HLA-G: Immune Regulation in Pregnancy and a Potential Role in Preeclampsia
Background: Preeclampsia effects anywhere from 1-10% of pregnant women worldwide and ~4% of pregnancies in the United States.1 Severe preeclampsia is also linked with placental abruption, pre-mature labor, liver failure, intrauterine growth restriction, and maternal death.2 Preeclampsia pathophysiology can be characterized first by impaired invasion of the trophoblast into the maternal decidua followed by placental proinflammatory, antiangiogenic and angiogenic factors causing endothelial dysfunction3 HLA-G expressed by extravillous trophoblasts (EVT) is implicated in control of trophoblast invasion, uterine vascular remodeling, and maintaining the immunosuppression that allows for maternal tolerance of the fetus through pregnancy.4 Preeclampsia is multifactorial and its pathophysiology has been linked with breakdown of maternal fetal immune tolerance, particularly insufficient regulatory T cell function which allows for susceptibility of the fetus and placenta to cytotoxic T cells and inflammatory responses.4 These findings suggest a potential mechanism of disease for preeclampsia and modulation could prove beneficial to developing therapies.
Objectives: In this literature review, we uncovered the role that HLA-G plays in immune regulation during pregnancy and explored possible mechanisms of immune tolerance breakdown during preeclampsia.
Search Methods: An online PubMed database search was performed for studies from 2017 to 2023 using the keywords “immune regulation in pregnancy”, “HLA-G in pregnancy,” and “HLA-G preeclampsia.”
Results: Studies show that HLA-G is expressed throughout the course of pregnancy in first trimester, extravillous trophoblasts, and chorionic term tissue.5 While expressed throughout pregnancy, HLA-G was shown to have variable expressivity between first trimester and term tissues. The highest percentage of cells expressing HLA-G found in term chorionic tissue as compared to extravillous trophoblasts.5 First trimester HLA-G+ cells had increased ability to induce regulatory T cells which could play a role in implantation of the fetus during the first trimester.5 With evidence that HLA-G is found in pregnancy, we then turned our attention to its expression in preeclampsia. When comparing serum HLA-G (sHLA-G) values in different hypertensive conditions during pregnancy, sHLA-G was found to be within normal limits in both controls and gestational hypertension but found to be uniquely reduced in both early-onset preeclampsia and late-onset preeclampsia.6 Additionally, term extravillous trophoblast tissue was found to have marked sex differences in HLA-G gene expression. Specifically, male fetuses at term were found to have higher levels of HLA-G expression than female fetuses.5 Surprisingly, there was a reduction in male births with multiparity preeclamptic births and male fetuses were more susceptible to maternal inflammation than female fetuses and found to have an increased immune response.7
Conclusions: HLA-G is reduced in preeclampsia which indicates a breakdown of maternal immunotolerance of the fetus in late-stage pregnancy that exposes the fetus and mother to inflammation. There is also a sex difference found in male fetuses that display increased HLA-G expression yet are found to increased susceptibility to maternal inflammation. Understanding of the reduction of HLA-G in preeclampsia, may be key to understanding why there is breakdown of immunosuppression in preeclampsia and can lend insight into potential mechanisms of treatment.
- Turbeville HR, Sasser JM. Preeclampsia beyond pregnancy: long-term consequences for mother and child. Am J Physiol Renal Physiol. 2020;318(6):F1315-F1326. doi:10.1152/ajprenal.00071.2020
- Portelli M, Baron B. Clinical Presentation of Preeclampsia and the Diagnostic Value of Proteins and Their Methylation Products as Biomarkers in Pregnant Women with Preeclampsia and Their Newborns. J Pregnancy. 2018;2018:2632637. Published 2018 Jun 28. doi:10.1155/2018/2632637
- Rouas-Freiss N, Moreau P, LeMaoult J, Papp B, Tronik-Le Roux D, Carosella ED. Role of the HLA-G immune checkpoint molecule in pregnancy. Hum Immunol. 2021;82(5):353-361. doi:10.1016/j.humimm.2021.01.003
- Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo implantation and the immune response to pregnancy. J Clin Invest. 2018;128(10):4224-4235. doi:10.1172/JCI122182
- Papuchova H, Kshirsagar S, Xu L, et al. Three types of HLA-G+ extravillous trophoblasts that have distinct immune regulatory properties. Proc Natl Acad Sci U S A. 2020;117(27):15772-15777. doi:10.1073/pnas.2000484117
- Jacobsen DP, Lekva T, Moe K, et al. Pregnancy and postpartum levels of circulating maternal sHLA-G in preeclampsia. J Reprod Immunol. 2021;143:103249.
- Wedenoja S, Yoshihara M, Teder H, et al. Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia. EBioMedicine. 2020;59:102872. doi: 10.1016/j.ebiom.2020.102872