IL-17 Producing T to Foxp3+CD4+ Regulatory T Cell Ratio as a Diagnostic and Prognostic Marker in Women With Recurrent Pregnancy Loss and Its Implications for Intravenous Immunoglobulin Therapy

Abstract

Problem: The imbalance in the Th17/Regulatory T (Treg) cell ratio is associated with recurrent pregnancy loss (RPL). This study aimed to determine a cut-off for the Th17/Treg cell ratio to predict pregnancy outcomes in RPL and evaluate the effectiveness of intravenous immunoglobulin (IVIG) based on this cut-off value.

Method of study: This retrospective cohort study included 49 idiopathic RPL and 75 controls. The subgroups of IL-17⁺ T cell to Foxp3⁺ T cell ratios in peripheral blood were measured using flow cytometry. The cut-off values of Th17/Treg cell ratios were determined by the ROC curve to distinguish between RPL and controls. The IVIG treatment effectiveness in pregnancy outcome was compared between high- and low-ratio groups. Pearson correlation assessed the Th17/Treg cell ratio's relationship with NK cell cytotoxicity (NKC), NK cell percentage, and Th1/Th2 cell ratio.

Results: Using the ROC curve, we identified six Th17/Treg cell ratio markers with diagnostic value, and the following two, CD3⁺IL-17⁺ T cell/CD3⁺Foxp3^high T cell ratio (sensitivity at 97%) and CD4⁺IL-17⁺ T cell/CD3⁺Foxp3^high T cell ratio (specificity at 93.61%), showed the highest statistical significance in diagnosing idiopathic RPL. Among the six diagnostic markers, in terms of predicting pregnancy outcomes with IVIG treatment, CD3⁺IL-17⁺ T cell/CD4⁺Foxp3⁺ T cell ratio was the most valuable prognostic marker. In RPL women with high CD3⁺IL-17⁺ T cell/CD4⁺Foxp3⁺ T cell ratio (≥ 1.096), the live birth rate (LBR) was improved with IVIG treatment. (IVIG treatment, 78.57% vs. no IVIG, 28.57%, p = 0.026). On the other hand, RPL women with low CD3⁺IL-17⁺ T cell/CD4⁺Foxp3⁺ T cell ratio did not demonstrate the effectiveness of IVIG (LBRs with IVIG treatment, 50.00% vs. no IVIG, 84.62%, p = 0.219). In a correlation study, the CD3⁺IL-17⁺ T cell/CD4⁺Foxp3⁺ T cell ratio was an independent prognostic marker, showing no correlation with NKC, NK cell percentage, and Th1/Th2 cell ratio.

Conclusion: The CD3⁺IL-17⁺ T/CD4⁺Foxp3⁺ T cell ratio may serve as a valuable marker for understanding the pathogenesis of RPL, predicting pregnancy outcomes, and selecting candidates for immunotherapy. Our study demonstrates that IVIG treatment can significantly improve LBR in women with a high CD3⁺IL-17⁺ T/CD4⁺Foxp3⁺ T ratio, offering a promising therapeutic approach for this challenging condition.

Keywords: Th17 cell; diagnostic marker; intravenous immunoglobulin; pregnancy outcomes; prognostic marker; recurrent pregnancy loss; regulatory T cell.