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Immunology of Human Reproduction
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Immunology of Human Reproduction

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 32432

Special Issue Editor

Prof. Dr. Jacek Malejczyk

E-Mail Website
Guest Editor
Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland
Interests: immunology of reproduction; endometriosis; cytokines; NK cells; treg cells; immunogenetics

Special Issue Information

Dear Colleagues,

The immune system plays a crucial role in the functioning of the male and female reproductive systems and pregnancy. Immune cells and factors actively involved in the physiology and pathology of reproduction include NK cells, T cells, accessory cells, and specific antibodies, as well as a variety of inflammatory and immunoregulatory cytokines. Over the past decades, great progress has been made in understanding the complex immune mechanisms underlying the function of the maternal–fetal interface and fetal growth. However, there are still many unanswered questions awaiting further explanation. Especially, immune deviations leading to recurrent spontaneous abortions and preeclampsia are of particular interest. Furthermore, it is also necessary to reveal the immune mechanisms that may underlie abrogated endometrial receptivity and implantation failures. Further studies are also necessary to explain how systemic and local inflammatory and autoimmune phenomena may affect the functioning of the reproductive organs and gamete production and account for female and male subfertility/infertility.

Considering that the immune system has a great impact on human reproductive health, I would like to encourage submissions to our Special Issue that address all aspects of human reproductive immunology and immunopathology, including immunology of various gynecological disorders and reproductive system cancers.

Prof. Dr. Jacek Malejczyk
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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • reproductive immunology
  • inflammation
  • autoimmunity
  • uterus
  • endometrium
  • placenta
  • pregnancy
  • recurrent spontaneous abortions
  • preeclampsia
  • infertility
  • endometriosis

Published Papers (7 papers)

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Research

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11 pages, 2787 KiB  
Article
A Comprehensive Investigation into the Distribution of Circulating B Cell Subsets in the Third Trimester of Pregnancy
by Ágnes Kövér, Rudolf Lampé, Krisztina Szabó, Tünde Tarr and Gábor Papp
J. Clin. Med. 2022, 11(11), 3006; https://doi.org/10.3390/jcm11113006 - 26 May 2022
Viewed by 1664
Abstract
Maternal B cells play a crucial role in the development and maintenance of pregnancy, due to their humoral activities and regulatory functions. In the study, we investigated the alterations in the distributions of naïve and memory B cell subsets, as well as regulatory [...] Read more.
Maternal B cells play a crucial role in the development and maintenance of pregnancy, due to their humoral activities and regulatory functions. In the study, we investigated the alterations in the distributions of naïve and memory B cell subsets, as well as regulatory B (Breg) cells, in the third trimester of pregnancy. Peripheral blood from 14 healthy pregnant women in the third trimester and 7 healthy non-pregnant women was collected and examined for the frequencies of B cell subsets, including IgD+CD27− naïve, IgD+CD27+ un-switched memory, IgD−CD27+ switched memory, CD38intCD24int mature–naïve, CD38−CD24hi primarily memory and CD38hiCD24hi transitional B cells by flow cytometry. Breg cell subsets were also characterized based on the expression of CD5, CD1d and IL-10. In pregnant women, the proportions of un-switched memory and transitional B cells were significantly decreased. Additionally, the frequencies of both CD5+CD1d+ Breg and IL-10-producing B10 cells were decreased in pregnancy. Changes in the distribution of transitional B cells as well as Breg cells may be crucial contributors for the development of altered maternal immune responses and tolerance needed for the maintenance of normal pregnancy in the third trimester. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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11 pages, 1184 KiB  
Article
Differences in Immune Checkpoints Expression (TIM-3 and PD-1) on T Cells in Women with Recurrent Miscarriages—Preliminary Studies
by Michał Zych, Aleksander Roszczyk, Monika Kniotek, Filip Dąbrowski and Radosław Zagożdżon
J. Clin. Med. 2021, 10(18), 4182; https://doi.org/10.3390/jcm10184182 - 16 Sep 2021
Cited by 8 | Viewed by 2475
Abstract
Background: Immune checkpoints are molecules that regulate the function of immune cells and control inflammation processes. An important role in this regard is played by TIM-3/Gal-9 and PD-1/PDL-1 interactions. Previous research performed in a mouse model of pregnancy loss confirmed that blocking TIM-3 [...] Read more.
Background: Immune checkpoints are molecules that regulate the function of immune cells and control inflammation processes. An important role in this regard is played by TIM-3/Gal-9 and PD-1/PDL-1 interactions. Previous research performed in a mouse model of pregnancy loss confirmed that blocking TIM-3 could induce fetal loss. Similarly, the PD-1 molecule maintains protective interactions between the mother’s immune cells and the fetus. The purpose of this study was to assess the expression of these molecules on a range of T lymphocyte subpopulations from non-pregnant women with recurrent spontaneous abortion (RSA) versus healthy fertile women. Methods: PBMCs were isolated by gradient centrifugation of blood obtained from 12 healthy women and 24 women with RSA and immediately stained for flow cytometry analysis. Standard immunophenotyping of PBMC was performed with the antibodies against classical lymphocyte markers: CD3, CD4, CD8, and CD56. Immune checkpoints were investigated using antibodies against PD-1(CD279) and TIM-3(CD366). Results: We found that expression of TIM-3 was significantly decreased on CD8+ T lymphocytes in the RSA group, and expression of PD-1 was upregulated on CD4+ T lymphocytes in the RSA group in comparison to the healthy controls. Conclusions: Considering our findings, therapeutic intervention towards immune checkpoints may be a promising treatment option for recurrent spontaneous abortion. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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15 pages, 1763 KiB  
Article
Endometriotic Peritoneal Fluid Stimulates Recruitment of CD4+CD25highFOXP3+ Treg Cells
by Joanna Olkowska-Truchanowicz, Alicja Sztokfisz-Ignasiak, Aneta Zwierzchowska, Izabela Janiuk, Filip Dąbrowski, Grażyna Korczak-Kowalska, Ewa Barcz, Katarzyna Bocian and Jacek Malejczyk
J. Clin. Med. 2021, 10(17), 3789; https://doi.org/10.3390/jcm10173789 - 25 Aug 2021
Cited by 15 | Viewed by 1978
Abstract
Endometriosis is a common gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus. The disease is associated with disturbed local and systemic immunity. It has been reported that the proportion of CD4+CD25highFOXP3+ Treg cells may [...] Read more.
Endometriosis is a common gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus. The disease is associated with disturbed local and systemic immunity. It has been reported that the proportion of CD4+CD25highFOXP3+ Treg cells may be significantly increased in the peritoneal fluid of patients with endometriosis. Therefore, the aim of our study was to investigate whether the proportions of Treg cells in the peritoneal cavity of patients with endometriosis are related to the chemotactic and stimulatory activity of the local peritoneal milieu. The peritoneal fluid was collected from 13 women with ovarian endometriosis and 12 control women without the disease. T cell populations were analyzed by flow cytometry, cytokines and chemokines were evaluated using the cytometric bead kit, and cell chemotaxis was studied by cell migration assay. We confirmed that the proportions of Treg cells are increased in the peritoneal fluid of women with endometriosis as compared to the control women. Endometriosis was also associated with elevated concentrations of IL-6, IL-10, and TGF-β1/2 as well as CCL20, CXCL8, CXCL9, and CXCL10. We did not reveal any changes in the proportion of peritoneal Th17 cells and concentrations of IL-17A. Peritoneal Treg cells positively correlated with concentrations of TGF-β, IL-10, and CCL20. Endometriotic peritoneal fluid stimulated chemotaxis of both CD4+ and Treg cells. This chemotactic activity positively correlated with concentrations of CCL20. CCL20 stimulated the migration of Treg cells, and the chemotactic activity of the endometriotic peritoneal fluid was inhibited by neutralizing anti-CCL20 antibodies. These results imply that increased proportions of the peritoneal Treg cells in women with endometriosis may result from attraction and activation by local chemokines and cytokines, especially CCL20 and TGF-β. Since Treg cells contribute to the immunopathogenesis of endometriosis, their chemotaxis and activation may be considered as a target for therapeutic intervention. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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16 pages, 3062 KiB  
Article
Decreased Production of TNF-α and IL-6 Inflammatory Cytokines in Non-Pregnant Idiopathic RPL Women Immunomodulatory Effect of Sildenafil Citrate on the Cellular Response of Idiopathic RPL Women
by Monika Kniotek, Michał Zych, Aleksander Roszczyk, Monika Szafarowska and Małgorzata Maria Jerzak
J. Clin. Med. 2021, 10(14), 3115; https://doi.org/10.3390/jcm10143115 - 15 Jul 2021
Cited by 11 | Viewed by 6598
Abstract
Sildenafil citrate (SC), a PDE5 inhibitor, a drug for erectile dysfunction (ED) and pulmonary hypertension (PAH), was found to exert a positive effect on pregnancy outcomes when administered intravaginally before conception. In our previous studies, sildenafil increased endometrial thickness and significantly decreased peripheral [...] Read more.
Sildenafil citrate (SC), a PDE5 inhibitor, a drug for erectile dysfunction (ED) and pulmonary hypertension (PAH), was found to exert a positive effect on pregnancy outcomes when administered intravaginally before conception. In our previous studies, sildenafil increased endometrial thickness and significantly decreased peripheral blood NK cell activity after the intravaginal administration in women with recurrent pregnancy loss (RPL). No data are available to confirm the effect of sildenafil on maternal T cell populations involved in shaping fetal-maternal tolerance and NK cell activity. Thus, the present study aimed to establish if SC influences NKT cells or the axis of Th17/Treg cells and Th1/Th2 cytokine production. Materials and methods: Twenty-one healthy fertile women and twenty-two nonpregnant women with idiopathic RPL were studied. The ELISA method was used to evaluate the production of cytokines, including IL-2, IL-12p40, IL-4, IL-10, IL-6, IL-17, IL-21, TGF-β, TNF-α, and IFN-γ in PBMC culture supernatants before and after supplementation with the physiological concentration of SC. The percentages of NKT (CD56+CD3+CD44+CD161+), Treg (CD4+CD25+FOXP3+) and Th17 (CD4+CD25+IL-17A+) cells were determined with flow cytometry method. Results: Unexpectedly, we found that the PBMCs of patients with RPL produced a significantly lower level of inflammatory cytokines (TNF-α and IL-6) and a higher level of anti-inflammatory cytokines (TGF-β and IL-10). SC significantly decreased IL-6, IL-12 and increased TGF-β cytokine concentration in fertile women. In the case of RPL patients’ PBMCs, SC improved the production of TNF-α and IL-10. Conclusions: Lower concentration of proinflammatory cytokines in idiopathic RPL women compared to fertile women might suggest the exhaustion of the immune system. The emphasized production of IL-10 by SC partially explains the previously observed downregulation of NK cell activity in RPL patients. The immunomodulatory effect of the drug might be utilized in anti-inflammatory therapies and help achieve positive pregnancy outcomes in women with reproductive failure due to a Th1/Th2 imbalance. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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13 pages, 3581 KiB  
Article
Expression of Pinopodes in the Endometrium from Recurrent Pregnancy Loss Women. Role of Thrombomodulin and Ezrin
by Silvia D’Ippolito, Fiorella Di Nicuolo, Massimiliano Papi, Roberta Castellani, Valentina Palmieri, Valeria Masciullo, Vincenzo Arena, Chiara Tersigni, Micaela Bernabei, Alfredo Pontecorvi, Giovanni Scambia and Nicoletta Di Simone
J. Clin. Med. 2020, 9(8), 2634; https://doi.org/10.3390/jcm9082634 - 13 Aug 2020
Cited by 17 | Viewed by 5245
Abstract
Background: Pinopode expression has been suggested as a marker of endometrial receptivity. Methods: We set up an experimental study comparing endometrial tissue from recurrent pregnancy loss (RPL, n = 30) and fertile control (CTR, n = 20) women in terms of pinopode expression/morphology; [...] Read more.
Background: Pinopode expression has been suggested as a marker of endometrial receptivity. Methods: We set up an experimental study comparing endometrial tissue from recurrent pregnancy loss (RPL, n = 30) and fertile control (CTR, n = 20) women in terms of pinopode expression/morphology; expression of thrombomodulin (TM) and ezrin; cytoskeletal organization. Endometrial samples were collected during implantation window and evaluated by scanning electron microscopy, western blot, and immunofluorescence. Results: We found that RPL endometrial tissue showed: (i) increased pinopodes density (* p < 0.05); (ii) a reduced diameter of pinopodes (* p < 0.05); (iii) a decreased TM and ezrin expression (p < 0.05). Additionally, confocal images showed a significantly reduced expression of phosphorylated (p)-ezrin, confirming the results obtained through immunoblot analysis. Immunofluorescence staining showed that in CTR samples, junctions between cells are intact and clearly visible, whereas actin filaments appear completely lost in RPL endometrial samples; this suggests that, due to the impaired expression and activity of TM and ezrin, actin does not bind to plasma membrane in order to orchestrate the cytoskeletal actin filaments. Conclusions: Our findings suggest that an impaired expression of TM and expression/activation of ezrin may affect the connection between the TM and actin cytoskeleton, impairing the organization of cytoskeleton and, eventually, the adequate pinopode development. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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16 pages, 4979 KiB  
Article
Investigation of the PD-1 and PD-L1 Immune Checkpoint Molecules Throughout Healthy Human Pregnancy and in Nonpregnant Women
by Matyas Meggyes, David U. Nagy and Laszlo Szereday
J. Clin. Med. 2020, 9(8), 2536; https://doi.org/10.3390/jcm9082536 - 6 Aug 2020
Cited by 16 | Viewed by 2702
Abstract
Background: A growing body of evidence supports the importance of PD-1 and PD-L1, especially in the materno-fetal interface, although limited information is available about the peripheral expression of these molecules during the trimesters of pregnancy. Methods: 13 healthy women were enrolled [...] Read more.
Background: A growing body of evidence supports the importance of PD-1 and PD-L1, especially in the materno-fetal interface, although limited information is available about the peripheral expression of these molecules during the trimesters of pregnancy. Methods: 13 healthy women were enrolled from the 1st, 10 from the 2nd and 12 from the 3rd trimester of pregnancy at the same time, 10 healthy, age-matched nonpregnant women formed the control group. From peripheral blood, mononuclear cells were separated and stored at –80 °C. From freshly thawed samples, surface and intracellular staining were performed for flow cytometric analyses. CD107a degranulation assay was used to evaluate the cytotoxicity. Results: significant alternation was detected in PD-1 expression by CD8+T cells and in PD-L1 expression by CD8+T, CD4+T and Treg cells. An interesting relationship was revealed between the PD-1 and PD-L1 expression by the investigated subpopulations in 2nd trimester of pregnancy. Different expression patterns of an activation receptor NKG2D by the PD-1+ CD8+T cells was observed during pregnancy. The notable relationship was further determined in cytotoxicity between PD-1+ and NKG2D+ CD8+T cells throughout pregnancy. Conclusions: the different PD-1 presence and the relationship with NKG2D could contribute to the dynamic changes of the Th1 and Th2 predominance throughout the three trimesters of a healthy pregnancy. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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Review

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16 pages, 2317 KiB  
Review
Immune Tolerance of the Human Decidua
by Hiromi Murata, Susumu Tanaka and Hidetaka Okada
J. Clin. Med. 2021, 10(2), 351; https://doi.org/10.3390/jcm10020351 - 18 Jan 2021
Cited by 37 | Viewed by 10582
Abstract
The endometrium is necessary for implantation, complete development of the placenta, and a successful pregnancy. The endometrium undergoes repeated cycles of proliferation, decidualization (differentiation), and shedding during each menstrual cycle. The endometrium—including stromal, epithelial, vascular endothelial, and immune cells—is both functionally and morphologically [...] Read more.
The endometrium is necessary for implantation, complete development of the placenta, and a successful pregnancy. The endometrium undergoes repeated cycles of proliferation, decidualization (differentiation), and shedding during each menstrual cycle. The endometrium—including stromal, epithelial, vascular endothelial, and immune cells—is both functionally and morphologically altered in response to progesterone, causing changes in the number and types of immune cells. Immune cells make up half of the total number of endometrial cells during implantation and menstruation. Surprisingly, immune tolerant cells in the endometrium (uterine natural killer cells, T cells, and macrophages) have two conflicting functions: to protect the body by eliminating pathogenic microorganisms and other pathogens and to foster immunological change to tolerate the embryo during pregnancy. One of the key molecules involved in this control is the cytokine interleukin-15 (IL-15), which is secreted by endometrial stromal cells. Recently, it has been reported that IL-15 is directly regulated by the transcription factor heart- and neural crest derivatives-expressed protein 2 in endometrial stromal cells. In this review, we outline the significance of the endometrium and immune cell population during menstruation and early pregnancy and describe the factors involved in immune tolerance and their involvement in the establishment and maintenance of pregnancy. Full article
(This article belongs to the Special Issue Immunology of Human Reproduction)
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