Roles And Mechanisms Of Myeloid Derived Suppressor Cells In Preeclampsia

Background:Preeclampsia(PE) is a major cause of maternal and perinatal death. Patients who had normal blood pressure before pregnancy appear series of symptoms such as high blood pressure, edema, proteinuria after 20 weeks of gestation. It can affect each maternal organ, and affect fetal growth and development, even lead to fetal distress and intra-uterine death. The etiology and pathological mechanism are still not clear so far. Researchers have demonstrated that maternal specific immune tolerance to fetal is an important factor to maintain normal pregnancy, and the changes of the state of immune tolerance are closely related to the pathogenesis of preeclampsia. Myeloid derived suppressor cell(MDSC), which has obvious heterogeneity, differentiate from myeloid hematopoietic stem cells in infection, tumor, autoimmune diseases, chronic inflammation and trauma cases, and play immunosuppressive roles through a variety of mechanisms. Studies have shown that MDSC proportions increase in maternal peripheral blood and umbilical cord blood of normal pregnancy, which suggests MDSC might play an important immunosuppressive function in maintenance of maternal-fetal tolerance in gestation. However, whether there are changes of the number and function of MDSC in preeclampsia patients, and the roles and related mechanisms in the occurrence and development process of preeclampsia is unclear. Objective:Our present study aims to clarify the roles and mechanisms of MDSC in the occurrence and development of preeclampsia by detecting changes in the number and function of MDSC and its subsets in maternal and fetal circulation system of preeclampsia patients and normal pregnancy, and combining immune cell subsets and related cytokines detection. Our study will provide new targets and strategies for the clinical treatment of preeclampsia. Methods:Approved by the first hospital ethics committee of Jilin University, and after signed the informed consent by preeclampsia patients and control groups, we collected peripheral blood and umbilical cord blood during childbirth. After separating cells, sera were cryopreserved. Mononuclear cells were separated from peripheral blood and umbilical cord blood by using Ficoll cells stratified fluid. Quantity and proportions of MDSC, T, B and NK lymphocytes and their subsets were analyzed by flow cytometry. Application kits were used to detect MDSC-related effector molecule levels in serum, such as Arginase-1, i NOS and reaction product NO. Trace sample multi-index flow protein quantitative technology(Cytometric Bead Array, CBA) was applied to detect related cytokine levels in serum. Graphpad Prism 6.0 software was used for statistical analysis. Results:(1) Compared with non-pregnant controls, MDSC and its two subsets, G-MDSC and M-MDSC proportions in PBMC and CBMC of normal pregnancy women increased significantly.(2) Compared with normal pregnant women, total MDSC and G-MDSC ratios in PBMC and CBMC of preeclampsia patients decreased, especially G-MDSC ratio in the PBMC of PE patients, which even had no difference with non-pregnant controls, while M-MDSC proportions in PE patients had no changes compared with normal pregnancy.(3) Compared with non-pregnant controls, effector molecule of MDSC, Arginase-1 level in PBMC and CBMC of normal pregnancy increased significantly, while Arginase-1 levels in PBMC of preeclampsia patients were significantly reduced, which had the same trends with the change of G-MDSC in peripheral blood.(4) Compared with normal pregnant women, effector molecule i NOS and reaction product NO levels in peripheral blood serum and cord blood serum of preeclampsia patients did not change significantly. Conclusion:(1) MDSC and its two subsets, G-MDSC and M-MDSC ratios in normal pregnancy maternal and fetal blood circulations increased significantly, suggests that MDSC may play an important role in maintaining maternal-fetal tolerance of normal pregnancy.(2) Total MDSC and G-MDSC ratios in maternal and fetal blood circulation with preeclampsia decreased greatly, but M-MDSC ratios had no difference with normal pregnancy. The results suggest that G-MDSC might be involved in the pathology of preeclampsia.(3) The effector molecule of MDSC, Arginase-1 levels in sera derived from peripheral blood of PE patients were lower obviously, which suggests that Arginase-1 deficiency may be an important factor for the abnormal immunosuppressive state in preeclampsia.