Immunology at the Maternal-Fetal Interface

Function

Decidualization and placentation are vital processes that establish the maternal-fetal interface, creating a supportive environment for embryonic development and implantation. Decidualization involves the transformation of endometrial stromal cells into specialized decidual cells, accompanied by the recruitment of leukocytes and the release of cytokines that regulate maternal tolerance and immune responses. Placentation enables nutrient exchange, protects against harmful antigens, and supports fetal growth, while ensuring placental immune defense to maintain a delicate balance between tolerance and protection.

Decidua Formation 

The decidua is a transitory interface that is present only during pregnancy. Decidua is derived from the uterine endometrium and is located between the myometrium and fetal membranes. Pre-decidualization occurs during the luteal phase of the menstrual cycle under the influence of estrogen and progesterone. However, implantation must occur before pre-decidualization is complete. Any disturbance in the decidualization process can lead to implantation failure.

The decidua is crucial in 3 vital components of the maternal-fetal interface, as mentioned below. 

Immune tolerance: Decidual cells are the first cells at the fetal-maternal interface to encounter fetal antigens. The 2 distinct immune interfaces are critical in maintaining immune tolerance.

• The first immune interface develops early in the first trimester and consists of decidual immune cells, trophoblastic cells from fetal villi, decidual stromal cells, and the spiral artery.
• The second immune interface forms as early as 8 weeks of gestation, comprising immune cells from the maternal circulation and syncytial trophoblast cells from the placental chorion.

Trophoblast invasion: Trophoblastic cells are derived from the blastocyst of the embryo, which lies between the embryo's external layer and the uterine layer. These trophoblasts differentiate into villous and extravillous trophoblast cells. During implantation, invading trophoblasts anchor the blastocyst to the decidua, initiating placentation. Trophoblast invasion can also occur in organs outside the uterus, such as the fallopian tubes, leading to an ectopic pregnancy.[4] 

Spiral arterioles remodeling: After implantation, fetal trophoblast and maternal leukocytes induce the remodeling of the spiral arteries, which involves the erosion of the fibrinoid wall and dilation of the vessels. This remodeling allows the placenta to be perfused with maternal blood, facilitating the exchange of nutrients and waste removal essential for placental function.

Placenta Development

The placenta is usually formed entirely by the third week of gestation and comprises anchoring and floating villi. The placenta has an external syncytiotrophoblast layer and an internal cytotrophoblast layer. The cytotrophoblast layer forms a significant barrier between the fetal and maternal compartments. By the second trimester, the layer gradually thins, and functionally, the placenta becomes hemomonochorial, with only a single layer of syncytiotrophoblast facilitating maternal-fetal exchange. 

Leukocytes at the Maternal-Fetal Interface

Maternal leukocytes at the maternal-fetal interface are recruited by cytokines produced by decidual stromal cells and trophoblasts. The majority consist of decidual natural killer (NK) cells (70%) and decidual macrophages (20%), with regulatory T cells (Tregs) comprising the remaining 10%.[5]

• Decidual NK cells contribute to decidualization and implantation. Decidual NK cells contribute to spiral artery remodeling and promote trophoblast invasion through cytokines such as interleukin (IL)-8. As pregnancy progresses, the number of decidual NK cells gradually declines, and they become less granulated.[6]

• Decidual macrophages act as antigen-presenting cells. IL-10 and macrophage colony-stimulating factor, secreted by trophoblasts, recruit decidual macrophages. These macrophages differentiate into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. At the maternal-fetal interface, M2 macrophages are predominant and have a key role in remodeling the spiral arteries and facilitating trophoblast invasion. Vascular endothelial growth factor and matrix metalloproteinase secreted by decidual macrophages promote angiogenesis and tissue remodeling. Decidual macrophages also have an essential function in the phagocytosis of apoptotic trophoblasts. Additionally, decidual macrophages are essential for protecting the fetus against infections.

• Treg cells promote maternal tolerance to fetal antigens and help maintain a stable environment for fetal survival. Additionally, Treg cells are crucial in downregulating the inflammatory response to support the implanting embryo.

T-Helper Type-2 Cytokines 

At the maternal-fetal interface, the maternal immune response shifts toward T-helper type-2 (Th2) and antibody-mediated immunity rather than cell-mediated immunity. Th2 cytokines, including IL-4, IL-5, and IL-10, increase in this region, promoting an anti-inflammatory state that supports the semi-allogenic fetus during pregnancy. An infective or noninfective insult at the placental level, triggering the secretion of pro-inflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-alpha (TNF-α), can lead to placental damage and result in complications such as preterm labor, abortion, or preeclampsia.[7]

Human Leukocyte Antigen-G

Human leukocyte antigen-G (HLA-G) is expressed by extra-villous trophoblasts and is crucial in embryo implantation. HLA-G promotes vascular permeability and angiogenesis, aiding in the remodeling of the spiral arteries. Additionally, HLA-G stimulates NK cells to release growth factors that support fetal growth. Lower levels of HLA-G have been associated with pregnancy complications such as placental abruption, preeclampsia, and recurrent miscarriages.[8]

Maternal Tolerance

Maternal tolerance is essential for a successful pregnancy, enabling the pregnant woman to carry her fetus despite the presence of foreign fetal antigens. When maternal tolerance fails, it can lead to complications such as miscarriage and preeclampsia. Modulation of the leukocyte profile at the maternal-fetal interface supports this tolerance. An imbalance, with an excess of decidual NK cells compared to T cells, may result from epigenetic silencing of T-cell chemoattractants in the stromal cells of the decidua. Cytokines such as IL-10 and transforming growth factor-beta (TGF-β) promote the differentiation of existing T cells into Treg cells in the decidua. Apoptosis also contributes to immune privilege. IL-10 and TGF-β, secreted by decidual macrophages, are crucial in preventing fetal rejection and supporting fetal growth throughout pregnancy, up until delivery.[9]

Placental Immune Defense

The placenta uses various defense mechanisms to protect the fetus from most infections, including:

• The structural integrity of the placenta serves as its primary defense. The external syncytiotrophoblast layer lacks cellular junctions and features a dense cytoskeletal network, which forms a robust brush border at the apical surface. These anatomical features work together to provide protection against pathogens.
• Antiviral cytokines secreted by the placenta also play a crucial role in immune defense. Interferon-gamma (IFN-γ), produced by the syncytiotrophoblast layer, is a key cytokine in restricting viral infections.[10]
• Toll-like receptors expressed on the trophoblast mediate the anti-infective signaling pathway.
• Immunoglobulin-G receptors expressed on the syncytiotrophoblast layer have a significant role in actively transporting protective maternal antibodies to the fetus. This active transport begins in the second trimester and gradually increases throughout the pregnancy, with the highest peak at term.

Issues of Concern

The maternal-fetal interface is crucial for the maintenance of pregnancy and serves 2 primary functions:

• The interface facilitates the exchange of nutrients and oxygen between the mother and fetus.
• The interface aids in the removal of waste products, ensuring a stable environment for fetal development.
• The interface protects the growing fetus from the extrauterine environment, including infections.

Disruptions in trophoblast invasion can lead to complications for both the mother and fetus. Impaired development of the maternal-fetal interface may result in implantation failure, infertility, recurrent miscarriage, or intrauterine growth restriction (IUGR).[11][12] The trophoblast invasion is superficial in preeclampsia when compared to unaffected pregnancies.[13] In patients with unexplained infertility, endometrial biopsies have revealed significantly fewer NK cells than in fertile individuals. Additionally, infertility and recurrent spontaneous abortions (RSAs) are indirectly correlated with impaired Treg cell function.

A maternal-fetal interface lacking IFN-γ signaling is more susceptible to viral infections in the fetus.[14] Despite the strong placental barrier, certain pathogens can bypass these defenses and cause severe fetal complications. Pathogens responsible for congenital infections are categorized as TORCH infections, which include toxoplasmosis, other infections (such as varicella, syphilis, parvovirus B19, Zika virus, and HIV), rubella, Cytomegalovirus, and herpes simplex virus.

Clinical Significance

Pregnancy presents a vulnerable situation for both the maternal and fetal dyad, putting them at risk for serious complications. Disruption of fetal tolerance may contribute to the immuno-pathophysiology underlying various pregnancy-related complications. Immune disruption at the maternal-fetal interface can help explain the pathophysiology of conditions such as unexplained infertility, recurrent abortion, endometriosis, preeclampsia, and placental abruption.

Recurrent Spontaneous Abortion 

RSA, defined as 3 or more miscarriages, can result from various factors, including anatomical defects and endocrine disorders such as diabetes, hypothyroidism, and polycystic ovarian syndrome. Immune dysfunction at the maternal-fetal interface may also contribute to RSA, as evidenced by the following:

• Impaired spiral artery remodeling and overexpression of angiogenic growth factors are associated with RSA.
• Autophagy levels are reduced in trophoblastic villi of RSA patients.
• RSA patients exhibit increased mature dendritic cells and decreased immature dendritic cells.
• Decreased M2 macrophage and Treg cell levels are linked with RSA.[15]

Endometriosis

The pathophysiology of endometriosis, characterized by the implantation of endometrial tissues outside the uterus, is influenced by immune dysfunction, leading to abnormal implantation and proliferation at ectopic sites. Key immune aberrations noted in endometriosis include:

• High levels of pro-inflammatory cytokines (IL-1 and TNF-α) and decreased levels of anti-inflammatory cytokines (IL-13). 
• Increased activation of peritoneal macrophages.
• Lower levels of Treg and NK cells.
• Polyclonal B-cell activation with increased antibody production.[16]

Preeclampsia

Preeclamptic pregnant women exhibit elevated pro-inflammatory cytokines (TNF-α, IL-6, and IL-8) and reduced anti-inflammatory cytokines (IL-10). Additionally, increased CD4+ T-cell infiltration in the placenta and an overrepresentation of M1 macrophages are commonly observed in preeclamptic pregnancies.[17] Increased inflammatory response to semi-allogeneic fetal antigens leads to impaired spiral artery remodeling, shallow trophoblast invasion, and placental infarction, predisposing to preeclampsia.

Placental Abruption

Placental abruption is associated with sterile inflammatory changes resulting from inadequate decidual suppressive activity and elevated levels of cytotoxic immune cells in the decidua. Upregulation of pro-inflammatory cytokines and tissue-specific angiogenic factors, such as vascular endothelial growth factor, disrupts vascular integrity, increasing the risk of placental abruption.[18]

Preterm Labor

Triggers such as infection, stress, or inflammation during pregnancy can prematurely shift the maternal immune state from anti-inflammatory to pro-inflammatory, triggering preterm labor. This process involves increased recruitment of effector CD4+ T cells in decidual tissues, leading to elevated secretion of pro-inflammatory cytokines such as IL-1β and TNF-α. Neutrophil levels are elevated in the decidua of pregnant women with preterm labor and chorioamnionitis. The roles of macrophages, NK cells, and dendritic cells in preterm labor remain under investigation.[19]

Advanced Maternal Age and the T-cell Subset

Advanced maternal age can disrupt the T-cell profile at the maternal-fetal interface, potentially leading to reduced fetal survival or IUGR. Women of advanced maternal age typically have fewer CD4+ Treg cells and an increased number of pro-inflammatory T cells, such as IFN-γ–producing CD4+ and CD8+ cells in the fetus.[20]

Virus Pathogenesis and the Role of Inflammation

Viral infections during pregnancy can significantly increase the risk of miscarriage, preterm birth, low birth weight, and fetal neurological impairments. The shift from Th1 to Th2 immunity during pregnancy suppresses CD4, CD8, and NK cell activity, weakening cell-mediated immunity against viral infections. This explains why certain viruses, such as herpes simplex, hepatitis E, and influenza, have more severe implications in pregnant women compared to nonpregnant individuals.[21] 

Immune Therapy During Pregnancy

• Intravenous immunoglobulin and allogenic lymphocyte immunotherapy increased the successful pregnancy rate among RSA patients of unknown etiology pursuing in-vitro fertilization.[22] In addition, these therapies can promote successful embryo implantation by increasing the percentage of Treg cells and suppressing the activity of NK cells.
• Cyclosporine A has also been used to enhance Treg cells in RSA patients.
• Progesterone has been shown to reduce the risk of miscarriage in patients with RSA. Additionally, it supports various functions, including improving maternal-fetal interface perfusion and regulating the immune response.
• Treg-enhancing drugs, adoptive Treg cell therapy, and low-dose IL are currently being tested for RSA treatment.
• Biologic agents, such as eculizumab, a monoclonal antibody targeting complement protein C5, offer promise for managing immune dysfunction in conditions such as preeclampsia and HELLP syndrome.[23]

Enhancing Healthcare Team Outcomes

Interprofessional healthcare providers, including physicians, advanced practitioners, nurses, and pharmacists, must collaborate to closely monitor maternal and fetal health, manage immunological risks, and prevent adverse outcomes. Regular follow-ups and timely interventions are essential for managing complications. Advanced diagnostic skills and the ability to interpret immunological tests are key to identifying conditions such as preeclampsia or recurrent pregnancy loss. An interprofessional approach is crucial for effectively addressing immune-related pregnancy complications. This strategy involves using evidence-based guidelines, incorporating emerging research, and tailoring care plans to each patient's unique needs to ensure optimal maternal and fetal health.

Seamless coordination among obstetricians, maternal-fetal medicine specialists, immunologists, and other healthcare professionals is essential for providing comprehensive care. This coordination involves aligning efforts to monitor immune function, address complications promptly, and educate patients about their condition and treatment options. By combining expertise, fostering teamwork, and prioritizing patient-centered care, healthcare professionals can improve maternal and fetal outcomes, reduce complications, and enhance patient safety and team performance in managing immunological challenges at the maternal-fetal interface.