophrenia and autism spectrum disorders.
In each of these models, the adult offspring of immunostimulated dams mounted a more robust inflammatory response than adult offspring of control dams injected with PBS. Our results show that mothers of autistic children in this cohort have significantly higher frequencies of proinflammatory cytokine gene polymorphisms, thereby conferring the genetic capability to respond more vigorously to immune stimulation by producing the types and amounts of cytokines that promote inflammatory reactions.
Moreover, analysis of preliminary data from the offspring indicates that the autistic children of these mothers inherit the maternal genotype.
- The maternal immune system during pregnancy and its influence on fetal development
- Immunological relationship between the mother and the fetus.
- Maternal/Fetal Immune Interactions: Why Doesn’t the Mother Reject the Fetus?
Thus, results obtained from our investigation of the experimental prenatal mouse model of maternal immune stimulation during pregnancy 73 appear to have biological relevance to humans. Maternal—fetal tolerance Billingham et al 1 in were the first to propose the concept of immune tolerance during pregnancy. They hypothesized that the semiallogeneic fetus is able to survive due to regulation of the immunologic interactions between mother and fetus.
Although there is a continuous interaction between the fetus and maternal cells throughout pregnancy, the fetus acts as a privileged site that is protected from immune rejection.
In addition, extracts from Day 80 placentas from mares have been shown to inhibit proliferation of maternal lymphocytes, and coculture of trophoblast cells with maternal lymphocytes caused reduction in proliferation and cytokine production.
On the other hand, the mother must maintain sufficient immune function to fight off infection. One mechanism that plays a role in maintenance of successful pregnancy is a switch from the Th1 cytokine profile to the Th2 profile. This switch is more prominent at the maternal—fetal interface.
Therefore, Th1-type immunity appears to be controlled to avoid overstimulation during pregnancy. Progesterone, estradiol, prostaglandin D2 PGD2and leukemic inhibitory factor generated during pregnancy promote the Th2 profile and are, in part, responsible for the Th2 bias associated with normal pregnancy.
Immune tolerance in pregnancy
Studies indicate increases in Th1 proinflammatory cytokines and reduction in Th2 cytokines in women who are in active labor.
This transcription factor regulates the expression of labor-associated genes such as COX-2, IL-8, and MMP-9 and triggers a cascade of labor-inducing events. Despite the proinflammatory nature of Th1 cytokines, they are essential for successful pregnancy, contributing to timely labor. Several studies have confirmed an increase in Tregs during pregnancy in blood, lymph nodes, and thymus, followed by decrease from midgestation onward until they reach nonpregnant levels at term or shortly thereafter.
They play a critical role in embryo implantation and in the maintenance of the maternal immune tolerance against semiallogeneic fetal antigens. Moreover, they detected higher number of Tregs in pregnant mice from allogeneic versus syngeneic matings, suggesting an involvement of paternal antigens in Treg expansion.
Therefore, both antigen-dependent and antigen-independent mechanisms are likely to be involved in Treg expansion. Tregs express various chemokine receptors whose ligands are expressed at the maternal—fetal interface, which might contribute to chemokine-mediated migration of Tregs to the decidua.
Schumacher et al have shown the importance of human chorionic gonadotropin as one of the main attractants of Tregs to the maternal—fetal interface. Pregnancy proceeded normally when whole lymphocyte populations were transferred. In contrast, lymphocytes depleted of Tregs resulted in fetal resorptions, and there was a massive infiltration of T-cells into the implantation sites. The results of these experiments all demonstrate that in allogenic matings, Tregs are necessary for prevention of a maternal immune response against the fetus.Management of Rh incompatibility between Mother & child - Dr. Rashmi Chaudhary
Clinical manifestations of an altered immune system in pregnancy The notion of pregnancy as an altered state of immune suppression is well documented. This newer theory proposes that the immune system during pregnancy is a functional and active system, wherein not only a maternal immune response exists but also a fetal—placental immune response, which in combination is powerful in defending both the mother and the fetus.
Endocrine regulation of immune cells Hormone concentrations vary with the initiation of pregnancy, and there are specific fluctuations in hormone levels throughout each trimester of pregnancy. In general, pregnancy hormones are thought to suppress maternal alloresponses, while promoting pathways of tolerance. These alterations are discussed in Table 1.
Table 1 Endocrine regulation of immune cells and immune function Abbreviations: Evidence of altered immune function in pregnancy: For example, pregnant women with varicella in the US or Canada fare better than those diagnosed in underdeveloped countries, where resources are limited.
Table 2 summarizes the more commonly recognized and studied pathogens related to pregnancy. As seen in Table 2infectious diseases during pregnancy are associated with not only maternal risks but fetal risks as well.