scholarly journals Decrease in Regulatory T-cells and Increase in T Helper 17 Cells in Women With Recurrent Spontaneous Abortion

2021 ◽  
Author(s):  
Mina Badiee ◽  
Mehri Ghafourian ◽  
Ata A. Ghadiri ◽  
Abdolah Mousavi Salehi ◽  
Roshan Nikbakhat ◽  
...  
Keyword(s):  
T Cells ◽  
Spontaneous Abortion ◽  
Transplant Rejection ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Recurrent Spontaneous Abortion ◽  
Case Group ◽  
T Helper 17 ◽  
Flow Cytometric ◽  
Significant Difference

Abstract BackgroundAppearance of improper immune responses against the fetus and/or inadequate immunoregulatory mechanisms during pregnancy may lead to recurrent spontaneous abortion (RSA). TH17 cells play a significant role in inducing inflammation, autoimmune disease, and acute transplant rejection, while regulatory T (Treg) cells moderate the function of immune system in order to retain homeostasis.MethodsThis case-control study was designed to evaluate TH17 as well as Treg cells in 25 women with RSA and 25 age-matched healthy non-pregnant women. Flow cytometric assay was performed using monoclonal antibodies to detect CD4+CD25+ Treg cells (CD25dim and CD25bright). FoxP3 and RORγt expressions were compared using real-time PCR, and pro-inflammatory and anti-inflammatory cytokines were measured by ELISA kits. Independent-samples T test was employed for statistical analysis. ResultsThe ratio of CD4+CD25bright T cells was remarkably lower in women with RSA (P<0.05), and CD4+CD25dim T cells did not show any significant difference among the groups (P>0.05). RORγt was up-regulated, and FoxP3 was down-regulated significantly in case group (P<0.05). The significant increase of IL-6 and IL-17 as well as the decrease of TGF-β was indicated in RSA group (P<0.05). Also, IL-10 did not vary among the groups (P>0.05). ConclusionThese remarks prove that the decrease in regulatory factors such as CD4+CD25bright T-cells, TGF-β and FoxP3 expression may disrupt immune tolerance and homeostasis during pregnancy. Also, the environment rich in RORγt, IL-6, and IL-17 suggests the detrimental role of TH17 cells, which may lead to fetal rejection.

Immunopharmacological properties of VitD3: 1,25VitD3 modulates regulatory T cells and Th17 cells and the cytokine balance in PBMCs from women with unexplained recurrent spontaneous abortion [URSA]

2021 ◽  
Vol 14 ◽  
Author(s):  
Jiefan Gao ◽  
Li Wang ◽  
Lei Bu ◽  
Yangyang Song ◽  
Xiao Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Spontaneous Abortion ◽  
Th17 Cells ◽  
Recurrent Spontaneous Abortion ◽  
Control Group ◽  
Case Group ◽  
Gene Expressions ◽  
Unexplained Recurrent Spontaneous Abortion

Background: VitD3 may contribute to a successful pregnancy through modulation of immune responses, so VitD3 deficiency may have a role in the immunopathogenesis of unexplained recurrent spontaneous abortion [URSA]. However, the mechanisms of immunomodulatory actions of VitD3 in decreasing the risk of recurrent spontaneous abortion have not been understood well. Objective: The purpose of this research was to investigate the influence of 1,25VitD3 on regulatory T cells /Th17 axis, the gene expressions and concentrations of related cytokines including, TGF-β, IL-10, IL-6, IL-23, and IL-17A in peripheral blood mononuclear cells [PBMCs] of healthy women as a control group and women with URSA. Method: Isolation of PBMCs was performed from peripheral blood of the subjects of the studied groups [20 women with URSA as a case group, and 20 control women]. The effects of 1,25VitD3 [50 nM, for 24 hours] on the studied parameters were evaluated and were compared to the positive and negative controls in vitro. Flow cytometry analysis was used to determine the percentages of regulatory T cells and Th17 cells. For gene expression measurement and cytokines assay, Real-time PCR and ELISA were carried out. Results: The proportion of regulatory T cells was markedly lower, while the proportion of Th17 cells in women with URSA was considerably higher than in the control group [P=0.01, P=0.01]. The ratio of the frequency of Tregs to the baseline [1,25VitD3/Untreated] increased, while the ratio of the frequency of Th17 cells to the baseline decreased in women with URSA relative to the controls [P= 0.01, P=0.04]. 1,25VitD3 increased IL-10 expressions at both the protein and mRNA levels in PBMCs in women with URSA relative to the control group [P=0.0001, P=0.04]. TGF-β levels in the cultured supernatants decreased significantly in the case group in the presence of 1,25VitD3 relative to the controls [P=0.03]. 1,25VitD3 treatment also significantly decreased gene expressions of IL-6, IL-17A, and IL-23 in PBMCs of women with URSA [P=0.01, P=0.001, P=0.0005], as well as the levels of those cytokines in cell culture supernatants [P=0.03, P=0.02, P=0.01, respectively] in women with URSA relative to the controls. Conclusion: According to the findings of this research, modulation of immune responses by 1,25VitD3 is accomplished by strengthening Tregs function and inhibiting inflammatory responses of Th17 cells which may have a positive impact on pregnancy outcome. Thus, as an immunomodulating agent, VitD3 may be effective in reducing the risk of URSA.

scholarly journals Gene expression analysis of membrane progesterone receptors in women with recurrent spontaneous abortion: a case control study

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Reyhane Rahnama ◽  
Mitra Rafiee ◽  
Saloomeh Fouladi ◽  
Maryam Akbari-Fakhrabadi ◽  
Ferdos Mehrabian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spontaneous Abortion ◽  
Progesterone Receptors ◽  
Recurrent Spontaneous Abortion ◽  
Case Group ◽  
Relative Expression ◽  
Significant Difference ◽  
History Of ◽  
Membrane Progesterone Receptors ◽  
Fertile Women

Abstract Objective Recurrent spontaneous abortion (RSA) is a condition which is defined as three consecutive pregnancy losses prior to 20 weeks from the last menstrual period. Progesterone is a steroid hormone that has an essential role in the implantation and maintenance of pregnancy. The progesterone signaling is performed by nuclear progesterone receptors (NPRs) and membrane progesterone receptors (mPR). The aim of this study was to analyze gene expression of mPR-α, mPR-β and NPR in the endometrium of patients with a history of RSA compared to normal fertile women. Results In this study, endometrial samples were obtained from 10 women with a history of RSA and 10 fertile women during days 10–14 of menstrual cycle. Relative expression of mPR-α, mPR-β and NPR genes were studied by a quantitative real time polymerase chain reaction (qRT-PCR) and compared between the two groups. The mean relative expression of mPR-β gene was significantly lower in the case group compared to the fertile women (p < 0.05). However, the gene expression of mPR-α and NPR showed no significant difference between two groups. The findings suggest a reduction of endometrial gene expression of mPR-β in RSA patients may play an important role in pathogenesis of RSA.

scholarly journals Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Ding ◽  
Rajneesh Malhotra ◽  
Tomas Ottosson ◽  
Magnus Lundqvist ◽  
Aman Mebrahtu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Secreted Proteins ◽  
External Stimulation ◽  
Marker Proteins ◽  
Positive Regulators ◽  
Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

scholarly journals FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4953-4960 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Aloisio Felipe-Silva ◽  
Bianca Heemskerk ◽  
Daniel J. Powell ◽  
John R. Wunderlich ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Metastatic Melanoma ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Production Capacity ◽  
Biological Marker ◽  
Foxp3 Expression ◽  
Treg Cells

Abstract Regulatory T (Treg) cells are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell numbers and the inability to adequately distinguish between activated and Treg cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor-infiltrating T cells in the single-cell suspensions of enzymatically digested tumors to differentiate Treg cells from effector T cells. Similar to Treg cells in the peripheral blood of healthy individuals, tumor-infiltrating FOXP3+CD4 T cells, unlike FOXP3− T cells, were unable to produce IL-2 and IFN-γ upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg cells even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg cells in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg cells in the intratumoral compared with peritumoral areas. Moreover, their frequencies were 3- to 5-fold higher in tumors than in peripheral blood from the same patients or healthy donors, respectively. These findings demonstrate that the tumor-infiltrating CD4 Treg cell population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequency in peripheral blood does not properly reflect tumor microenvironment.

scholarly journals CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11977
Author(s):  
Jocelyn C. Pérez-Lara ◽  
Enrique Espinosa ◽  
Leopoldo Santos-Argumedo ◽  
Héctor Romero-Ramírez ◽  
Gabriela López-Herrera ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Treg Cells ◽  
Transmembrane Glycoprotein ◽  
Ifn Γ

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

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