Immune regulatory network in successful pregnancy and reproductive failures

Ghaebi, Mahnaz; Nouri, Mohammad; Ghasemzadeh, Aliyeh; Farzadi, Laya; Jadidi‐Niaragh, Farhad; Ahmadi, Majid; Yousefi, Mehdi

doi:10.1016/j.biopha.2017.01.016

Cited by 107 publications

(73 citation statements)

References 231 publications

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“…At present, a large body of evidence has demonstrated that decidual Treg cells contribute to creating a local tolerant microenvironment and maintaining a successful pregnancy; however, the role and importance of other Th subsets in the decidua is still largely unknown or remains controversial (3, 16, 23, 24, 70). Consistent with our results (Figures 4E–L), it was reported that IFN-γ and IL-17, secreted by human decidual Th1 and Th17 cells, play an important role in vascular remodeling (71) and trophoblast invasion (23), and that Th2 cytokines are not prerequisite to maintain a normal pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…Their differentiation is controlled by the following lineage-specific “master” transcription factors: T-box-binding transcription factor (T-bet) for Th1, GATA-binding protein 3 (GATA3) for Th2, and RAR-related orphan receptor gamma (RORγ) for Th17 cells; whereas Treg cells are defined and driven by expressing the forkhead transcription factor FOXP3 (5, 13, 21, 22). Although growing evidences suggest that Treg cells in the decidua contribute to maternal-fetal immune tolerance and pregnancy maintenance, the role and necessity of other decidual Th-cell subsets in a normal pregnancy is still largely unknown or remains controversial (3, 16, 23, 24). …”

Section: Introductionmentioning

confidence: 99%

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Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy

Zeng

Liu

et al. 2017

Front. Immunol.

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Decidual CD4+ T (dCD4 T) cells are crucial for the maternal-fetal immune tolerance required for a healthy pregnancy outcome. However, their molecular and functional characteristics are not well elucidated. In this study, we performed the first analysis of transcriptional and alternative splicing (AS) landscapes for paired decidual and peripheral blood CD4+ T (pCD4 T) cells in human early pregnancy using high throughput mRNA sequencing. Our data showed that dCD4 T cells are endowed with a unique transcriptional signature when compared to pCD4 T cells: dCD4 T cells upregulate 1,695 genes enriched in immune system process whereas downregulate 1,011 genes mainly related to mRNA catabolic process and the ribosome. Moreover, dCD4 T cells were observed to be at M phase, and show increased activation, proliferation, and cytokine production, as well as display an effector-memory phenotype and a heterogenous nature containing Th1, Th17, and Treg cell subsets. However, dCD4 T cells undergo a comparable number of upregulated and downregulated AS events, both of which are enriched in the genes related to cellular metabolic process. And the changes at the AS event level do not reflect measurable differences at the gene expression level in dCD4 T cells. Collectively, our findings provide a comprehensive portrait of the unique transcriptional signature and AS profile of CD4+ T cells in human decidua and help us gain more understanding of the functional characteristic of these cells during early pregnancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy

Zeng

Liu

et al. 2017

Front. Immunol.

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“…Numerous processes such as immune changes at the fetal-maternal interface and peripheral immune responses are involved in the induction of maternal tolerance, 15 and it has been demonstrated that in some cases of reproductive disturbances, function and/or the number of immune cells are altered. 16,17 Regulatory T (Treg) cells, natural killer (NK) cells, T helper (Th) 1, Th2, Th17, and macrophages are the main immune cells in regulation of maternal tolerance and prevention of fetus rejection. 18,19 During the pre-implantation, premenstrual, menses, and also the early pregnancy, there is a large accumulation of endometrial leukocytes in the endometrium.…”

Section: Immunolog Ic Proce Ss E S During Impl Antati On and E Arlymentioning

confidence: 99%

Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and Challenges

Taheri

Nejabati

Latifi

et al. 2018

American J Rep Immunol

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Due to the expression of paternal antigens by the embryo, pregnancy is considered as a semi-allograft and so immunological dysregulation is considered as one of the important causes in repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It has been revealed that lymphocytes immunotherapy (LIT) could be an appropriate approach to prevent pregnancy loss in such patients. Various mechanisms have been suggested for effectiveness of LIT such as enhancing expression of anti-paternal cytotoxic antibodies (APCA), progesterone-induced blocking factor (PIBF), anti-idiotypic antibodies (Ab2), and mixed lymphocyte reaction blocking antibodies (MLR-Bf), as well as reduction in the T helper 1/T helper 2 ratio and deviation in the pattern of cytokines production. However, there are controversial results about the beneficial effect of LIT treatment in RIF and RPL patients. In the current study, we reviewed findings of LIT in RIF and RPL patients with a focus on possible mechanisms of alloimmunization in preserving pregnancy. Besides, we highlighted possible reasons for mixed results about the effectiveness of LIT and way of solving the problem. Also, we proposed potential laboratory and clinical criteria to recruit patients for LIT.

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“…8,9 In addition, the proportion and functional imbalance of T cells in each subgroup are also considered to be harmful in early pregnancy. [11][12][13] T regulatory (Treg) cells and T helper 17 (Th17) cells are two remarkable, distinct subsets of CD4 + T cells and have almost opposite functions in autoimmunity, inflammation, and immunological rejection of extraneous antigens. [11][12][13] T regulatory (Treg) cells and T helper 17 (Th17) cells are two remarkable, distinct subsets of CD4 + T cells and have almost opposite functions in autoimmunity, inflammation, and immunological rejection of extraneous antigens.…”

mentioning

confidence: 99%

“…10 Related studies about how the immune response operates have greatly widened the knowledge of immunomodulatory mechanisms in normal pregnancy and RPL. [11][12][13] T regulatory (Treg) cells and T helper 17 (Th17) cells are two remarkable, distinct subsets of CD4 + T cells and have almost opposite functions in autoimmunity, inflammation, and immunological rejection of extraneous antigens. 6,7 Forkhead box protein 3 (Foxp3) is an important nuclear transcription factor for Treg cell differentiation.…”

mentioning

confidence: 99%

The role and mechanism of vitamin D‐mediated regulation of Treg/Th17 balance in recurrent pregnancy loss

Zhai

Zhou

et al. 2019

American J Rep Immunol

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Problem Vitamin D has a pivotal role in regulating immune responses in women with recurrent pregnancy loss (RPL), but the underlying mechanism has not been completely clarified. This study aimed to determine the correlation between vitamin D and Treg/Th17 and the effects of vitamin D supplementation on Treg/Th17 balance in RPL patients. Methods of study The level of vitamin D was determined in women with normal pregnancy and RPL by electrochemiluminescence. The percentages of CD4+Foxp3+ Treg, CD4+IL‐17+ Th17, and CD4+Foxp3+IL‐17+ T cells were determined by flow cytometry before and after vitamin D supplementation. Changes about Treg/Th17 balance after culturing with active vitamin D in vitro were determined. Vitamin D metabolic activity of peripheral blood mononuclear cells was also detected by RT‐PCR. Results Compared with normal pregnancy, both the level of vitamin D and the Treg/Th17 ratio were significantly decreased in women with RPL. There was a positive correlation between the level of vitamin D and the Treg/Th17 ratio in the RPL group. Within the RPL group, those who received 2 months of vitamin D supplementation showed a significantly increased Treg/Th17 ratio compared with those without vitamin D supplementation. In vitro analysis showed that adding different concentrations of active vitamin D increased the Treg/Th17 ratio, also the mRNA levels of the vitamin D receptor and the metabolic enzyme CYP24A1 increased significantly. Conclusion The occurrence of RPL may be related to vitamin D insufficiency and Treg/Th17 imbalance. The Treg/Th17 imbalance seen in women with RPL can be restored by vitamin D supplementation both in vivo and in vitro. The effects of vitamin D on the immune regulation of RPL indicate that vitamin D might be used as an alternative therapy in the future.

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Immune regulatory network in successful pregnancy and reproductive failures

Cited by 107 publications

References 231 publications

Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy

Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy

Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and Challenges

The role and mechanism of vitamin D‐mediated regulation of Treg/Th17 balance in recurrent pregnancy loss

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