Intravenous Immunoglobulin G Modulates Peripheral Blood Th17 and Foxp3+Regulatory T Cells in Pregnant Women with Recurrent Pregnancy Loss

Background: Vitamin D insufficiency and deficiency can be associated with adverse effects on pregnancy outcomes, which may include recurrent pregnancy loss through the mechanisms that are yet unknown. The aim of this study was to evaluate the effect of 1,25VitD3 on regulatory T cells (Tregs) and T helper17 (Th17) cell populations In vitro in unexplained recurrent pregnancy loss (URPL) patients and healthy women. Methods: Samples from 20 non-pregnant women with a history of URPL were compared to 20 normal non-pregnant women. Peripheral blood mononuclear cells (PBMC) were divided into 3 wells for each subject: in the presence of 1, 25 VitD3 (50 nM, for 16 hours), PHA (positive control) (10μM), and without any treatment (as a baseline or negative control). The percentage of regulatory T cells and Th17 cells was measured by flow cytometry at baseline and then after cell culture experiments. Results: Our study indicated that the percentage of Tregs in patients with URPL was significantly lower than the control group (2.42 ± 0.27 vs. 3.41 ± 0.29, P= 0.01). The percentage of Th17 cells was significantly greater in URPL patients compared to the control group (2.91 ± 0.33 vs. 1.18± 0.15, P=0.001). 1, 25VitD3 treatment significantly increased the percentage of Tregs from the baseline in the URPL group compared to that in the control group (1.23 ± 0.03 vs. 1.00 ± 0.03, P= 0.01). Conclusion: Vitamin D deficiency may be a contributor to recurrent pregnancy loss and suggests supplementation of women with Vit D pre-pregnancy may be protective against URPL.

Download Full-text

The Fluctuation of Regulatory T Cells during Pregnancy and Obstetrical Complications

10.21203/rs.2.22966/v1 ◽

2020 ◽

Author(s):

Yuan-Yuan Zhao ◽

Ning Li ◽

Hongchu Bao ◽

Nayoung Sung ◽

Xiaolu Zhang ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Pregnant Women ◽

T Cell Activation ◽

Peripheral Blood ◽

Cell Activation ◽

Recurrent Pregnancy Loss ◽

Normal Pregnancy ◽

Phenotypic Characteristics ◽

Complicated Pregnancy

Abstract Background: Regulatory T cells (Tregs) are critical immunomodulators during pregnancy by preventing maternal T-cell activation against fetal cells. However, how characteristics of maternal Tregs vary during pregnancy is still unclear. We analyzed the proportion and phenotypic characteristics of peripheral blood Tregs in normal pregnant women, women with recurrent pregnancy loss (RPL) or gestational diabetes mellitus (GDM), and non-pregnant women.Methods: We investigated the proportion of CD4+ Tregs, CD8+ Tregs and the expression of PD-1, GITR, HLA-G and CTLA-4 on them in the peripheral blood of normal pregnancies during 1st (n = 28), 2nd (n = 43), and 3rd trimester (n = 33); In addition, we evaluated pregnancies in the 1st trimester complicated by RPL (n = 21), in the 2nd (n = 17) and 3rd trimester (n = 28) complicated by GDM. Non-pregnant women (n = 57) were also investigated using flow cytometry.Results: During normal pregnancy, the proportion of CD4+ Tregs in all trimester and CD8+ Tregs in 2nd and 3rd trimester were higher(P ＜ 0.05，respectively) compared with non-pregnancy women. Moreover, the proportion of CD4+ Tregs was higher in 2nd trimester compared to 1st and 3rd trimester (P ＜ 0.01) while the proportion of CD8+ Tregs was higher in 3rd trimester compared to 1st and 2nd trimester (P ＜ 0.05). Compared to non-pregnant studies, the proportion of GITR+/CD8+ Tregs and HLA-G+/CD8+ Tregs in all trimester were higher(P ＜ 0.05, respectively). Moreover, the proportion of PD-1+/CD4+ Tregs, GITR+/CD4+ Tregs, PD-1+/CD8+ Tregs and CTLA-4+/CD8+ Tregs in 3rd trimester were significantly higher compared to 1st, 2nd trimester and non-pregnant group(P ＜ 0.05, respectively).In RPL and GDM groups, the proportions of CD4+ Tregs in all trimesters were decreased while the proportions of CD8+ Tregs in all trimesters were increased compared to normal pregnant group (P ＜ 0.05，respectively).In RPL group, the proportion of PD-1+/CD4+ Tregs, GITR+/CD4+ Tregs and HLA-G+/CD4+ Tregs were decreased compared to 1st trimester normal pregnant group (P ＜ 0.05，respectively). In 2nd trimester GDM group, the proportion of HLA-G+/CD4+ Tregs were decreased compared to 2nd trimester normal pregnant group (P ＜ 0.05，respectively). In 3rd trimester GDM group, the proportion of PD-1+/CD4+ Tregs, GITR+/CD4+ Tregs, PD-1+/CD8+ Tregs, GITR+/CD8+ Tregs and HLA-G+/CD8+Tregs were decreased compared to 3rd trimester normal pregnant group (P ＜ 0.05, respectively).Conclusions: The proportion of CD4+ Tregs and CD8+ Tregs increased during pregnancy, the proportions and subsets of CD4+ Tregs decreased and those of CD8+ Tregs increased in pregnancies complicated by RPL and GDM, indicating that regulatory T cells play a role in pregnancy maintenance, and the abnormal expression of Tregs might be related to the complicated pregnancy.

Download Full-text

Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted regulatory T cells frequency and function

Journal of Cellular Biochemistry ◽

10.1002/jcb.27821 ◽

2018 ◽

Vol 120 (4) ◽

pp. 5424-5434 ◽

Cited By ~ 7

Author(s):

Sara Jafarzadeh ◽

Majid Ahmadi ◽

Sanam Dolati ◽

Leili Aghebati‐Maleki ◽

Shadi Eghbal‐Fard ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Intravenous Immunoglobulin ◽

Live Birth ◽

Immunoglobulin G ◽

Birth Rate ◽

Recurrent Miscarriage ◽

Live Birth Rate ◽

Intravenous Immunoglobulin G ◽

And Function

Download Full-text

Increased amount of regulatory T cells may be required in attaining an ongoing uncomplicated pregnancy after unexplained recurrent pregnancy loss.

Placenta ◽

10.1016/j.placenta.2021.07.073 ◽

2021 ◽

Vol 112 ◽

pp. e22

Author(s):

Juliette Krop ◽

Marie-Louise van der Hoorn ◽

Hanneke Kapsenberg ◽

Carin van der Keur ◽

Frits Koning ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Uncomplicated Pregnancy

Download Full-text

An imbalance in interleukin-17-producing T and Foxp3+ regulatory T cells in women with idiopathic recurrent pregnancy loss

Human Reproduction ◽

10.1093/humrep/der301 ◽

2011 ◽

Vol 26 (11) ◽

pp. 2964-2971 ◽

Cited By ~ 108

Author(s):

S. K. Lee ◽

J. Y. Kim ◽

S. E. Hur ◽

C. J. Kim ◽

B. J. Na ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Interleukin 17

Download Full-text

Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis

Frontiers in Immunology ◽

10.3389/fimmu.2021.737862 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samantha Green ◽

Marina Politis ◽

Kathrine S. Rallis ◽

Alba Saenz de Villaverde Cortabarria ◽

Athina Efthymiou ◽

...

Keyword(s):

Systematic Review ◽

T Cells ◽

Regulatory T Cells ◽

Pregnant Women ◽

Peripheral Blood ◽

Meta Analysis ◽

Adverse Outcomes ◽

Case Control Studies ◽

Inconsistency Index ◽

In Pregnancy

BackgroundSeveral studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes.ObjectiveThe aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB).MethodLiterature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women versus women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed.ResultsFrom 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03–1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13–1.65; I²=84%). No difference was found in the number of Tregs between early versus late pre-eclampsia (SMD,-1.17; 95% CI, -2.79–0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34–5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry vs. qPCR vs. immunofluorescence tissue staining) showed similar associations.ConclusionLower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link.Systematic Review RegistrationPROSPERO, identifier CRD42020205469.

Download Full-text