Research In Reproductive Immunology Research Articles

Update on the research on the antigens of anti-sperm antibodies over the last decade

This review summarizes the advancements over a decade of research on antigens of anti-sperm antibodies (ASAs), which are key to male immune infertility. Despite the progress in assisted reproductive technologies, understanding the roles and mechanisms of ASAs and their antigens remains vital for immune infertility management. We conducted a comprehensive literature search on PubMed from January 2013 to December 2023 using the following keywords: “anti-sperm antibody,” “sperm antigen,” and “immune infertility.” In this review, we focus on the discoveries in sperm antigen identification and characterization through proteomics, gene disruption technology, and immunoinformatics, along with the development of fertility biomarkers. Here, we discuss the clinical applications of improved ASA detection methods and the progress in the development of immunocontraceptive vaccines. The intersection of advanced diagnostic techniques and vaccine development represents a promising frontier in reproductive health. The findings also highlight the need for standardized ASA detection methods and a comprehensive molecular-level approach to understanding ASA-related infertility. These insights underscore the significance of ongoing reproductive immunology research in enhancing clinical fertility outcomes and contraceptive vaccine development.

A survey of current research trends and potential future directions in reproductive immunology clinical trials

Abstract Reproductive immunology is a relatively recent field with a wide spectrum of research opportunities. Within the reproductive system, immune system dysfunction has been suggested to contribute to a variety of conditions - such as endometriosis, infertility, recurrent miscarriage, preeclampsia, and preterm delivery. Although there is preliminary research supporting these possible connections, further studies are necessary. A survey was conducted of current clinical trials to show the current state of reproductive immunology research to assess needs in less researched conditions. The survey was performed by accessing the ClinicalTrials.gov registry. “Reproductive immunology” was entered into the database, and the following filters were applied: “recruiting,” “active, not recruiting,” and “enrolling by invitation.” 153 studies were obtained, and the associated conditions were counted for how many times they were listed. Similar conditions were combined into one category – e.g. different types of leukemias were categorized as “Leukemia.” Although the rate of new female breast cancer cases is significantly higher than the rate of new leukemias in the general population, this survey suggests reproductive immunology research is more focused on leukemia than breast cancer. Male and female reproductive/breast cancer/endometrial cancer/endometriosis (6.17%), autoimmune diseases (4.43%), and pregnancy/contraception (0.58%) are less frequently listed compared to leukemia (45.28%) and hematologic diseases (15.80%) in the clinical trials registry as associated conditions. This information can potentially guide future research towards less studied conditions in the relatively new field of reproductive immunology.

Reproductive immunology from the perspective of the clinician

Investigators generate new and innovative ideas needed to advance knowledge, while physicians want proven treatments that provide the best care for their patients. Along with advances in reproductive immunology research, there have also been controversies such as immunologic treatments for recurrent pregnancy loss. Research deficiencies that are wasteful and misleading include: over-interpretation and extrapolation from animal studies to the human, inadequate sample sizes, lack of appropriate control groups, use of surrogate markers, associations presented as causation, un-blinded testing and treatments, unreproducible results, and non-standardized outcomes. The purpose of the EQUATOR Network (Enhancing the QUAlity Of health Research) is to improve the quality of research and its publication. These guidelines (CONSORT, STROBE, PRISMA, STARD, ARRIVE) have been accepted as mandatory by virtually all major medical journals, and all investigators should prospectively incorporate them into their study designs. From the perspective of a clinician-scientist and an editor, my premise is that the purpose of much basic science research and all clinical research is to improve the medical care of patients. Unproven and costly diagnostic tests and treatments for potential immunologic clinical problems can no longer be justified. The primary and most important outcome that should be reported for all pregnancy-related immunologic studies is the live birth rate of a healthy infant. Today’s clinicians and patients expect unbiased research that leads to evidence-based recommendations for practical and effective treatments.

Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance.

Referring to two recent publications, we here propose that clinical reproductive immunology has for decades stagnated because reproductive medicine, including assisted reproduction (AR), has failed to accept embryo implantation as an immune system-driven process, dependent on establishment of maternal tolerance toward the implanting fetal semi-allograft (and complete allograft in cases of oocyte donation). Pregnancy represents a biologically unique period of temporary (to the period of gestation restricted) tolerance, otherwise only known in association with parasitic infections. Rather than investigating the immune pathways necessary to induce this rather unique state of tolerance toward the rapidly growing parasitic antigen load of the fetus, the field, instead, concentrated on irrelevant secondary immune phenomena (i.e., "immunological noise"). It, therefore, does not surprise that interesting recent research, offering new potential insights into maternal tolerance during pregnancy, was mostly published outside of the field of reproductive medicine. This research offers evidence for existence of inducible maternal tolerance pathways with the ability of improving maternal fecundity and, potentially, reducing such late pregnancy complications as premature labor and preeclampsia/eclampsia due to premature abatement of maternal tolerance. Increasing evidence also suggests that tolerance-inducing immune pathways are similar in successful pregnancy, successful organ transplantation and, likely also in the tolerance of "self" (i.e., prevention of autoimmunity). Identifying and isolating these pathways, therefore, may greatly benefit all three of these clinical areas, and research in reproductive immunology should be accordingly redirected.

Mouse is the new woman? Translational research in reproductive immunology.

In an outbred mating typical of human reproduction, the embryo and feto-placental unit express paternal antigens to which the mother's immune system can react. However, the embryo and feto-placental unit can engineer the maternal immune defense system towards helpful rather than harmful reactions. Indeed, this begins with the prospective mother's exposure to paternal seminal plasma. In this review, the pregnancy complications of implantation failure (infertility), recurrent spontaneous abortion, pre-eclampsia and intrauterine growth restriction, and premature labor are examined to determine the degree of similarity between events in women and events in lab mouse models. The artificially induced model of endometriosis (which contributes to infertility) is also compared to what occurs in women. One may conclude that the female mouse provides a good analog of the human female. Nevertheless, it is always important to validate mouse data with human studies. The discussion focuses on the intrauterine interface between embryonic and placental tissues and maternal uterine tissues and the dialogue that is referred to as cross-talk. Issues relating to bidirectional transplacental traffic of immune system cells are not discussed as there is very little relevant data.

Reproductive Immunology Research: A Tight Interaction between Diverse Scientific and Clinical Disciplines Including Immunology, Obstetrics, Hematology, and Endocrinology.

involveswidelydistributedsignals in response to the given environmental input, while bothsystemsmustinteracttoobtaintheirnormalfunctionality(2).Fur-thermore, dysregulation of physiological interactions between thetwosystemscanleadtoseverepregnancy-relateddisordersorcom-plications,such as fetal loss,preterm labor,preeclampsia (PE),andpoor fetal development (3). On the other hand, by amelioratingautoimmuneconditionssuchasmultiplesclerosisandrheumatoidarthritis, while other conditions such as systemic lupus are dete-riorated, pregnancy as a condition may provide a unique insightinto novel immunomodulatory strategies (4,5).The scientific focus on reproductive–immune research hashistorically provided substantial understanding of the inter-face between these two physiological systems. With such recentprogress in the field, we felt that it is valuable and well-timed toreviewthebroadvarietyof therelevantphysiologicandpathologicaspects – from menstruation to fertilization and implantation,and from placentation and pregnancy

B cells: the old new players in reproductive immunology.

Reproductive immunology research has long focused on T cell responses to paternal antigens and tolerance mechanisms supporting fetal well-being. The participation of B cells herein was not widely studied. Because of the fascinating immunological uniqueness of pregnancy, it is however to be expected that such pleiotropic cells play a considerable role. In fact, on the one hand B cells contribute toward pregnancy tolerance by secreting the immunomodulatory cytokine IL-10 but on the other hand can seriously harm pregnancy because of their capacity of producing autoantibodies. As for protective B cells, new evidences in mouse models arise suggesting that IL-10 producing B cells, the so-called B10 cells, help in maintaining tolerance toward semi-allogenic fetal antigens. They may be also important to fight danger signals at the fetal-maternal interface as, e.g., in the case of infections with the aim to restore the disrupted fetal tolerance. In human pregnancies, IL-10 producing B cells increase with pregnancy onset but not in the case of spontaneous abortions. In vitro, they are able to suppress TNF-α production by T cells from pregnant individuals. Their generation and functionality will be discussed throughout this review article. B cells can be deleterious to pregnancy as well. Aberrant B cell compartment is associated with obstetric pathologies. In particular, the capacity of B2 cells to produce specific autoantibodies or of B-1a B cells to secrete natural autoantibodies that can turn autoreactive will be discussed herein.

New frontiers in reproductive immunology research: bringing bedside problems to the bench

The 31st Annual Meeting of the American Society for Reproductive Immunology provided an excellent platform for basic and clinical scientists to brainstorm on current reproductive health issues such as repeated implantation and pregnancy failure, preterm birth, preeclampsia and genital tract infections such as HIV. The goal of the meeting was to foster cross-pollination of ideas as well as to encourage participation of young investigators in the field. The conference was preceded by the 4th Annual Post-Graduate Workshop with the theme of bringing bedside problems to the bench and facilitating collaboration between clinicians and basic scientists. Christopher Davies and Richard Bronson chaired the conference, which hosted approximately 180 delegates representing more than 26 countries across Asia, Australia, Latin America, Europe and North America.

PIBF – Progesteron induzierter Blockierfaktor

Pregnancy is a unique immunological situation in which 2 allogeneic organisms live in intimate symbiosis without developing rejection reactions. At different locations, interfaces exist between mother and foetus with direct contact between both individuals: 1) maternal blood surrounds foetal villi, which are covered with syncitiotrophoblast cells; 2) cytotrophoblast cells invade the decidua, in which they touch tissue lymphocytes; 3) trophoblast cells, which substitute endothelium of maternal arterioles filled with maternal blood; and 4) trophoblast particles, which are expressed from syncytiotrophoblast and circulate within the maternal blood until they settle in the lung capillaries, where they become degraded by alveolar macrophages. Several factors are known which support the specific immunotolerance of the mother to her foetus and are focussed by current research in reproductive immunology. One of these factors is progesterone-induced blocking factor (PIBF). Originally, it was discovered as a 34 kDa protein, which is released from lymphocytes of healthy pregnant women under the influence of progesterone. PIBF has immunomodulatory functions in vivo and in vitro, which are important for the establishment of immunotolerance between mother and foetus and, thereby, for the regular course of pregnancy. Finally, during the last years, several tumours have been identified to produce PIBF, which supports their immune escape and which may have the potential to become a novel tumour biomarker and which may lead to the development of new therapeutic strategies.

Thirty Years of Reproductive Immunology: An Introduction

Since the birth of Reproductive Immunology when Peter Medawar first posed the question of why the semi-allogeneic fetus is not rejected by the mother, scientists have been intrigued by the role of the immune system in pregnancy. In 1981, the American Society of Reproductive Immunology was founded, and over the past 30 years, it has seen the field flourish and expand to encompass a wide range of topics. We now know that the immune system and immunological processes are involved in more than just fetal immunotolerance, by playing a role in maintaining host protection throughout the non-pregnant genital tract; preparing the endometrium for implantation of the blastocyst; and supporting both pregnancy and parturition. Moreover, disruptions in these well-controlled immune functions can play important contributory roles in infectious diseases, infertility, and a number of pregnancy complications. By understanding the basic immunological mechanisms in reproduction, only then can we begin to determine better ways to predict and prevent infertility, obstetrical problems, and women’s health issues. The aim of this special issue is to highlight some of the key areas of human Reproductive Immunology research as up-to-date reviews by leaders in the field. This special issue begins with two overviews of the interactions between the immune system and reproduction. Dr Yoshinaga presents an overview on the role of immunological factors in pregnancy. He defines the role of blastocyst implantation factors as immunological products regulating the process of implantation and reproduction. Dr Mor and Cardenas discuss what are the potential interactions between the maternal and fetal immune systems in normal pregnancy. The next section presents four reviews on the role of immune cells during implantation and pregnancy. Dr Mandelboim provides the first review on how the unique properties of uterine NK cells facilitate the establishment of pregnancy and discusses their origins. Dr Zenclussen and colleagues assess the role of T regulatory cells in promoting immune tolerance against the fetus. Drs Nagamatsu and Schust give an in-depth overview of the phenotype and functions of decidual macrophages throughout gestation and discuss their roles in certain pregnancy disorders. Finally, Dr Croy and her team talk about how studies in mice are helping to answer questions regarding the role of NK cells at the maternal–fetal interface in vasoregulation and angiogenesis. In the next section, cytokines and other regulatory factors in pregnancy, Jessica Thaxton and Surendra Sharma discuss the immunomodulatory properties of IL-10 and its importance in pregnancy. Udo Markert and colleagues give an overview of the role of cytokines, MMPs, and galectins in the regulation of trophoblast invasion. We next present three reviews on immunotolerance in pregnancy, which begins with Drs Petroff and Perchellet describing how placental B7 family members regulate T-cell responses generated toward the fetus. Dr Mincheva-Nilsson and colleagues give a highly detailed overview of the characteristics of placental-derived exosomes and their role in regulating the maternal immune system during pregnancy. Lastly, Dr. Redman describes the role of placental-derived material, as well as other immunological mechanisms, in the pathogenesis of preeclampsia. The next section is on sexually transmitted infections and inflammation. Dr Wira and colleagues present an extremely detailed review on the role of steroid sex hormones in regulating the innate mucosal immunity of the non-pregnant female genital tract and how disruptions in natural antimicrobial production may render women vunerable to sexually transmitted infections. Dr Kaushic and her group discuss the ability of the female reproductive tract to generate specific anti-HIV responses. Alison Carey and Kenneth Beagley assess the impact Chlamydia trachomatis infection of the female reproductive tract has on women’s health and what methods are being employed in vaccine development. In the final section of this special issue, clinical aspects of reproductive immunology, Drs Koga and Mor discuss in detail the role of Toll-like receptors in normal pregnancy as well as in pregnancy complications. The review presents potential clinical applications as a result of our understanding of Toll-like receptor biology. Dr Saito’s review discusses up-to-date information on T cells and pregnancy and their clinical association with pregnancy complications, such as preeclampsia and preterm labor. Similarly, Dr Kwak-Kim and colleagues give a clinical overview of how research on reproductive immunology may be applicable for clinical practice. We conclude this special issue with an historical overview of the field of Reproductive Immunology by Dr Gerard Chaouat. His provocative discussion challenges old and new concepts and invite for novel approaches to understand this complex but relevant subject that is the immunology of pregnancy. I thank all the authors involved in celebrating the field of Reproductive Immunology through their outstanding contributions.

The Use of Gene Therapy Tools in Reproductive Immunology Research

Mammalian pregnancy is a complex phenomenon allowing the maternal immune system to support its allogeneic fetus, while still being effective against pathogens. Gene therapy approaches have the potential to treat devastating inherited diseases for which there is a little hope of finding a conventional cure. In reproductive medicine, experimental trials have been made so far only for correcting gene defects in utero. The use of gene therapy for improving pregnancy-rate success or avoiding pregnancy-related diseases i.e. miscarriage or pre-eclampsia, remains a very distant goal with unresolved moral and ethical aspects. However, gene therapy may help determining the role of several genes in supporting fetal growth and/or avoiding its rejection experimentally and might further help to identify new targets of intervention. Gene therapy strategies to avoid fetal rejection may include the transfer and expression of cyto-protective molecules locally at the fetal-placental interface. In addition, the ex-vivo genetic modification of immune cells for tolerance induction is a novel and tempting approach. In this regard, we have confirmed the role of the cyto-protective and immunomodulatory molecule Heme Oxygenase-1 (HO-1), by treating animals undergoing abortion with an adenovirus coding for HO-1. Since the sole application of a control vector did not provoke deleterious effects in pregnancy outcome, we propose the use of experimental gene therapy for unveiling molecular and cellular pathways leading to pregnancy success.

The immunology of successful pregnancy

Immune responses play an important role in various reproductive processes, including ovulation, menstruation and parturition. Clearly, during pregnancy, when the mother must accept a semi-allogeneic fetus, immune responses also play a very important role. This was first recognized by Medawar in 1953, when the concept of the fetal allograft was presented in order to explain the immunological relationship between mother and fetus. Since then, the immunology of pregnancy has been the leading subject within reproductive immunology research. Yet, the question of why the semi-allogeneic fetus is not rejected by the mother remains unresolved. The present review provides an update of current knowledge on the subject of the so-called 'immunological paradox of pregnancy'.

A rational basis for antiphospholipid antibody testing and selective immunotherapy in assisted reproduction: a rebuttal to the American Society for Reproductive Medicine Practice Committee opinion

A rational basis for antiphospholipid antibody testing and selective immunotherapy in assisted reproduction: a rebuttal to the American Society for Reproductive Medicine Practice Committee opinion

Report of a joint National Institutes of Health (NIH)/ Agency for International Development (AID)/ Program for Applied Research in Fertility Regulation (PARFR) Workshop on Research and Development of Immunological Methods of Fertility Regulation

Reproductive immunology has been identified as a topic of interest by several national and international agencies supporting contraceptive development. Owing to these interests, a joint NIH/AID/PARFR Workshop on Research and Development of Immunological Methods of Fertility Regulation was convened at NIH. The purpose of the Workshop was to review current research in reproductive immunology with specific reference to research on sources of antigens that have the potential for eliciting an immune response and which can interfere with reproductive processes in both the male and the female. The Workshop resulted in recommendations to investigators and funding agencies interested in conducting and supporting research and development activities in this field, respectively. It was the consensus that immunological approaches offer some unique advantages in fertility regulation, however, a considerable research effort must be mounted to recognize their full potential.