Observations from the last few years, it is evident that PE is related to unrestricted proinflammatory activation of the maternal immune system. Earlier studies have indicated a substantial role of many cytokines in mediating the pathogenesis of PE. However, the pathogenic role of IL-17 and IL-23, two crucial proinflammatory cytokines, has never been seriously looked at in the context of PE, and we aimed at fulfilling this lacuna.
Before examining the biological relevance of proinflammatory cytokines in PE, we compared different clinical characteristics among the three groups, i.e., PE patients, pregnant cases, and healthy non-pregnant women. Data clearly showed a reduction in duration of gestation, % vaginal delivery, and fetal birth weight in subjects with PE as compared to pregnant women without any disease. On the other hand, pre-eclamptic women demonstrated an increased body mass index (BMI), % caesarian section, blood pressure, WBC count, serum urea, and uric acid levels as compared to healthy controls. All these data were consistent with an earlier report (Darmochwal-Kolarz et al. 2017).
We observed elevated IL-17A levels in PE patients in comparison to the pregnant ladies and healthy cases. However, earlier reports remained controversial concerning the importance of IL-17 in PE. For example, a study by Jonsson et al. (Jonsson et al. 2006) showed no evidence of possible links between cytokine levels and PE pathologic conditions. On the contrary, our result is corroborated with earlier observations indicating a remarkably higher titer of IL-17A in the sera of pregnant subjects complicated by fetal growth restriction (FGR) and PE as compared to healthy pregnant normotensive women (Darmochwal-Kolarz et al. 2017). These results were further strengthened by several other reports mentioning that there was a higher prevalence of Th17 cells in peripheral blood and enhanced expression of RORγt mRNA (transcription factor of Th17 cells) in placentas of pre-eclamptic subjects as compared normal healthy ones (Darmochwal-Kolarz et al. 2012), (Toldi et al. 2011), (Jianjun et al. 2010). Overall, all these studies possibly indicate a pathogenic role of IL-17A in PE.
In contrast, we did not observe a possible difference in serum level IL-23A levels among three different studied groups. These results are contradictory to an earlier report (Poordast et al. 2017) where a significantly lower level of this cytokine was demonstrated in pregnant groups (with and without PE) in comparison to healthy non-pregnant subjects. However, in line with our observations, a report by Darmochwal-Kolarz et al. (Darmochwal-Kolarz et al. 2017) also failed to demonstrate the difference of Il-23A among pregnant subjects with placental insufficiency (fetal growth restriction and PE) and healthy pregnant women. Our result showing a comparable level of IL-23 in subjects with PE and healthy pregnant women matched with the report, as mentioned above. Moreover, a comparable level of this cytokine in both the pregnant groups and healthy non-pregnant subjects indicate a negligible role of IL-23 in the context of pregnancy and its related complication in PE.
Common polymorphisms in the IL-17A gene have been associated with hypertension (Huang et al. 2017)and various organ dysfunctions(Domanski et al. 2019). As the primary clinical characteristics of PE are high blood pressure and dysfunction of kidney and liver, we hypothesized that variants in the IL-17A gene would be associated with predisposition to the development of PE. Out of three SNPs investigated in the present study, we observed a significant association of rs2275913 polymorphism with a predisposition to PE: heterozygous and minor allele was more frequent in PE cased when compared to pregnant women and healthy women. In contrast, the previous reports in Brazilian(Tanaka et al. 2019), Han Chinese (Wang et al. 2015), and the Iranian population (Anvari et al. 2015) failed to demonstrate such association. Similarly, other variants of IL-17 polymorphism (rs1974226 and rs374806) were also not associated with susceptibility to PE. Furthermore, IL-23A (rs11171806) variants were also more frequent in PE compared to healthy and pregnant women indicating a susceptible genetic factor for PE development. The possible mechanism of how IL-23A rs11171806 is associated with PE susceptibility is not known. Mutation at 703 nucleic acids (G > A) position leads to a synonymous Ser106Ser, not affecting the three-dimensional structure of the IL-23A protein. Furthermore, in the present study, we also failed to observed differential IL-23A serum levels among different clinical categories. Also, the distribution of IL-12B (rs3212227) variants was comparable in PE patients and other clinical categories, indicating no significant role of IL-12B polymorphism in predisposition to PE development.
In the current report, a strong association of IL-17A (rs2275913) and IL-23A (rs11171806) polymorphism with susceptibility to PE was observed. Also, we noticed elevated IL-17A levels in PE patients in comparison to healthy women and pregnant women, and IL-23A remained comparable. Based on these results, we hypothesized that common polymorphisms in IL-17A and IL-23A would be correlated with serum levels of IL-17A and IL-23A, respectively. Serum levels of IL-23A were not associated with different genotypes of IL-23 gene (rs11171806), as the mutation (G > A) lead to no change in amino acids (Ser106Ser). Interestingly, IL-17A (rs2275913) polymorphism was observed to contributing serum levels of IL-17A: homozygous (AA) and heterozygous mutant (GA) displayed higher serum IL-17 compared to GG genotype. In line with the present report, earlier studies(Huang et al. 2017; Tang et al. 2018) have also demonstrated the functional relevance of IL-17A (rs2275913) with plasma or serum levels of IL-17A. Genetic variation at the promoter region of IL-17A gene would possibly enhance the binding of transcription factor and increased production of IL-17A cytokine.