Evaluation of Th17 and Treg cytokines in patients with unexplained recurrent pregnancy loss

Maral Farshchi; Elham Abdollahi; Nafiseh Saghafi; Ahmad Hosseini; Sara Fallahi; Sirus Rostami; Parifar Rostami; Houshang Rafatpanah; Mojtaba Habibagahi

Evaluation of Th17 and Treg cytokines in patients with unexplained recurrent pregnancy loss

J Clin Transl Res. 2022 May 25;8(3):256-265. eCollection 2022 Jun 29.

Authors

Maral Farshchi¹, Elham Abdollahi^{1

2}, Nafiseh Saghafi², Ahmad Hosseini³, Sara Fallahi⁴, Sirus Rostami⁴, Parifar Rostami⁴, Houshang Rafatpanah¹, Mojtaba Habibagahi³

Affiliations

¹ Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran.
² Department of Gynecology and Obstricts, Mashhad University of Medical Sciences, Mashhad, Iran.
³ Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴ Shiraz IVF Center, Shiraz University of Medical Sciences, Shiraz, Iran.

PMID: 35813894
PMCID: PMC9260344

Abstract

Background and aim: The Th17/Treg balance in peripheral blood and reproductive tissues may have a role in the etiology of unexplained recurrent pregnancy loss (URPL). In this study, we evaluated the major cytokine of Treg cells transforming growth factor-beta (TGF-β), and their specific transcription factor Forkhead box P3 (FOXP3), as well as the most highlighted cytokine of Th17 cells (interleukin [IL]-17A) in both URPL patients and healthy women.

Methods: Samples were extracted from the peripheral blood, endocervix, endometrium, and vagina of 14 patients with URPL and 12 normal non-pregnant women as a control (normal) group. Quantitative reverse transcription polymerase chain reaction was used to determine gene expression. Enzyme-linked immunosorbent assay was used to determine the levels of cytokines in the serum and cervicovaginal fluid.

Results: We found that in the URPL group, FOXP3 gene expression was considerably higher in peripheral blood than in the normal group (P=0.043). TGF-β levels in the cervicovaginal fluid were different in the URPL and normal groups (P=0.015). In comparison to the control group, women with URPL had significantly greater IL-17 gene expression in the peripheral blood (P=0.01).

Conclusion: Lower TGF-β levels in the cervicovaginal fluid of patients compared to controls may be related with increased IL-17 and FOXP3 mRNA levels in patients with URPL. Dysregulation of local immune responses in reproductive tissues may represent dysregulation of systemic regulatory immunological responses in the pathogenesis of URPL.

Relevance for patients: Dysregulation of immune responses may play a role in the pathogenesis of URPL at least in some patients with URPL. We conclude that the breakdown of tolerance in the local immune responses is more critical than the breakdown of tolerance in systemic tolerance in the pathogenesis of URPL. Therefore, modulating immune responses in the endometrium and decidua may be the focus of future therapeutic approaches in URPL. The impact of seminal plasma on the expansion of Tregs may provide a novel therapeutic intervention that has already been used in assisted reproductive technologies. Therefore, we suggest that transvaginal TGF-β in women with URPL may induce maternal tolerance which leads to the successful pregnancy.

Keywords: T helper 17 cells; Tregs; immunological responses; unexplained recurrent pregnancy loss.