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Insights in Reproductive Immunology and Placental Pathology
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Insights in Reproductive Immunology and Placental Pathology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 15 June 2024 | Viewed by 7241

Special Issue Editor

Prof. Dr. Dariusz Szukiewicz

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Guest Editor
Department of Biophysics, Physiology and Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, Chalubinskiego 5 (4th Floor), 02-004 Warsaw, Poland
Interests: inflammation; cytokine network; sirtuins; endothelial signaling; human placenta; stem cells; pathophysiology of diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Reproductive immunology is a rapidly developing field that focuses on the study of the phenomenon of immunotolerance between the mother and the fetus. In the light of the latest research results, interaction rather than competition between the reproductive and immune systems enables the normal preservation of the reproductive function. This interaction covers all stages: from the formation of female and male gametes, through fertilization, implantation and placentation, intrauterine development of the fetus, to the delivery of a healthy newborn at term. Malfunctioning of the immune/reproductive interaction at each of these stages may predispose one to infertility or an abnormal course of pregnancy. It is noteworthy that intensively studied immunology of stem cells, which are abundantly present in the reproductive tissues (e.g., placenta, endometrium), significantly increased our knowledge in the field of reproductive immunology. This does not change the fact that the essence of immunotolerance in pregnancy, and thus most issues in the immunopathology of pregnancy, remain unclear.

This Special Issue is dedicated to all aspects of reproductive immunology, including the immunology of pregnancy in health and disease. All placental disorders related to the activity of the immune system are also included within the scope of this Special Issue. When considering your submission, please keep in mind that IJMS is a journal of molecular science. However, submissions of clinical studies with biomolecular experiments or pathological research with case sample data are welcomed.

Prof. Dr. Dariusz Szukiewicz
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gamete immunology
  • in vitro fertilization
  • infertility
  • immunocontraception
  • implantation
  • placentation
  • immunotolerance
  • reproductive immunology
  • inflammation
  • cytokine network
  • placenta-derived stem cells
  • placental development
  • placental insufficiency
  • endometriosis
  • immunopathology of pregnancy
  • sex hormones

Related Special Issues

Published Papers (7 papers)

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Research

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18 pages, 7017 KiB  
Article
Expression of Placental Lipid Transporters in Pregnancies Complicated by Gestational and Type 1 Diabetes Mellitus
by Paweł Jan Stanirowski, Mateusz Wątroba, Michał Pyzlak, Jarosław Wejman and Dariusz Szukiewicz
Int. J. Mol. Sci. 2024, 25(6), 3559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063559 - 21 Mar 2024
Viewed by 722
Abstract
The objective of the study was to assess the expression of proteins responsible for placental lipid transport in term pregnancies complicated by well-controlled gestational (GDM) and type 1 diabetes mellitus (PGDM). A total of 80 placental samples were obtained from patients diagnosed with [...] Read more.
The objective of the study was to assess the expression of proteins responsible for placental lipid transport in term pregnancies complicated by well-controlled gestational (GDM) and type 1 diabetes mellitus (PGDM). A total of 80 placental samples were obtained from patients diagnosed with PGDM (n = 20), GDM treated with diet (GDMG1, n = 20), GDM treated with diet and insulin (GDMG2, n = 20), and a non-diabetic control group (n = 20). Umbilical and uterine artery blood flows were assessed by means of ultrasound in the period prior to delivery and computer-assisted quantitative morphometry of immunostained placental sections was performed to determine the expression of selected proteins. The morphometric analysis performed for the vascular density-matched placental samples demonstrated a significant increase in the expression of fatty acid translocase (CD36), fatty acid binding proteins (FABP1, FABP4 and FABP5), as well as a decrease in the expression of endothelial lipase (EL) and fatty acid transport protein (FATP4) in the PGDM-complicated pregnancies as compared to the GDMG1 and control groups (p < 0.05). No significant differences with regard to the placental expression of lipoprotein lipase (LPL) and FATP6 protein between GDM/PGDM and non-diabetic patients were noted. Maternal pre-pregnancy weight, body mass index, placental weight as well as the expression of LPL and FABP4 were selected by the linear regression model as the strongest contributors to the fetal birth weight. To conclude, in placentas derived from pregnancies complicated by well-controlled PGDM, the expression of several lipid transporters, including EL, CD36, FATP4, FABP1, FABP4 and FABP5, is altered. Nonetheless, only LPL and FABP4 were significant predictors of the fetal birth weight. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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15 pages, 3693 KiB  
Article
HLA-G Expression/Secretion and T-Cell Cytotoxicity in Missed Abortion in Comparison to Normal Pregnancy
by Antonia Terzieva, Marina Alexandrova, Diana Manchorova, Sergei Slavov, Lyubomir Djerov and Tanya Dimova
Int. J. Mol. Sci. 2024, 25(5), 2643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25052643 - 24 Feb 2024
Viewed by 644
Abstract
The main role of HLA-G is to protect the semi-allogeneic embryo from immune rejection by proper interaction with its cognate receptors on the maternal immune cells. Spontaneous abortion is the most common adverse pregnancy outcome, with an incidence rate between 10% and 15%, [...] Read more.
The main role of HLA-G is to protect the semi-allogeneic embryo from immune rejection by proper interaction with its cognate receptors on the maternal immune cells. Spontaneous abortion is the most common adverse pregnancy outcome, with an incidence rate between 10% and 15%, with immunologic dysregulation being thought to play a role in some of the cases. In this study, we aimed to detect the membrane and soluble HLA-G molecule at the maternal–fetal interface (MFI) and in the serum of women experiencing missed abortion (asymptomatic early pregnancy loss) in comparison to the women experiencing normal early pregnancy. In addition, the proportion of T cells and their cytotoxic profile was evaluated. We observed no difference in the spatial expression of HLA-G at the MFI and in its serum levels between the women with missed abortions and those with normal early pregnancy. In addition, comparable numbers of peripheral blood and decidual total T and γδT cells were found. In addition, as novel data we showed that missed abortion is not associated with altered extravilous invasion into uterine blood vessels and increased cytotoxicity of γδT cells. A strong signal for HLA-G on non-migrating extravilous trophoblast in the full-term normal placental bed was detected. In conclusion, HLA-G production at the MFI or in the blood of the women could not be used as a marker for normal pregnancy or missed abortions. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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17 pages, 7824 KiB  
Article
Adenomyotic Lesions Are Induced in the Mouse Uterus after Exposure to NSAID and EE2 Mixtures at Environmental Doses
by Brigitte Boizet-Bonhoure, Stéphanie Déjardin, Mélissa Girard, Quentin Durix, Francis Poulat and Pascal Philibert
Int. J. Mol. Sci. 2024, 25(4), 2003; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25042003 - 07 Feb 2024
Viewed by 788
Abstract
The aim of this study was to assess the long-term effect of exposure to environmentally relevant doses of non-steroidal anti-inflammatory drugs (NSAIDs; ibuprofen, and diclofenac) and 17β-ethinylestradiol (EE2) on the mouse uterus. NSAID-EE2 mixtures were administered in the drinking water from gestational day [...] Read more.
The aim of this study was to assess the long-term effect of exposure to environmentally relevant doses of non-steroidal anti-inflammatory drugs (NSAIDs; ibuprofen, and diclofenac) and 17β-ethinylestradiol (EE2) on the mouse uterus. NSAID-EE2 mixtures were administered in the drinking water from gestational day 8 until 8 weeks post-birth (i.e., during embryo development, lactation, puberty, and sexual maturity). The incidence of adenomyosis lesions (presence of endometrial glands in the inner myometrium) increased up to 60% in the uterus of 8-week-old exposed females (F1) and to 85% in F2 females (exposed father). Histological analysis revealed aberrant proliferation and apoptosis, vacuolization of epithelial cells, and increased incidence of abnormal glands in the luminal and glandular epithelium in F1 and F2 uteri. Moreover, myofibroblast proportion (alpha-smooth muscle actin (α-SMA) expression analysis) and collagen expression (Picrosirius red stain; a fibrosis hallmark) were increased in F1 and F2 endometrium. Connexin-43 was aberrantly distributed in the endometrial stroma and glands of F1 and F2 uteri. Conversely, uterine 17β-estradiol and progesterone levels were not affected in F1 and F2 females. These findings demonstrated that in mice, chronic exposure to NSAID and EE2 mixtures at environmental doses intergenerationally affects uterine physiology, particularly the endometrium. It may serve as a model to study the pathophysiology of human adenomyosis. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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15 pages, 3277 KiB  
Article
Soluble Forms of Immune Checkpoints and Their Ligands as Potential Biomarkers in the Diagnosis of Recurrent Pregnancy Loss—A Preliminary Study
by Michał Zych, Aleksander Roszczyk, Filip Dąbrowski, Monika Kniotek and Radosław Zagożdżon
Int. J. Mol. Sci. 2024, 25(1), 499; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010499 - 29 Dec 2023
Viewed by 1253
Abstract
Immune checkpoints (ICPs) serve as regulatory switches on immune-competent cells. Soluble ICPs consist of fragments derived from ICP molecules typically located on cell membranes. Research has demonstrated that they perform similar functions to their membrane-bound counterparts but are directly present in the bloodstream. [...] Read more.
Immune checkpoints (ICPs) serve as regulatory switches on immune-competent cells. Soluble ICPs consist of fragments derived from ICP molecules typically located on cell membranes. Research has demonstrated that they perform similar functions to their membrane-bound counterparts but are directly present in the bloodstream. Effective control of the maternal immune system is vital for a successful pregnancy due to genetic differences between the mother and fetus. Abnormalities in the immune response are widely acknowledged as the primary cause of spontaneous abortions. In our research, we introduce a novel approach to understanding the immune-mediated mechanisms underlying recurrent miscarriages and explore new possibilities for diagnosing and preventing pregnancy loss. The female participants in the study were divided into three groups: RSA (recurrent spontaneous abortion), pregnant, and non-pregnant women. The analysis of soluble forms of immune checkpoints and their ligands in the serum of the study groups was conducted using the Luminex method Statistically significant differences in the concentrations of (ICPs) were observed between physiological pregnancies and the RSA group. Among patients with RSA, we noted reduced concentrations of sGalectin-9, sTIM-3, and sCD155, along with elevated concentrations of LAG-3, sCD80, and sCD86 ICPs, in comparison to physiological pregnancies. Our study indicates that sGalectin-9, TIM-3, sLAG-3, sCD80, sCD86, sVISTA, sNectin-2, and sCD155 could potentially serve as biological markers of a healthy, physiological pregnancy. These findings suggest that changes in the concentrations of soluble immune checkpoints may have the potential to act as markers for early pregnancy loss. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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Review

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14 pages, 1182 KiB  
Review
The Role of Regulatory T Cells and Their Therapeutic Potential in Hypertensive Disease of Pregnancy: A Literature Review
by Kyle Headen, Vaidile Jakaite, Vita Andreja Mesaric, Cristiano Scotta, Giovanna Lombardi, Kypros H. Nicolaides and Panicos Shangaris
Int. J. Mol. Sci. 2024, 25(9), 4884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25094884 (registering DOI) - 30 Apr 2024
Abstract
Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and foetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. [...] Read more.
Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and foetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. Tregs, which play a critical role in maintaining immune homeostasis, are crucial in pregnancy to prevent immune-mediated rejection of the foetus. The review highlights that Tregs contribute to immunological adaptation in normal pregnancy, ensuring foetal acceptance. In contrast, HDP is associated with Treg dysfunction, which is marked by decreased numbers and impaired regulatory capacity, leading to inadequate immune tolerance and abnormal placental development. This dysfunction is particularly evident in PE, in which Tregs fail to adequately modulate the maternal immune response against foetal antigens, contributing to the pathophysiology of the disorder. Therapeutic interventions aiming to modulate Treg activity represent a promising avenue for HDP management. Studies in animal models and limited clinical trials suggest that enhancing Treg functionality could mitigate HDP symptoms and improve pregnancy outcomes. However, given the multifactorial nature of HDP and the intricate regulatory mechanisms of Tregs, the review explores the complexities of translating in vitro and animal model findings into effective clinical therapies. In conclusion, while the precise role of Tregs in HDP is still being unravelled, their central role in immune regulation during pregnancy is indisputable. Further research is needed to fully understand the mechanisms by which Tregs contribute to HDP and to develop targeted therapies that can safely and effectively harness their regulatory potential for treating hypertensive diseases of pregnancy. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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15 pages, 1151 KiB  
Review
The Role of TGF-β during Pregnancy and Pregnancy Complications
by Baohong Wen, Huixin Liao, Weilin Lin, Zhikai Li, Xiaoqing Ma, Qian Xu and Feiyuan Yu
Int. J. Mol. Sci. 2023, 24(23), 16882; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242316882 - 28 Nov 2023
Viewed by 1384
Abstract
Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays significant roles in hormone secretion, placental development, and embryonic growth during pregnancy. TGF-β is implicated in embryo implantation and inhibits the [...] Read more.
Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays significant roles in hormone secretion, placental development, and embryonic growth during pregnancy. TGF-β is implicated in embryo implantation and inhibits the invasion of extraepithelial trophoblast cells. It also moderates the mother-fetus interaction by adjusting the secretion pattern of immunomodulatory factors in the placenta, consequently influencing the mother’s immune cells. The TGF-β family regulates the development of the nervous, respiratory, and cardiovascular systems by regulating gene expression. Furthermore, TGF-β has been associated with various pregnancy complications. An increase in TGF-β levels can induce the occurrences of pre-eclampsia and gestational diabetes mellitus, while a decrease can lead to recurrent miscarriage due to the interference of the immune tolerance environment. This review focuses on the role of TGF-β in embryo implantation and development, providing new insights for the clinical prevention and treatment of pregnancy complications. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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24 pages, 1355 KiB  
Review
The Role of Sirtuin-1 (SIRT1) in the Physiology and Pathophysiology of the Human Placenta
by Mateusz Wątroba, Grzegorz Szewczyk and Dariusz Szukiewicz
Int. J. Mol. Sci. 2023, 24(22), 16210; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242216210 - 11 Nov 2023
Cited by 1 | Viewed by 1174
Abstract
Sirtuins, especially SIRT1, play a significant role in regulating inflammatory response, autophagy, and cell response to oxidative stress. Since their discovery, sirtuins have been regarded as anti-ageing and longevity-promoting enzymes. Sirtuin-regulated processes seem to participate in the most prevalent placental pathologies, such as [...] Read more.
Sirtuins, especially SIRT1, play a significant role in regulating inflammatory response, autophagy, and cell response to oxidative stress. Since their discovery, sirtuins have been regarded as anti-ageing and longevity-promoting enzymes. Sirtuin-regulated processes seem to participate in the most prevalent placental pathologies, such as pre-eclampsia. Furthermore, more and more research studies indicate that SIRT1 may prevent pre-eclampsia development or at least alleviate its manifestations. Having considered this, we reviewed recent studies on the role of sirtuins, especially SIRT1, in processes determining normal or abnormal development and functioning of the placenta. Full article
(This article belongs to the Special Issue Insights in Reproductive Immunology and Placental Pathology)
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