Association Between Maternal Soluble Human Leukocyte Antigen-G and Pre-eclampsia: A Case– control Study View PDF

Pre-eclampsia is a pregnancy-related multisystem complication, where hypertension and dysfunction of organs are observed following 20 weeks of pregnancy [1]. It is the cause of between 3% - 8% of all pregnancies all over the world and is among the most common causes of maternal and perinatal morbidity and mortality [2-4]. Although there has been extensive research on the pathophysiological processes that lead to pre-eclampsia, the exact pathophysiological processes are still not clearly understood. Recent studies indicate that failure to stabilize the placenta, endothelial dysfunction, and deregulated maternal immune activities are very important in the pathogenesis of the disease [5, 6]. To have a successful pregnancy, the immune system of the mother and the semi-allogenic fetus have to interact on a very fine balance. HLA-G is one of the major molecules that play a role in the maintenance of maternal-fetal immune tolerance, which is a non-classical major histocompatibility complex class I molecule that is mainly expressed by extravillous trophoblast cells [4]. In contrast to classical HLA molecules, HLA-G has a low polymorphism and potent immunomodulatory activity that inhibits the natural killer (NK) cells, cytotoxic T lymphocytes, and antigen-presenting cells, as well as immune-mediated rejection of the unborn child [7, 8]. HLA-G, through these processes, helps in the development of immune tolerance and normal placenta growth.

HLA-G is provided in membrane-bound and soluble isoforms. The sHLA-G may be identified in maternal blood and has been suggested as a potential biomarker of pregnancy results [9, 10]. It has been found that various research studies examined the relationship between maternal circulating sHLA-G levels and pregnancy complications, especially pre-eclampsia. Indicatively, previous studies found that a lowering of the maternal plasma sHLA-G levels during pregnancy was found to raise the risk of pre-eclampsia and intrauterine growth restriction (IUGR) [11, 12].

Besides the individual clinical studies, systematic reviews and metaanalyses have also supported the role of sHLA-G in pre-eclampsia. The recent meta-analysis has shown that the maternal circulating levels of sHLA-G had significantly decreased in the pregnancies affected by preeclampsia in contrast to the healthy controls, therefore, showing the diagnostic potential of this biomarker [13]. Nevertheless, the clinical usefulness of maternal sHLA-G is still uncertain, and the present study can help in this area in the following ways. Second, it compares reduced sHLA-G levels and the risk of pre-eclampsia through statistical modeling. Third, it studies the diagnostic performance of the maternal sHLA-G based on receiver operating characteristic (ROC) analysis. Lastly, it adds more information on the involvement of immune tolerance mechanisms in pre-eclampsia pathogenesis, which may help justify the use of sHLA-G as a biomarker to detect the disease early.

Pre-eclampsia is a multisystem condition, with onset of hypertension and dysfunction of the organ present after 20 weeks of gestation period and is a leading cause of maternal and perinatal morbidity and mortality across the globe [14]. Even though the exact pathogenesis of it is not entirely known, there is an increasing amount of evidence that the maladaptation of the immune system between the mother and fetus is a key factor in the pathogenesis of diseases. In the list of molecules that mediate maternal-fetal immunity tolerance, HLA-G has become a source of significant immune response regulation in pregnancy [15].

HLA-G is a non-classical major histocompatibility complex class I molecule whose expression is mainly seen on extravillous trophoblasts in the maternal-fetal interface [16]. HLA-G, in contrast to classical class I molecules of the HLA, has limited polymorphism and also has strong immunomodulatory effects, which help in the maintenance of maternal immune tolerance to the semi-allogeneic fetus. HLA-G suppresses NK cells, cytotoxic T lymphocytes, and antigen-presenting cells and, thus, inhibitor of maternal immune rejection of the developing fetus [17]. Besides having isoforms bound by the membrane, sHLA-G are also discharged into maternal circulation and can be detected in maternal serum during pregnancy.

Several studies have been conducted to establish the relationship between the levels of circulating sHLA-G and pregnancy complications, especially pre-eclampsia [12, 18]. Among the first studies examining this association, Steinborn et al. [11] had reported that low maternal plasma levels of sHLA-G in the second trimester were linked to an elevated risk of later in pregnancy acquiring pre-eclampsia and IUGR. Such results indicated that the reduced concentrations of sHLA-G might indicate the dysfunctional activity of trophoblasts or a lack of maternal immunological tolerance in the initial phase of gestation. The clinical importance of maternal sHLA-G levels has since been further explored using subsequent clinical studies as a marker of pregnancies with complications associated with placental dysfunction. Laskowska et al. [19] compared the maternal serum level of sHLA-G in pregnancies with IUGR and pre-eclampsia as compared with normal controls and found that there were different levels of sHLA-G in the affected pregnancies relative to the normal controls. Their results revealed that there is the possibility of abnormal expression of sHLA-G correlated with pathological placenta development and the dysfunction of maternal immune interactions with the fetus.

Longitudinal studies have more recently found further evidence to support the role of sHLA-G in the pathogenesis of pre-eclampsia [13, 20]. Jacobsen et al. [12] prospectively measured the levels of sHLA-G in the maternal circulation during pregnancy and postpartum and found that women with pre-eclampsia exhibited greatly reduced levels of sHLA-G than did the normotensive pregnant women and proposed that immunoregulatory signaling was impaired in the impacted pregnancies. Other associations with lower levels of sHLA-G included the links with indicators of placental dysfunction that also connected immune dysregulation with maladjusted placental development. Besides individual clinical studies, there are a number of systematic reviews and meta-analyses examining the predictive ability of sHLA-G as a predictor of pre-eclampsia. In a systematic review study, Maghsudlu et al. [18] established that maternal serum sHLA-G levels in the first trimester were significantly low in women who ended up developing pre-eclampsia, indicating that sHLA-G could be used as an early biomarker of the disease. On the other hand, a recent meta-analysis conducted by Bhattarai et al. [13] validated that the levels of circulating sHLA-G among the mothers were significantly lower in pre-eclamptic pregnancies than in the normotensive controls, although heterogeneity among the studies signified that further large-scale studies are required.

These results highlight the importance of the immune regulation by HLA-G to the normal placentation and the sustenance of a successful pregnancy.The lowering or varied release of HLA-G can affect invasion of the trophoblast and maternal immune tolerance, and therefore, this contributes to the onset of pre-eclampsia. Nevertheless, although there is growing evidence on the role of sHLA-G in pregnancy complications, there is a need to conduct further clinical research to determine the diagnostic and prognostic utility of sHLA-G as a biomarker to early diagnose pre-eclampsia