Regulation of the innate immune cells during pregnancy: An immune checkpoint perspective.

The foetus can be regarded as a half-allograft implanted into the maternal body. In a successful pregnancy, the mother does not reject the foetus because of the immune tolerance mechanism at the maternal-foetal interface. The innate immune cells are a large part of the decidual leukocytes contributing significantly to a successful pregnancy. Although the contributions have been recognized, their role in human pregnancy has not been completely elucidated. Additionally, the accumulated evidence demonstrates that the immune checkpoint molecules expressed on the immune cells are co-inhibitory receptors regulating their activation and biological function. Therefore, it is critical to understand the immune microenvironment and explore the function of the innate immune cells during pregnancy. This review summarizes the classic immune checkpoints such as PD-1, CTLA-4 and some novel molecules recently identified, including TIM-3, CD200, TIGIT and the Siglecs family on the decidual and peripheral innate immune cells during pregnancy. Furthermore, it emphasizes the role of the immune checkpoint molecules in pregnancy-associated complications and reproductive immunotherapy.

NK cells that differ in expression of NKp46 might play different roles in endometrium.

NKp46 is a natural cytotoxicity receptor expressed by NK cells and its expression is decreased in reproductive failure patients. NKp46 can be subdivided into NKp46dim and NKp46bright according to different fluorescence staining intensities. We investigated the role of the NKp46 receptor in determining the reproductive outcomes. Uterine endometrium was collected from 34 women with reproductive failure and divided into the pregnant and failed groups based on the results of a pregnancy reaction test during a 1-year follow-up period. NKp46 receptor and other activating or inhibitory receptors expressed on NK cells as well as intracellular cytokine production by NK cells were analyzed by multicolor flow cytometry. In the failed group, the percentage of NKp46dim NK cells (P < 0.05) was significantly higher and percentages of NKp46bright NK cells (P < 0.01) and CD16-/CD56bright NK cells (P < 0.05) were significantly lower than those in the pregnant group. NKp46dim NK cells were significantly and positively correlated with CD16+/NKp46dim NK cells; NKp46bright NK cells were significantly and positively correlated with CD16-/NKp46bright NK cells. CD16+/NKp46dim NK cells were significantly and positively correlated with IFN-γ- and/or TNF-α-producing NK cells; CD16-/NKp46bright NK cells were significantly and positively correlated with TGF-ß1-producing NK cells. We suggest that the NKp46 receptor plays different roles in reproduction based on the different fluorescence intensities associated with NK cells, i.e. NKp46dim NK cells are involved in killing cells, whereas NKp46bright NK cells are involved in cytokine production, indicating that NKp46 could be a predictive marker to see a tolerate condition for embryos.

Effects of SARS-CoV-2 infection on human reproduction.

The worldwide infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts human health and life on multiple levels. People infected with SARS-CoV-2 suffer from physical disorders and psychological distress. At present, no direct evidence indicates that SARS-CoV-2 negatively influences human reproduction, and the possibility that gametes and embryos are affected requires further investigation. To evaluate the potential effects of SARS-CoV-2 infection on human reproduction and fetal health, this review summarizes the basic and clinical research of SARS-CoV-2 on reproduction up to date, hoping to offer guidance and advice to people at reproductive age and provide clues for the prevention and treatment of associated diseases.

Ovarian morphometrical evaluation to assess reproductive activity suppression in heavy weight finishing gilts immunized against gonadotropin-releasing hormone.

It is known that immunizing gilts against gonadotropin-releasing hormone (GnRH) is an efficient castration method that increases their growth performance. However, it is still unknown the ovarian histophysiology outcomes after this procedure. Therefore, the aim of this study was to investigate in detail, using morphological and morphometrical methods, changes in the ovarian structure that result in the suppression of ovarian activity, as well as to gain knowledge on the ovarian structure to assist in ovarian histopathological diagnoses. Seventy-two pre-pubertal finishing gilts were allocated to two experimental groups: immunized (IC; n = 36; gilts which received two injections of 2 mL of Vivax® - one at 15 and another at 19 weeks of age) and control (CT; n = 36, females which received two saline injections following the same protocol). All gilts were euthanized at 25 weeks of age and the ovaries of 5 gilts from each experimental group collected for biometrical and histomorphometrical analysis. IC gilts showed higher body weights, but smaller ovaries compared to CT females. In addition, the number of small follicles (≤ 2 mm) on the ovarian surface was higher, while no large follicles (> 6 mm) nor corpora lutea were found in the ovaries of IC gilts. Histomorphometrical analysis revealed that IC females showed higher numbers of quiescent and active primordial, primary, pre-antral and final stage atretic follicles. Moreover, follicle size, antrum diameter and area of the granulosa layer from mature follicles were smaller in IC gilts. Collectively, these results demonstrate that the efficacy of immunization against GnRH is related to the blockage of follicular recruitment and selection, thus suppressing reproductive activity in finishing gilts.

Identifications of immune-responsive genes for adaptative traits by comparative transcriptome analysis of spleen tissue from Kazakh and Suffolk sheep.

Aridity and heat are significant environmental stressors that affect sheep adaptation and adaptability, thus influencing immunity, growth, reproduction, production performance, and profitability. The aim of this study was to profile mRNA expression levels in the spleen of indigenous Kazakh sheep breed for comparative analysis with the exotic Suffolk breed. Spleen histomorphology was observed in indigenous Kazakh sheep and exotic Suffolk sheep raised in Xinjiang China. Transcriptome sequencing of spleen tissue from the two breeds were performed via Illumina high-throughput sequencing technology and validated by RT-qPCR. Blood cytokine and IgG levels differed between the two breeds and IgG and IL-1ß were significantly higher in Kazakh sheep than in Suffolk sheep (p < 0.05), though spleen tissue morphology was the same. A total of 52.04 Gb clean reads were obtained and the clean reads were assembled into 67,271 unigenes using bioinformatics analysis. Profiling analysis of differential gene expression showed that 1158 differentially expressed genes were found when comparing Suffolk with Kazakh sheep, including 246 up-regulated genes and 912 down-regulated genes. Utilizing gene ontology annotation and pathway analysis, 21 immune- responsive genes were identified as spleen-specific genes associated with adaptive traits and were significantly enriched in hematopoietic cell lineage, natural killer cell-mediated cytotoxicity, complement and coagulation cascades, and in the intestinal immune network for IgA production. Four pathways and up-regulated genes associated with immune responses in indigenous sheep played indispensable and promoting roles in arid and hot environments. Overall, this study provides valuable transcriptome data on the immunological mechanisms related to adaptive traits in indigenous and exotic sheep and offers a foundation for research into adaptive evolution.

The intersection of stress, sex and immunity in fishes.

While sexual dimorphism in immune responses has been documented in other vertebrates, evidence for a similar phenomenon in fish is lacking. Here, we review the relationship between immunity, stress, spawning, and sex hormones in fish to gain a better understanding of sex-based differences in fish immune responses and its consequences for aquaculture. It is well known that there is a strong link between the stress response and immune function in fish. In addition, research to date has demonstrated that sexual dimorphism in the stress response exists in many species; yet, the relationship between the sexual dimorphic stress responses and immune function has rarely been explored together. Aside from stress, spawning is also known to trigger changes in fish immune responses. Estrogens and androgens have been shown to modulate the immune system which could account for differences between the two sexes of fish when spawning; however, evidence regarding the sexual dimorphism of these changes varies between fishes and is likely related to the spawning strategy employed by a given species. Sex hormones are also used in aquaculture practices to produce monosex populations, and exposure to these hormones early in development has been shown to impact the development of immune organs in several fishes. While female fish are generally thought to be more robust than males, aquaculture practices should also consider the role that maternal stress has on the immune function of the offspring and what role this plays in compromising the immune response of farmed fish.

Natural killer cells and reproductive success.

Natural killer (NK) cell assessment has been attempted since the 1990s and, apart from antibody testing, is probably the commonest immune test available to clinicians. It is clear that simple enumeration of uterine NK cells by immunohistochemistry is inadequate, although better methodology such as flow cytometry may prove to be more beneficial in the future. Blood testing is an appealing noninvasive test that may be a marker for immune dysfunction, rather than a guide to uterine numbers per se. It is currently performed in women with repeated reproductive failure and should be done using tests of activation. Patients value investigation and clinicians should prefer it to blind empirical immune therapy in repeated reproductive failure cases. But, in addition to blood NK testing, a fundamental new NK genetic test (the KIR/HLA-C interaction) is likely to provide an even more effective diagnostic tool. Insights from KIR/HLA-C analysis imply that new immune therapy trials will need to take KIR/HLA-C results into account.

Novel predictive and therapeutic options for better pregnancy outcome in frozen embryo transfer cycles.

Since 1978, in the first decades of in vitro fertilization (IVF), the use of ovarian hyperstimulation allowed for the development and transfer of multiple embryos. As IVF technology improved, the number of multiple pregnancies increased, which led to gradual reduction in the number of embryos that were transferred. Embryo freezing (vitrification) was recommended to allow subsequent transfer if the fresh cycle was unsuccessful. However, experimentation has continued to improve pregnancy outcomes. We discuss here the significance of frozen embryo transfer cycle and the impact of uterine and peripheral immunity dominated by NK cells and regulatory T cells and human chorionic gonadotropin on pregnancy outcome in this innovative mode of IVF therapy.

Role of Kisspeptin in Regulation of Reproductive and Immune Reactions.

The work is focused on physiological role of the hormone kisspeptin produced by neurons of the hypothalamus anterior zone, which is a key regulator of reproduction processes. Role of the hormone in transmission of information on metabolic activity and induction of the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus that determines gestation processes involving fertilization, placentation, fetal development, and child birth is considered. The literature data on molecular mechanisms and effects of kisspeptin on reproductive system including puberty initiation are summarized and analyzed. In addition, attention is paid to hormone-mediated changes in the cardiovascular system in pregnant women. For the first time, the review examines the effect of kisspeptin on functional activity of immune system cells presenting molecular mechanisms of the hormone signal transduction on the level of lymphoid cells that lead to the immune tolerance induction. In conclusion, a conceptual model is presented that determines the role of kisspeptin as an integrator of reproductive and immune functions during pregnancy.

Photoperiodic manipulation modulates the innate and cell mediated immune functions in the fresh water snake, Natrix piscator.

Objectives of the current work were to investigate the role of photoperiod and melatonin in the alteration of immune responses in a reptilian species. Animals were kept on a regimen of short or long days. Blood was obtained and leucocytes were isolated to study various innate immune responses. Lymphocytes were separated from blood by density gradient centrifugation and were used to study proliferation. Respiratory burst activity was measured through nitrobluetetrazolium reduction assay while nitric oxide production by leucocytes was assayed by nitrite assay. Lymphocytes were isolated and used to study proliferation with and without B and T cell mitogens. Photoperiodic manipulation acted differentially on leucocyte counts. Nitrite release was increased while superoxide production was decreased in cultures obtained from the snakes kept on the short day regimen. Significant enhancement of mitogen induced lymphocyte proliferation was observed in cultures from the animals kept in either long or short days compared to cultures from the animals kept in natural ambient day length. Use of in vitro melatonin showed that lymphocytes from the animals, kept in long days, were more reactive. Photoperiod induces changes in immune status which may permit adaptive functional responses in order to maintain seasonal energetic budgets of the animals. Physiological responses (like elevated immune status) are energetically expensive, therefore, animals have evolved a strategy to reduce immune functions at times when energy is invested in reproductive activities. Natrix piscator breeds from September to December and elevated pineal hormone in winter suppresses reproduction while immunity is stimulated.

Effects in broiler hens of genetic lines differing in fertility, biotin supplementation, and age on relative abundance of oviductal transforming growth factor-ß and carbonic anhydrase mRNA transcripts.

There was evaluation of effects of biotin administration on oviductal abundance of transforming growth factor-ß (TGF-ß) and carbonic anhydrase (CA) mRNA transcript in younger and older broiler hens of relatively lesser and greater fertility lines. Additionally, effects of biotin supplementation on attenuation of age-related subfertility were evaluated. Hens from the relatively greater (Line D, n = 60) and lesser (Line B, n = 60) fertility rate line were randomly assigned to three treatment groups. Biotin was not or was administered in drinking water from 30 to 33 (younger age) and 53 to 56 (older age) wk of age to have access to no biotin (T0), or 0.3 (T1), or 0.45 (T2) mg/L of biotin. There was assessment the relative oviductal abundances of TGF-ß and CA mRNA transcript abundances. Supplemental biotin and age had no effect on the relative abundance of oviductal TGF-ß mRNA transcript in hens of Line D. There, however, was a ten-fold greater abundance of TGF-ß in hens of the T0 group of Line B compared with Line D. Relative abundance of TGF-ß mRNA transcript was greater in younger hens of Line B; however, biotin supplementation of older hens of the T2 group of Line B resulted in a similar TGF-ß abundance to that of younger hens. Inconstant with the TGF-ß abundance, CA abundance in hens of Line B was not affected by supplemental biotin or bird age. Overall, differences in TGF-ß or CA abundances did not affect fertility of broiler hens.

The immunogenetics of sexual parasitism.

Sexual parasitism has evolved as a distinctive mode of reproduction among deep-sea anglerfishes. The permanent attachment of males to host females observed in these species represents a form of anatomical joining, which is otherwise unknown in nature. Pronounced modifications to immune facilities are associated with this reproductive trait. The genomes of species with temporarily attaching males lack functional aicda genes that underpin affinity maturation of antibodies. Permanent attachment is associated with additional alterations, culminating in the loss of functional rag genes in some species, abolishing somatic diversification of antigen receptor genes, the hallmark of canonical adaptive immunity. In anglerfishes, coevolution of innate and adaptive immunity has been disentangled, implying that an alternative form of immunity supported the emergence of this evolutionarily successful group of vertebrates.

Vitamin D Effects on the Immune System from Periconception through Pregnancy.

Vitamin D is a well-known secosteroid and guardian of bone health and calcium homeostasis. Studies on its role in immunomodulatory functions have expanded its field in recent years. In addition to its impact on human physiology, vitamin D influences the differentiation and proliferation of immune system modulators, interleukin expression and antimicrobial responses. Furthermore, it has been shown that vitamin D is synthesized in female reproductive tissues and, by modulating the immune system, affects the periconception period and reproductive outcomes. B cells, T cells, macrophages and dendritic cells can all synthesize active vitamin D and are involved in processes which occur from fertilization, implantation and maintenance of pregnancy. Components of vitamin D synthesis are expressed in the ovary, decidua, endometrium and placenta. An inadequate vitamin D level has been associated with recurrent implantation failure and pregnancy loss and is associated with pregnancy-related disorders like preeclampsia. This paper reviews the most important data on immunomodulatory vitamin D effects in relation to the immune system from periconception to pregnancy and provides an insight into the possible consequences of vitamin D deficiency before and during pregnancy.

Genotypes and their interaction effects on reproduction and mating-induced immune activation in Drosophila melanogaster.

Mating causes considerable alterations in female physiology and behaviour, and immune gene expression, partly due to proteins transferred from males to females during copulation. The magnitude of these phenotypic changes could be driven by the genotypes of males and females, as well as their interaction. To test this, we carried out a series of genotype-by-genotype (G × G) experiments using Drosophila melanogaster populations from two distant geographical locations. We expected lines to have diverged in male reproductive traits and females to differ in their responses to these traits. We examined female physiological and behavioural post-mating responses to male mating traits, that is behaviour and ejaculate composition, in the short to mid-term (48 hr) following mating. We then explored whether a sexually transferred molecule, sex peptide (SP), is the mechanism behind our observed female post-mating responses. Our results show that the genotypes of both sexes as well as the interaction between male and female genotypes affect mating and post-mating reproductive traits. Immune gene expression of three candidate genes increased in response to mating and was genotype-dependent but did not show a G × G signature. Males showed genotype-dependent SP expression in the 7 days following eclosion, but female genotypes showed no differential sensitivity to the receipt of SP. The two genotypes demonstrated clear divergence in physiological traits in short- to mid-term responses to mating, but the longer-term consequences of these initial dynamics remain to be uncovered.

Evaluating the existence and benefit of major histocompatibility complex-based mate choice in an isolated owl population.

How mate preferences evolve in the first place has been a major conundrum for sexual selection. Some hypotheses explaining this assume fitness benefit derived from subsequent generations. Major histocompatibility complex (MHC)-based mate choice is a representative example of the mate choice that is associated with such trans-generational mechanisms. To provide evidences for fitness benefit of MHC-based mate choice, previous studies assessed the association between own MHC genotype and own fitness components. However, the association between MHC-based mate choice in the parental generation and fitness components in the resultant offspring generation has only rarely been measured in wild populations. Focusing on the isolated population of the monogamous Ryukyu Scops Owl (Otus elegans interpositus) on Minami-daito Island, Japan, we found evidence of MHC-based mate choice. However, we found no evidence of MHC-based mate choice increasing own reproductive success or offspring survival. This is a rare case study that directly examines the existence of the trans-generational indirect benefit of MHC-based mate choice for genetic compatibility from trans-generational data in a wild bird population. By investigating the fitness benefits of mate choice, this study serves to facilitate our understanding of the evolution of MHC-based mate choice.

The Role of B7 Family Molecules in Maternal-Fetal Immunity.

Pregnancy is a complex but well-arranged process, and a healthy fetus requires immune privilege and surveillance in the presence of paternally derived antigens. Maternal and fetal cells interact at the maternal-fetal interface. The upregulation and downregulation of maternal immunity executed by the leukocyte population predominantly depend on the activity of decidual natural killer cells and trophoblasts and are further modulated by a series of duplex signals. The B7 family, which consists of B7-1, B7-2, B7-H1, B7-DC, B7-H2, B7-H3, B7-H4, B7-H5, BTNL2, B7-H6, and B7-H7, is one of the most characterized and widely distributed signaling molecule superfamilies and conducts both stimulatory and inhibitory signals through separate interactions. In particular, the roles of B7-1, B7-2, B7-H1, and their corresponding receptors in the progression of normal pregnancy and some pregnancy complications have been extensively studied. Together with the TCR-MHC complex, B7 and its receptors play a critical role in cell proliferation and cytokine secretion. Depending on this ligand-receptor crosstalk, the balance between the tolerance and rejection of the fetus is perfectly maintained. This review aims to provide an overview of the current knowledge of the B7 family and its functions in regulating maternal-fetal immunity through individual interactions.

The Inflammasome in Reproductive Biology: A Promising Target for Novel Therapies.

The inflammasome is a key regulator of innate immunity involved in the inflammatory response to infections as well as disease through the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1ß and IL-18. Even though the inflammasome was first described in the context of infections, most research in recent years has focused on targeting the inflammasome as a therapeutic option in sterile inflammatory events. Recent evidence indicates a clear involvement of the inflammasome in Reproductive Biology such as infertility and preeclampsia. In this mini-review, I summarize the current findings on the inflammasome that have been described in the field of Reproductive Biology and highlight the potential that the inflammasome has as a novel therapeutic option in this field. The topics covered in this review as it pertains to the inflammasome field cover the literature published on male and female infertility, endometriosis, preeclampsia, placental inflammation, and reproductive senescence.