Phuong-Lan Vo

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.

Works Cited:

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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.
7. 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