Altered crosstalk of estradiol and progesterone with Myeloid‐derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal‐fetal tolerance

• Published in: American journal of reproductive immunology (1989) 2019-02, Vol.81 (2), p.e13081-n/a
• Main Authors: Verma, Priyanka, Verma, Rachna, Nair, Rohini R., Budhwar, Snehil, Khanna, Anuradha, Agrawal, Nisha Rani, Sinha, Ruchi, Birendra, Ruchi, Rajender, Singh, Singh, Kiran
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Abortion, Spontaneous - immunology; Apoptosis; Caspase; Cells, Cultured; Cytokines; Cytokines - metabolism; Decidua; Decidua - physiology; early miscarriage; Endometrium; Enzyme-linked immunosorbent assay; estradiol; Estradiol - metabolism; Estrogen receptors; Female; Fetuses; Flow cytometry; Humans; Immunohistochemistry; Leukocytes (mononuclear); Lymphocytes T; Miscarriage; Myeloid-Derived Suppressor Cells - physiology; myeloid‐derived suppressor cells; Peripheral blood mononuclear cells; Pregnancy; Progesterone; Progesterone - metabolism; successful pregnancy; Suppressor cells; Testosterone; Th1 Cells - immunology; Th1-Th2 Balance; Th1/Th2 immunity; Th2 Cells - immunology; Transplantation Tolerance; Young Adult
• ISSN: 1046-7408; 1600-0897
• DOI: 10.1111/aji.13081

Problem Decline in myeloid‐derived suppressor cells (MDSCs) and Th2 cytokines levels lead to early miscarriage (EM) but how the hormonal milieu of the body regulates MDSCs and Th1/Th2 cytokine balance is still a matter of investigation. Method of study Peripheral blood and decidua samples were collected from 20 EM patients, and 20 healthy pregnant women opted for elective abortion. MDSCs and G‐MDSCs levels were analyzed in peripheral blood mononuclear cells, and Th1/Th2 cytokines levels were determined in serum via flow cytometry. Estrogen (E2), Progesterone (P4), and Testosterone levels were measured via ELISA. Further, proliferation and apoptosis in decidual samples were checked via immunoblot/immunohistochemistry of estrogen receptor ‐α (ER‐α), STAT‐3/pSTAT‐3, and caspase‐3, respectively. Results Our results clearly indicate that in EM patients; decline in E2 and P4 significantly correlates with decline in MDSCs, particularly with subtype granulocytic MDSCs (G‐MDSCs) and skewness of the Th1/Th2 cytokines balance toward Th1 response. Downregulation of ER‐ α and increased caspase‐3 expression in endometrium decidua signifies poor endometrial receptivity in EM. STAT‐3 activation regulates proliferation, differentiation and suppressive potency of MDSCs. In decidua of EM, significantly lower expression of pSTAT‐3 indicates that these processes pertaining to MDSCs are compromised. Conclusion Altogether, this unfavorable systemic milieu may drive toward early breakdown of maternal‐fetal tolerance in EM. Therefore, regulated crosstalk of E2, P4 with MDSCs and balanced Th1/Th2 cytokines is prerequisite for successful pregnancy. The main findings of our study are represented in the pictorial view, where estrogen and progesterone maintains Th1/Th2 cytokine balance and also helps in accumulation of MDSCs, specifically G‐MDSCs in the blood of pregnant women, that is, pre‐requisite for successful implantation and development of fetus against maternal immunity. On the other hand in EM cases decline in E2 and P4 leads to shifts of maternal immunity towards Th1 (inflammatory side) that is also accompanied by decline in MDSCs and G‐MDSCs levels. Lower E2 and P4 also caused decline in decidual neovascularization and development that ultimately brings rejection of fetus by maternal immune system and possibly triggers to miscarriage.