Regulatory B cells with IL‐35 and IL‐10 expression in a normal and abortion‐prone murine pregnancy model

Abstract

Determination of appropriate immunological interactions between the mother and the fetus and the establishment of immune tolerance are fundamental prerequisites for a successful pregnancy. Among them, the induction of a tolerogenic response to paternal antigens is considered necessary for the success of pregnancy. Disturbed immune tolerance can cause pregnancy disorders, such as spontaneous and recurrent miscarriages or preeclampsia. The crucial work of Aluvihare et al published in 2004 1 indicated for the first time that cell population with the CD4 + CD25 + phenotype played a leading role in maintaining pregnancy in mice. Following studies unambiguously confirmed that these were Treg cells characterized by the CD4 + CD25 + Foxp3 + phenotype. 2,3 It has been proven that in humans, there is an increase in Treg number during normal pregnancy and a decrease in their number and activity in spontaneous abortion cases. 3 It was also confirmed in the murine abortion-prone model of pregnancy (characterized by high rate of fetal resorption and Abstract Problem: Interleukin 35 is a relatively newly discovered cytokine that is produced by regulatory B cells (Bregs) and contributes to their suppressive function, which may contribute to fetal tolerance development and pregnancy maintenance. Therefore, the aim of this study was to determine the frequency of Bregs and expression of IL-35 and IL-10 in these cells in a normal and abortion-prone murine pregnancy model. Methods of study:The frequency of Bregs and expression level of IL-35 and IL-10 in these cells were measured in peripheral blood, uterine draining lymph nodes, uterus, and decidua using flow cytometry. The analysis was performed on days 3 and 14 of pregnancy in normal mice (CBA/JxBALB/c) and abortion-prone (CBA/JxDBA/2J) murine pregnancy model. Results: A decreased percentage of Breg cells expressing IL-35 on day 3 of pregnancyin the uterine draining lymph nodes and in peripheral blood in mice from the abortion group compared with the normal pregnancy group was observed. A similar decrease was also observed in the Breg cells population producing IL-10 in peripheral blood. In the uterus (3 dpc) and decidua (14 dpc), a lower percentage of CD19 + IL-35 + was also noted in the abortion-prone model. Conclusion:We indicated that the early stages of abortion-prone pregnancy (3 dpc) in mice were characterized by diminished frequency of B cells producing IL-35 at both local and peripheral levels. These results and the observed lower level of IL-35 in women suffering from recurrent spontaneous abortion suggest that IL-35 may be involved in the maintenance of pregnancy. K E Y W O R D Sabortion-prone, interleukin 35, maintenance of pregnancy, regulatory B cells

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model

“…It was also demonstrated that IL-10 secreting B cells (B10), but not B effector cells that do not produce IL-10, are prominent in the maintenance of the immune balance during pregnancy [ 43 ]. Furthermore, in our previous work, we have shown that at 14 dpc, abortion-prone mice have an increased proportion of CD19 + CD5 + CD1d high+ cells in the uterine draining lymph nodes when compared to that of mice with healthy pregnancies [ 44 ]. What is more, the frequency of CD19 + CD5 + cells in preeclampsia cases is higher than that of the second and third trimester of healthy pregnancy cases and is correlated with the production of autoantibodies.…”

Immunosuppressive Mechanisms of Regulatory B Cells

“…These cells are increased in the spleen of mice with lupus and are able to suppress Th1 responses and expand Tregs in an IL-35-dependent manner ( 62 ). IL-35 + Bregs have been detected in human decidua ( 361 ), while low frequencies have been found in decidua of abortion-prone mice ( 362 ). IL-35 + B cells have also been detected in intestinal mucosa from patients with Crohn's Disease (CD), but not from ulcerative colitis (UC) ( 363 ).…”

Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy

“…Bregs play a key role in the downregulation of the inflammatory response through an IL-10-dependent mechanism ( 86 ). In addition, compared with normal mice, the percentage of Bregs expressing IL-35 in the peripheral blood of abortive mice is reduced, suggesting the potential involvement of IL-35 in pregnancy maintenance ( 87 ). Can the TGF-β1 released by Bregs also participate in the regulation of the immune balance of the maternal-fetal interface?…”