Drs Yuping Wang and David F. Lewis from Louisiana State University Health Sciences Center – Shreveport discuss the impact of vitamin D in regulating immune tolerance and foetal development in pregnancy
Vitamin D is a nutrient by its name, but it is actually a steroid hormone. In humans, vitamin D synthesis begins in the skin after exposure to sufficient sunlight. Following two hydroxylation steps, first in the liver by 25 hydroxylase and second in the kidneys by 1α-hydroxylase, bioactive vitamin D (1,25(OH)2D3) is produced. Vitamin D substrates from diet (either cholecalciferol or ergocalciferol) are inactive and need to be absorbed and then hydroxylated in the liver and kidneys to become active. Historically, vitamin D is well-known for its role in maintaining calcium homeostasis to support bone health and growth. With the finding of the vitamin D receptor (VDR) in almost all cell types and organs in the body, more and more non-bone related biological functions of vitamin D are being discovered. Sufficient vitamin D levels in pregnant women are not only vital to achieving healthy pregnancy outcomes for both the mother and the developing foetus, but are also important for long-term beneficial effects in offspring during childhood.
Pregnancy is a unique immunological state. During pregnancy, the maternal immune system is adapted to actively tolerate the semi-allogeneic foetus. Vitamin D modulates innate and adaptive immunity and plays an important role in regulating immune tolerance during pregnancy. The immune tolerance and adaptive response occur at both the maternal-foetal interface and in the maternal system. Insufficient tolerance could lead to pregnancy problems and disorders, such as infertility, spontaneous abortion, Rh disease, and preeclampsia, etc.
Vitamin D mediated immune tolerance in pregnancy
The maternal-foetal interface is composed of the maternal-derived decidua and the foetal-derived placenta, being the prime area of immune regulation in pregnancy. 1,25(OH)2D3 modulates numerous genes associated with implantation, immune response, and cytokine generation in decidual cells and placenta cells. For example, 1,25(OH)2D3 upregulates homeobox A10 (HOXA10) expression in decidual cells . HOXA10 is a transcriptional factor involved in the regulation of embryonic development, morphogenesis, differentiation, and hematopoietic lineage commitment. 1,25(OH)2D3 promotes Toll-like receptor-4 (TLR-4) and indoleamine-pyrrole 2,3-dioxygenase (IDO) expression in immune regulatory cells, including natural killer (NK) cells, dendritic cells, macrophages, and T-cells in the decidua tissue and placental trophoblasts.
TRL-4 and IDO are two important immunosuppressor regulators. TLR-4 plays a fundamental role in pathogen recognition and mediates the production of cytokines necessary for the activation of innate immunity. IDO exerts immunosuppressive function by suppressing T-cell and NK cell proliferation and by generating T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Tregs are immunosuppressive and maintain tolerance to self-antigens and prevents autoimmune diseases. MDSCs also possess strong immunosuppressive activities. Both TLR-4 and IDO engage in immune tolerance during pregnancy. Through the regulation of TLR-4 and IDO pathway signaling, 1,25(OH)2D3 could inhibit B-cell and T-cell proliferation and differentiation, resulting in a shift towards T helper (Th) 2 of the Th1/Th2 immune balance and suppress inflammatory cytokine production, including IL-1, IL-6, and TNFα . In addition, vitamin D may also promote PD-1/ PD-L1 signaling, which has a critical role in the induction and maintenance of immune tolerance by modulating the threshold of T-cells and limiting T-cell effector responses.
Since decidual cells and placental trophoblasts express 1α-hydroxylase (the enzyme catalyzes the synthesis of 1,25(OH)2D3) and VDR throughout pregnancy; it is believed that 1,25(OH)2D3 acts in both autocrine and paracrine fashions to regulate innate and adaptive immune responses at the maternal-foetal interface and maintain tolerance of the developing foetus while protecting against infection and inflammation during pregnancy.
Placental mechanisms of immune tolerance
The placenta functions as an immunological barrier between the mother and the foetus during pregnancy. Placental syncytiotrophoblasts directly contact the maternal blood and play critical roles in immune tolerance during pregnancy. This is because trophoblasts lack most of the MHC class I antigens and are absent of MHC class II antigens, including human leukocyte antigen (HLA)-DR, all of which are responsible for recognising antigens and initiating immune responses. However, trophoblasts express nonclassical MHC class Ib genes such as HLA-G. HLA-G is a unique HLA and exerts immune tolerance properties. HLA-G is a ligand for NK cell inhibitory receptor KIR2DL4. Therefore, it can protect trophoblast cells from NK cell attack and NK cell-induced immune response . HLA-G could also induce MDSCs to inhibit the maternal T-cell response. These mechanisms are thought to be critical in preventing deleterious maternal immune responses against the foetus.
In addition to the HLA system, the placenta is the principal site for extra-renal synthesis of 1,25(OH)2D3 to maintain highly localised tissue levels of this hormone at the maternal-foetal interface. Trophoblasts express all vitamin D metabolite enzymes (25 hydroxylase, 1α-hydroxylase, and 24-hydroxylase) and VDR , and trophoblast synthesis of vitamin D has the potential to modulate decidual NK cells, dendritic cells, macrophages, and T-cells in the decidua too. Other than the promotion of immune tolerance signaling molecule expression and production such as TLR-4 and IDO, 1,25(OH)2D3 also protects trophoblasts from oxidative stress-induced insults and inhibits inflammatory responses. As a result, trophoblast interface with maternal tissues is not only able to escape immunological recognition by downregulation of MHC proteins, but also actively induce a peripheral tolerance from maternal origin. Therefore, healthy trophoblast function is critical to ensure healthy pregnancy outcomes.
Maternal vitamin D levels on foetal growth, the immune system and beyond
Cord blood and neonatal vitamin D levels are positively correlated with maternal vitamin D levels in pregnancy. It is well-known that maternal vitamin D deficiency has detrimental effects on foetal bone and teeth development. Studies also found that vitamin D deficiency is associated with increased risks of respiratory and infectious diseases and autism spectrum disorder in early childhood  , which indicate the importance of vitamin D in the foetal immune system and childhood neurodevelopment. Interestingly, a diverse pre-birth cohort study observed lower systolic and diastolic blood pressure among children with higher total vitamin D levels at birth . Similar results were also found from the ALSPAC (Avon Longitudinal Study of Parents and Children) study, in which lower systolic blood pressure at 9.9 years among children were born to mothers with higher total vitamin D levels at 25 weeks’ gestation . These data suggest the relationship between maternal vitamin D levels with neonatal and early childhood vascular function. Therefore, sufficient maternal vitamin D levels and proper vitamin D supplementation during pregnancy are important not only for the mother to reduce incidence of pregnancy complications, but also reduce the incidence of infectious diseases, bone and neurodevelopmental problems, and have beneficial effects on cardio-vasculature in children early in life. These data support the concept that intrauterine exposure to vitamin D may contribute to early life programming in childhood.
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