Alla Arefieva

Evidence indicates that seminal plasma (SP) has pregnancy-favorable biological effects, but there is no definitive proof that exposure to SP increases pregnancy rates in assisted reproductive techniques. We previously showed that this discrepancy may be due to male stress altering SP composition. This study investigated the association between male stress biomarkers in saliva, serum and SP and key determinants of female fertility in women exposed to their partner’s SP during the intracytoplasmic sperm injection (ICSI) cycle. The prospective pilot study included couples with tubal infertility who had unprotected intercourse during the ICSI cycle, supplemented by intravaginal SP injection on the oocyte retrieval day. Salivary cortisol and seminal noradrenaline were quantified by enzyme-linked immunosorbent assay to assess the activity of the hypothalamic–pituitary–adrenal axis and sympathetic nervous systems. Seminal interleukin-18 was measured using LegendPlex™ technology. Cluster analysis of male stress biomarkers identified two neuroendocrine-immune (NEI) phenotypes, characterized by signs of acute (phenotype-1) and chronic (phenotype-2) stress. Women with NEI phenotype-2 partners had fewer collected, mature, and fertilized oocytes, thinner endometrium, and significantly lower pregnancy rates (18.2%) compared to those with NEI phenotype-1 partners (84.6%). These data may suggest a dual role for SP in female fertility, depending on the type of male stress.

This study aimed to determine whether male stress is related to seminal stress biomarkers and pregnancy achievement in women exposed to their partner’s seminal plasma (SP) in the intracytoplasmic sperm injection (ICSI) cycle. In this pilot prospective study, 20 couples undergoing ICSI, as well as 5 fertile sperm donors and 10 saliva donors, were investigated. Women were exposed to their partner’s SP via unprotected sexual intercourse during the ICSI cycle and intravaginal application on the day of ovum pick-up (Day-OPU). Semen samples were collected from male partners by masturbation on the Day-OPU. Saliva and serum samples were collected prior to masturbation. Body fluids were frozen at − 80 °C until assayed. Biomarkers of activity of the sympathetic adrenomedullary axis (salivary alpha-amylase and adrenaline), sympathetic neural axis (noradrenaline and dopamine), hypothalamic–pituitary–adrenal (HPA) system (cortisol), and immune system (C-reactive protein and interleukin (IL)-18) were estimated to examine their association with SP composition and clinical pregnancy achievement. The clinical pregnancy rate was 45.0%. In the unsuccessful ICSI group, blunted levels of salivary and serum cortisol were found compared to the successful ICSI group and the fertile sperm donors. With regard to seminal markers, decreased cortisol level and elevated noradrenaline, noradrenaline/cortisol ratio, and lL-18 levels were strongly associated with ICSI failure (areas under the ROC curves were, 0.813, 0.848, 0.899, and 0.828, respectively). These findings confirm that stress response systems activity affects SP composition, which in turn is associated with ICSI outcomes in women exposed to their partner’s SP during an ICSI cycle. Graphical Abstract

Problem: We hypothesized that expression of transmembrane glycoprotein CD200 on paternal lymphocytes used for pre‐gestational lymphocyte immunotherapy (LIT) of recurrent spontaneous abortion (RSA) can suppress the pro‐inflammatory Th1‐type immunity required for successful implantation. To reveal the association between CD200 expression, female immune background after LIT, and pregnancy establishment, we have performed this work.Method of study: Pre‐gestational alloimmunizations were given to 37 women using paternal peripheral blood leukocytes, combined with additional alloimmunizations in case of pregnancy. Lymphocyte phenotypes were determined by flow cytometry. Cytokines produced by mitogen‐stimulated female peripheral blood cells were estimated by FlowCytomix™ technology.Results: We have shown that 78.4% (29/37) of women became pregnant within 12 menstrual cycles after pre‐gestational LIT. Pregnancy establishment depends on the intensity of CD200 expression, which is significantly higher on the CD200⁺ lymphocytes administered to women who later did not achieve pregnancy (P < .05). The expression of CD200 negatively correlates with the ratios of Th1/Th2 cytokines produced by female peripheral blood cells (P < .05) and positively correlates with the frequency of female circulating regulatory T cells after LIT (P < .05). The ROC analysis showed that the intensity of CD200 expression and the Th1/Th2 ratios are the significant predictors of pregnancy establishment after pre‐gestational LIT (P < .05 and P < .01, respectively).Conclusion: Elevated CD200 expression on allogeneic lymphocytes most likely suppresses the pro‐inflammatory Th1‐type immunity needed for successful embryo implantation. Therefore, a personalized approach of LIT should be applied to avoid negative effects of such immunomodulation on pregnancy establishment.

The transmembrane CD200 glycoprotein belongs to the immunoglobulin family and it is widely represented on a variety of cell types, while its structurally similar CD200R receptor is expressed, mainly, on myeloid and lymphoid cells. An immunomodulatory role of CD200 and CD200R interaction is to activate the intracellular inhibitory cascade of reactions, leading to suppression of effector immune cells and attenuation of the inflammatory process. Thus, the CD200R activation stimulates the differentiation of naive T cells to regulatory T cells, increasing the indolamine 2,3-dioxygenase activity, and enhances the synthesis of IL-10 and TGF-β cytokines, contributing to development of a Th2-dependent anti-inflammatory environment. These immune regulatory events provide the development of immune tolerance and are required for controlling the development of autoimmune processes, hypersensitivity, engraftment of transplanted organs and tissues, as well as protecting the fetus from spontaneous abortion. Tolerogenic potential of interaction between CD200 and CD200R molecules can be effectively used for treatment of various diseases (e.g., Alzheimer’s, rheumatoid arthritis, allergies). In this review, we will address the role of CD200/CD200R interactions in stimulating the post-transplant engraftment and protecting a fetus from spontaneous abortion. Many in vivo and in vitro studies have suggested a key role of CD200/CD200R interaction in immune maintenance of both processes.

Seminal plasma (SP) is thought to be a crucial factor which affects the expansion of regulatory T cells (Tregs) in female reproductive tract during embryo implantation. We propose that seminal transforming growth factor (TGF) β1 is responsible for local accumulation of circulating Tregs, which manifests as changes in Treg frequency in peripheral blood, whereas seminal interleukin (IL) 18 interferes with TGF-β1-dependent cellular reactions. The purpose of the present study is to determine whether the frequency of circulating Tregs is associated with the levels of seminal cytokines and pregnancy establishment in women exposed to partner’s SP during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle. Twenty-nine women were exposed to SP via timed intercourse before the day of ovum pickup (day-OPU) and also subjected to intravaginal SP application just after OPU. Measurements of seminal TGF-β1 and IL-18 were made by FlowCytomix technology. The percentage of CD4⁺CD25⁺CD127^low+/– Tregs among total circulating CD4⁺T cells was determined by flow cytometry and the difference between Treg values on the day of embryo transfer and day-OPU was calculated. The percentage of Tregs on the day-OPU, identified as a predictive factor of clinical pregnancy after IVF/ICSI, showed a positive correlation with IL-18 concentration and content of this cytokine per ejaculate ( P < .001 and P < .004, respectively) and negative correlation with the TGF-β1/IL-18 ratio ( P < .014).These findings indicate that the adverse effect of seminal IL-18 excess on implantation may be realized by the prevention of postcoital TGF-β1-related migration of circulating Tregs, which clearly manifests as elevated level of Treg frequency in peripheral blood.

The immunological profiles of human specific IgE (sIgE) and specific IgG4 (sIgG4) vary by genetic predisposition, living conditions in different geographical locations and patient’s age. The aim of our study was to analyze sIgE and sIgG4 patterns and their age-dependent changes in patients from the Moscow region. For identifying sIgE and sIgG4 profiles the blood samples from 513 patients aged 6 months to 17 years who were showing symptoms of allergic diseases were analyzed using microarrays containing 31 allergens. The highest sIgE prevalence was observed for birch pollen (32%) among pollen allergens, cat dander (24%) among indoor allergens, and egg whites (21%) among food allergens. The most common sIgG4 response was developed toward egg whites (80% of patients). Age-related elevation was identified for patients with increased sIgE to pollen allergens and indoor allergens (cat or dog dander and house dust mites). For each allergen, the proportion of cases with significant levels of sIgG4 appeared to increase with patients’ age. The data on allergen-specific sIgE and sIgG4 prevalence show both general trends and some local special aspects that are indicative for the Moscow region. This information should be useful in terms of epidemiology of allergic diseases.

Allergic and autoimmune diseases represent immunopathological reactions of an organism to antigens. Despite that the allergy is a result of exaggerated immune response to foreign antigens (allergens) and autoimmune diseases are characterized by the pathological response to internal antigens (autoantigens), the underlying mechanisms of these diseases are probably common. Thus, both types of diseases represent variations in the hypersensitivity reaction. A large percentage of both the adult and pediatric population is in need of early diagnostics of these pathologies of the immune system. Considering the diversity of antibodies produced in allergic and autoimmune disease and the difficulties accompanying clinical diagnosing, molecular diagnostics of these pathological processes should be carried out in several stages, including screening and confirmatory studies. In this review, we summarize the available data on the molecular diagnostics and therapy of allergic and autoimmune diseases and discuss the basic similarities and differences in the mechanisms of their development.