The association of IL-33 and Foxp3 gene polymorphisms with recurrent pregnancy loss in Egyptian women

Zidan, Haidy E.; Abdul-Maksoud, Rehab S.; Mowafy, Hala E; Elsayed, Walid S.H.

doi:10.1016/j.cyto.2018.03.025

Cited by 19 publications

(24 citation statements)

References 35 publications

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“…In a somewhat similar study, transcriptome analysis compared endometrial tissues from women experiencing recurrent implantation failure to controls (either spontaneously fertile women or women with at least 1 successful implantation via in vitro fertilization) and identified 82 consistently differentially expressed genes (79). Of the 82 genes identified by this study, 13 (or 15.8%) were identified as modulators of decidualization in our screen (80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96). These findings are in Dataset S7.…”

Section: Discussionmentioning

confidence: 57%

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Haller

Yin

2019

Proc. Natl. Acad. Sci. U.S.A.

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Failure of embryo implantation accounts for a significant percentage of female infertility. Exquisitely coordinated molecular programs govern the interaction between the competent blastocyst and the receptive uterus. Decidualization, the rapid proliferation and differentiation of endometrial stromal cells into decidual cells, is required for implantation. Decidualization defects can cause poor placentation, intrauterine growth restriction, and early parturition leading to preterm birth. Decidualization has not yet been systematically studied at the genetic level due to the lack of a suitable high-throughput screening tool. Herein we describe the generation of an immortalized human endometrial stromal cell line that uses yellow fluorescent protein under the control of the prolactin promoter as a quantifiable visual readout of the decidualization response (hESC-PRLY cells). Using this cell line, we performed a genome-wide siRNA library screen, as well as a screen of 910 small molecules, to identify more than 4,000 previously unrecognized genetic and chemical modulators of decidualization. Ontology analysis revealed several groups of decidualization modulators, including many previously unappreciated transcription factors, sensory receptors, growth factors, and kinases. Expression studies of hits revealed that the majority of decidualization modulators are acutely sensitive to ovarian hormone exposure. Gradient treatment of exogenous factors was used to identify EC50 values of small-molecule hits, as well as verify several growth factor hits identified by the siRNA screen. The high-throughput decidualization reporter cell line and the findings described herein will aid in the development of patient-specific treatments for decidualization-based recurrent pregnancy loss, subfertility, and infertility.

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Section: Discussionmentioning

confidence: 57%

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Haller

Yin

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The likely involvement of Tregs in uRPL is also supported by the studies carried out on the forkhead box P3 (FOXP3), a transcription factor essential for the development and function of Tregs. There is an increased occurrence of the following mutant genotypes and alleles of FOXP3 single nucleotide polymorphisms in women with uRPL compared with control women: rs2232365, rs3761548, rs5902434, and rs2294021 [172,173]. Moreover, FOXP3 expression was reduced in peripheral blood and decidua in women with uRPL compared with normal women [163].…”

Section: Tregsmentioning

confidence: 99%

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Ticconi

Pietropolli

Simone

et al. 2019

IJMS

159

101

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Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal–fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.

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“…In this regard, it is well-known that after a short period of a pro-inflammatory Th1 immune profile needed for embryo implantation, pregnancy well-being is associated with a shift into a Th2 anti-inflammatory status that dominates until end of pregnancy, when a Th1 pro-inflammatory response is required for parturition (25,26,(41)(42)(43)(44)(45)(46)(47)(48)(49). As IL-33/ST2 axis was shown to be critical in inducing and maintaining a Th2 immune profile both in physiological and pathological settings (35,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60), it is possible to speculate that expansion of ST2-expressing B1 B cells is part of the intricate immune mechanism launched during pregnancy to induce and maintain an anti-inflammatory Th2 profile. Supporting this idea, we observed that toward end of pregnancy, when a shift into Th1 profile is demanded, percentages of ST2-expressing B1 B cells were decreased.…”

Section: Discussionmentioning

confidence: 99%

Expression of IL-33 Receptor Is Significantly Up-Regulated in B Cells During Pregnancy and in the Acute Phase of Preterm Birth in Mice

et al. 2020

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Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.

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The association of IL-33 and Foxp3 gene polymorphisms with recurrent pregnancy loss in Egyptian women

Cited by 19 publications

References 35 publications

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Expression of IL-33 Receptor Is Significantly Up-Regulated in B Cells During Pregnancy and in the Acute Phase of Preterm Birth in Mice

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