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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: 28 February 2025 | Viewed by 10997

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Prof. Dr. Udo Jeschke

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Guest Editor

Interdisciplinary Center of Experimental Tumor Research, University Hospital Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany
Interests: ovarian cancer; breast cancer; cervical cancer; endometrial cancer, placenta
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Antonis Makrigiannakis

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Guest Editor

Department of Obstetrics and Gynecology, Medical School, University of Crete, 71003 Heraklion, Greece
Interests: implantation; receptivity; endometrium; RIF; early pregnancy; trophoblast
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue on “Reproductive Immunology: Cellular and Molecular Biology 2.0”.

Reproductive immunology in the 21st century still deals with a problem that has been known for decades—the fetus as semi-allograft and its response to the maternal immune system. Therefore, there is a strong need to solve problems such as spontaneous and recurrent miscarriages and, in addition, repeated implantation failure.
Furthermore, socioeconomical changes in an aging society are an additional challenge especially for the reproductive medicine specialist. Although highly developed in vitro fertilization techniques are available, many couples still face the problem of childlessness.
A quite new player in the field is the microbiome of the reproductive tract. For decades, it was believed that the uterus is sterile but an up to date analysis revealed that we not only have a vaginal microbiome but also a cervical, uterine, male, and even a placental microbiome.
Therefore, we would like to invite our colleagues to submit articles that deal with cellular and molecular mechanisms in the field of reproductive immunology to this Special Issue.

Prof. Dr. Udo Jeschke
Prof. Dr. Antonis Makrigiannakis
Guest Editors

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Keywords

spontaneous and recurrent miscarriage
repeated implantation failure
maternal immune cells
microbiome
assisted reproduction

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Related Special Issues

Reproductive Immunology: Cellular and Molecular Biology 2.0 in International Journal of Molecular Sciences (6 articles)
Reproductive Immunology: Cellular and Molecular Biology in International Journal of Molecular Sciences (20 articles)

Published Papers (8 papers)

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Research

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9 pages, 665 KiB

Open AccessArticle

Low Levels of Complement Factor H in the First Trimester of Pregnancy Are Associated with Spontaneous Preterm Birth

by Carlos Hernán Becerra-Mojica, Eliana Mora-Guevara, Miguel Antonio Parra-Saavedra, Ruth Aralí Martínez-Vega, Luis Alfonso Díaz-Martínez and Bladimiro Rincón-Orozco

Int. J. Mol. Sci. 2024, 25(19), 10549; https://doi.org/10.3390/ijms251910549 - 30 Sep 2024

Viewed by 640

Abstract

Preterm birth (PTB) remains a significant public health concern, and prediction is an important objective, particularly in the early stages of pregnancy. Many studies have relied on cervical characteristics in the mid-trimester, with limited results. It is therefore crucial to identify novel biomarkers to enhance the ability to identify women at risk. The complement pathway is implicated in the process of placentation, and recent proteomics studies have highlighted the potential roles of some complement proteins in the pathophysiology of PTB. To determine the association between the occurrence of spontaneous preterm birth (sPTB) and the concentration of complement C3, factor B, and factor H in the blood of pregnant women during the first trimester. This prospective cohort study included women with singleton pregnancies, both with and without a history of sPTB, from two health institutions in Bucaramanga, Colombia. The outcome was sPTB before 37 weeks. A blood sample was obtained between 11 + 0 to 13 + 6 weeks. ELISA immunoassay was performed to quantify the levels of C3, factor B, and factor H. A total of 355 patients were analyzed, with a rate of sPTB of 7.6% (27/355). The median plasma concentration for C3, factor B, and factor H were 488.3 μg/mL, 352.6 μg/mL, and 413.2 μg/mL, respectively. The median concentration of factor H was found to be significantly lower in patients who delivered preterm compared to patients who delivered at term (382 μg/mL vs. 415 μg/mL; p = 0.034). This study identified a significant association between low first-trimester levels of factor H and sPTB before 37 weeks. These results provide relevant information about a new possible early biomarker for sPTB. However, the results must be confirmed in different settings, and the predictive value must be examined Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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19 pages, 4240 KiB

Open AccessArticle

NLRP3 Inflammasome in the Pathogenesis of Miscarriages

by Wioleta Justyna Omeljaniuk, Marzena Garley, Anna Pryczynicz, Joanna Motyka, Angelika Edyta Charkiewicz, Elżbieta Milewska, Piotr Laudański and Wojciech Miltyk

Int. J. Mol. Sci. 2024, 25(19), 10513; https://doi.org/10.3390/ijms251910513 - 29 Sep 2024

Viewed by 731

Abstract

Despite significant advances in prenatal medicine, spontaneous miscarriage remains one of the most common and serious pregnancy complications, affecting an increasing number of women. Since many aspects of the pathogenesis of spontaneous miscarriage remain unexplained, the aim of this study has been to assess the involvement of the NLRP3 inflammasome as a potential causative factor. The concentrations of NLRP3, IL-1β, IL-18, and cytochrome C in the serum of patients after miscarriage were measured by means of the immunoenzymatic method. In the placental tissue, the expression of NLRP3, IL-1β, IL-18, and Caspase-1 as well as that of the classical apoptosis biomarkers Fas, FasL, Bcl-2, and Ca was evaluated by means of immunohistochemistry techniques. Additionally, in whole blood, the concentrations of elements crucial for pregnancy progression, such as Ca, K, Mg, and Na, were examined by means of the ICP-OES method. Significantly higher concentrations of NLRP3 and IL-18 were demonstrated in the serum of patients with miscarriage as compared to the control group. In the placental tissue samples, a higher expression of IL-1β, IL-18, and Caspase-1 proteins was noted in women who had experienced miscarriage as compared to the control group. At the same time, a significantly lower expression of FasL and Bcl-2 proteins as well as Ca deposits was observed in women after miscarriage as compared to those with a normal pregnancy outcome. Significantly lower concentrations of Ca and K were recorded in the blood of patients with spontaneous miscarriage as compared to pregnant women. The analysis of the results x indicated a greater involvement of the inflammasome in women with spontaneous miscarriage associated with oxidative–antioxidative imbalance than in the case of miscarriage related to NET formation. Our research has provided evidence for the involvement of the inflammasome in the process of spontaneous miscarriage and identifies a new direction for diagnostics that includes NLRP3 as a preventive element in prenatal care, particularly in light of the steadily declining number of pregnancies and the increasing number of reproductive failures. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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23 pages, 7119 KiB

Open AccessArticle

Reproductive Tract Microbial Transitions from Late Gestation to Early Postpartum Using 16S rRNA Metagenetic Profiling in First-Pregnancy Heifers

by Shaked Druker, Ron Sicsic, Shachar Ravid, Shani Scheinin and Tal Raz

Int. J. Mol. Sci. 2024, 25(17), 9164; https://doi.org/10.3390/ijms25179164 - 23 Aug 2024

Viewed by 725

Abstract

Studies in recent years indicate that reproductive tract microbial communities are crucial for shaping mammals’ health and reproductive outcomes. Following parturition, uterine bacterial contamination often occurs due to the open cervix, which may lead to postpartum uterine inflammatory diseases, especially in primiparous individuals. However, investigations into spatio-temporal microbial transitions in the reproductive tract of primigravid females remain limited. Our objective was to describe and compare the microbial community compositions in the vagina at late gestation and in the vagina and uterus at early postpartum in first-pregnancy heifers. Three swab samples were collected from 33 first-pregnancy Holstein Friesian heifers: one vaginal sample at gestation day 258 ± 4, and vaginal and uterine samples at postpartum day 7 ± 2. Each sample underwent 16S rRNA V4 region metagenetic analysis via Illumina MiSeq, with bioinformatics following Mothur MiSeq SOP. The reproductive tract bacterial communities were assigned to 1255 genus-level OTUs across 30 phyla. Dominant phyla, accounting for approximately 90% of the communities, included Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, and Fusobacteria. However, the results revealed distinct shifts in microbial composition between the prepartum vagina (Vag-pre), postpartum vagina (Vag-post), and postpartum uterus (Utr-post). The Vag-pre and Utr-post microbial profiles were the most distinct. The Utr-post group had lower relative abundances of Proteobacteria but higher abundances of Bacteroidetes, Fusobacteria, and Tenericutes compared to Vag-pre, while Vag-post displayed intermediate values for these phyla, suggesting a transitional profile. Additionally, the Utr-post group exhibited lower bacterial richness and diversity compared to both Vag-pre and Vag-post. The unsupervised probabilistic Dirichlet Multinomial Mixtures model identified two distinct community types: most Vag-pre samples clustered into one type and Utr-post samples into another, while Vag-post samples were distributed evenly between the two. LEfSe analysis revealed distinct microbial profiles at the genus level. Overall, specific microbial markers were associated with anatomical and temporal transitions, revealing a dynamic microbial landscape during the first pregnancy and parturition. These differences highlight the complexity of these ecosystems and open new avenues for research in reproductive biology and microbial ecology. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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19 pages, 4626 KiB

Open AccessArticle

Diet-Induced Obesity in Mice Affects the Maternal Gut Microbiota and Immune Response in Mid-Pregnancy

by Lieske Wekema, Sam Schoenmakers, Nicole Schenkelaars, Anne Laskewitz, Romy H. Huurman, Lei Liu, Lisa Walters, Hermie J. M. Harmsen, Régine P. M. Steegers-Theunissen and Marijke M. Faas

Int. J. Mol. Sci. 2024, 25(16), 9076; https://doi.org/10.3390/ijms25169076 - 21 Aug 2024

Viewed by 766

Abstract

Maternal obesity during pregnancy is associated with adverse pregnancy outcomes. This might be due to undesired obesity-induced changes in the maternal gut microbiota and related changes in the maternal immune adaptations during pregnancy. The current study examines how obesity affects gut microbiota and immunity in pregnant obese and lean mice during mid-pregnancy (gestational day 12 (GD12)). C57BL/6 mice were fed a high-fat diet or low-fat diet from 8 weeks before mating and during pregnancy. At GD12, we analyzed the gut microbiota composition in the feces and immune responses in the intestine (Peyer’s patches, mesenteric lymph nodes) and the peripheral circulation (spleen and peripheral blood). Maternal obesity reduced beneficial bacteria (e.g., Bifidobacterium and Akkermansia) and changed intestinal and peripheral immune responses (e.g., dendritic cells, Th1/Th2/Th17/Treg axis, monocytes). Numerous correlations were found between obesity-associated bacterial genera and intestinal/peripheral immune anomalies. This study shows that maternal obesity impacts the abundance of specific bacterial gut genera as compared to lean mice and deranges maternal intestinal immune responses that subsequently change peripheral maternal immune responses in mid-pregnancy. Our findings underscore the opportunities for early intervention strategies targeting maternal obesity, ideally starting in the periconceptional period, to mitigate these obesity-related pregnancy effects. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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15 pages, 1601 KiB

Open AccessArticle

Semen Protein CRISP3 Promotes Reproductive Performance of Boars through Immunomodulation

by Yonghui Bu, Ping Wang, Siqi Li, Li Li, Shouquan Zhang and Hengxi Wei

Int. J. Mol. Sci. 2024, 25(4), 2264; https://doi.org/10.3390/ijms25042264 - 14 Feb 2024

Cited by 3 | Viewed by 1407

Abstract

Semen proteins play an important role in male reproductive performance and sperm fertilization ability and can be used as potential biomarkers to evaluate male fertility. The role of cysteine-rich secretory protein 3 (CRISP3) in male reproduction remains unknown. This study aimed to investigate the role of CRISP3 in the reproductive performance of boars. Our results showed that the CRISP3 protein content was significantly and positively correlated with boar fertility, sow delivery rate, and litter size. CRISP3 is highly expressed in the bulbourethral gland of adult boars and is enriched in the seminal plasma. It is localized in the post-acrosomal region of the sperm head and migrates to the anterior end of the tail after capacitation. The CRISP3 recombinant protein did not affect sperm motility and cleavage rate, but it significantly downregulated the mRNA expression of inflammatory factors IL-α, IL-1β, and IL-6 and the protein expression of IL-α and IL-6 in lipopolysaccharide (LPS)-induced RAW264.7 cells, indicating that CRISP3 has an immunomodulatory function. In conclusion, our study suggests that semen CRISP3 protein levels positively correlate with reproductive performance, which may be achieved by regulating immune responses in the female reproductive tract. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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16 pages, 3261 KiB

Open AccessArticle

Examination of the TIGIT-CD226-CD112-CD155 Immune Checkpoint Network during a Healthy Pregnancy

by Matyas Meggyes, David U. Nagy, Timoteus Feik, Akos Boros, Beata Polgar and Laszlo Szereday

Int. J. Mol. Sci. 2022, 23(18), 10776; https://doi.org/10.3390/ijms231810776 - 15 Sep 2022

Cited by 9 | Viewed by 3287

Abstract

Background: The importance of immune checkpoint molecules is well known in tumor and transplantation immunology; however, much less information is available regarding human pregnancy. Despite the significant amount of information about the TIGIT and CD226 immune checkpoint receptors in immune therapies, very little research has been conducted to study the possible role of these surface molecules and their ligands (CD112 and CD155) during the three trimesters of pregnancy. Methods: From peripheral blood, immune cell subpopulations were studied, and the surface expression of immune checkpoint molecules was analyzed by flow cytometry. Soluble immune checkpoint molecule levels were measured by ELISA. Results: Notable changes were observed regarding the percentage of monocyte subpopulation and the expression of CD226 receptor by CD4⁺ T and NKT cells. Elevated granzyme B content by the intermediate and non-classical monocytes was assessed as pregnancy proceeded. Furthermore, we revealed an important relationship between the CD226 surface expression by NKT cells and the serum CD226 level in the third trimester of pregnancy. Conclusions: Our results confirm the importance of immune checkpoint molecules in immunoregulation during pregnancy. CD226 seems to be a significant regulator, especially in the case of CD4⁺ T and NKT cells, contributing to the maternal immune tolerance in the late phase of pregnancy. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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Review

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27 pages, 1426 KiB

Open AccessReview

Microbial Gatekeepers of Fertility in the Female Reproductive Microbiome of Cattle

by Mounir Adnane and Aspinas Chapwanya

Int. J. Mol. Sci. 2024, 25(20), 10923; https://doi.org/10.3390/ijms252010923 - 10 Oct 2024

Viewed by 1007

Abstract

This review paper delves into the intricate relationship between the genital microbiome and fertility outcomes in livestock, with a specific focus on cattle. Drawing upon insights derived from culture-independent metagenomics studies, the paper meticulously examines the composition and dynamics of the genital microbiome. Through advanced techniques such as high-throughput sequencing, the review illuminates the temporal shifts in microbial communities and their profound implications for reproductive health. The analysis underscores the association between dysbiosis—an imbalance in microbial communities—and the development of reproductive diseases, shedding light on the pivotal role of microbial gatekeepers in livestock fertility. Furthermore, the paper emphasizes the need for continued exploration of uncharted dimensions of the female reproductive microbiome to unlock new insights into its impact on fertility. By elucidating the complex interplay between microbial communities and reproductive health, this review underscores the importance of innovative strategies aimed at enhancing fertility and mitigating reproductive diseases in livestock populations. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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10 pages, 1282 KiB

Open AccessReview

A New Look at Immunogenetics of Pregnancy: Maternal Major Histocompatibility Complex Class I Educates Uterine Natural Killer Cells

by Manon Bos and Francesco Colucci

Int. J. Mol. Sci. 2024, 25(16), 8869; https://doi.org/10.3390/ijms25168869 - 15 Aug 2024

Viewed by 1150

Abstract

Our incomplete knowledge of maternal–fetal interface (MFI) physiology impedes a better understanding of the pathological mechanisms leading to pregnancy complications, such as pre-eclampsia and fetal growth restriction. At the MFI, uterine natural killer (uNK) cells do not attack fetal cells but engage in crosstalk with both fetal and maternal cells to support feto-placental development. However, mother and fetus are genetically half-mismatched and certain combinations of variable immune genes—human leukocyte antigens (HLAs) and killer-cell immunoglobulin-like receptor (KIR), indeed, the most variable gene sets in the genome—associate with pregnancy outcomes, suggesting that these interactions regulate uNK cell function. How do these interactions influence the physiology and pathology at the MFI? Uterine NK cell function is regulated by both maternal and fetal Major Histocompatibility Complex (MHC); however, evidence for fetal cells educating uNK cells is lacking, and new evidence shows that maternal rather than fetal MHC class I molecules educate uNK cells. Furthermore, uNK cell education works through self-recognition by the ancient and conserved NKG2A receptor. Pregnant mice lacking this receptor produce normal litter sizes, but a significant portion of the offspring have low birthweight and abnormal brain development. Evidence from a genome-wide association study of over 150,000 human pregnancies validates the finding because women whose NKG2A receptor is genetically determined to engage their own MHC class I molecules are exposed to lower risk of developing pre-eclampsia, suggesting that maternal uNK cell education is a pre-requisite for a healthy pregnancy and, likely, for healthy offspring too. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology 3.0)

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