Vol 24, No 3 (2021)

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Neutrophilokines and the morphofunctional state of circulating neutrophils in ovarian tumors

Abakumova T.V., Gening T.P., Antoneeva I.I., Gening S.O., Gnoevykh V.V.


There is currently no clear understanding of the molecular participants providing cytotoxic and/or cytostatic activity of neutrophils (Nph) in relation to tumor cells. Cytokines produced by neutrophils are necessary for their paracrine and autocrine interactions with surrounding cells. In order to assess the effect of regulatory neutrophilokines on the morphofunctional state of circulating Nph in benign ovarian tumors and ovarian cancer, the ELISA method was used to assess the level of IL-4, IL-6, IL-10, IL-8, IL-18, IFNγ, MCP-1 and MMP-1in neutrophils, expression of CD11b, CD63, CD16, CD95. Determined the rigidity of the membrane and the ability of neutrophils to form NET. Statistical processing of the obtained data was carried out using the software Statistica 13.0, Jamovi It was found that in ovarian cancer the rigidity of neutrophils depends on the level of IL-10, MCP-1, IL-18, IL-8, IL-4, IFNγ, IL-6 in neutrophils. The method of multiple regression revealed the dependence of the ability to form NETs on the level of IL-4 and IL-6 in Nph. Revealed an inverse correlation between the rigidity of the membrane Nph and their ability to form traps in ovarian cancer. In benign ovarian tumors, a noticeable direct correlation was found between the rigidity of the neutrophil membrane and the adhesive marker CD11b. In ovarian cancer, a correlation was found between the rigidity of the Nph membrane and the CD63 degranulation marker. At benign ovarian tumors, no correlations were found between the number of activated neutrophils and the level of intracellular cytokines in Nph. In ovarian cancer, correlations were found between the number of CD11b+Nph and the level of IL-6, IL-8 in them; between the amount of CD63, CD95 and intracellular IL-8. The amount of CD16+Nph correlated with the level of MMP-1 and IL-8 in Nph. The amount of CD95+Nph correlated with the level of IL-18 in Nph. Thus, the change in the level of neutrophilokines in benign ovarian tumors did not correlate with changes in the ability to NETosis, expression of activation markers, but was accompanied by an increase in the rigidity of the membrane of circulating neutrophils. In ovarian cancer, an increase in IL-8 correlated with a decrease in CD16 expression and an increase in CD63; a decrease in CD16 correlated with an increase in MMP-1. An increase in membrane rigidity in ovarian cancer was associated with changes in all considered neutrophilokines (IL-4, IL-6, IL-8, IL-10, IL-18, MCP-1, IFNγ). The combination of IL-4, IL-6, IL-18 indices, NET number and membrane rigidity of circulating Nph (according to the results of multivariate analysis) can be used for differential diagnosis of ovarian cancer.

Russian Journal of Immunology. 2021;24(3):355-362
pages 355-362 views

Heterogeneity of NK-cells in pulmonary tuberculous granulomas, including association with HIV infection

Berdyugina O.V.


Interest in the study of cell population heterogeneity among immune system grows with advances in multicolor flow cytometry techniques. Natural killer cells are represented by several subpopulations. Their maturation is a continuous process that begins with CD27-CD11b--cells and ends with mature cells with the CD27-CD11b+-phenotype. Phthisiology is one of the areas for studying the NK-cell polymorphism due to the fact that the mechanism of prolonged persistence of M. tuberculosis in the human body is not fully understood. Moreover, there is increasing number of patients with infectious comorbidities, including the human immunodeficiency virus (HIV) infection. The aim of this study was to determine some subpopulations of NK cells in the patients with pulmonary tuberculous granuloma, as well as in the absence of a synergistic HIV infection.
The study involved 46 people grouped in three cohorts. The 1st group included 24 practically healthy people, the 2nd group consisted of 12 patients with pulmonary tuberculous granuloma without clinical and laboratory signs of HIV infection, and the 3rd group was represented by 10 patients with pulmonary tuberculous granuloma infected with HIV. The causative agent of pulmonary tuberculosis in all patients was drug-resistant. All the patients with HIV infection had stage 4 disease. Immunological status was assessed by flow cytometry. The following cell populations were detected: CD45+CD3+CD19-, CD45+CD3-CD19+, CD45+CD3-CD16+CD56+, CD3+CD16+CD56+, CD45+CD3-CD8+, CD45+CD3-HLA-DR+, CD45+CD3-CD16+CD56+CD11b+. Leukocytosis and leukogram were determined with a 5 Diff Mythic 22 AL clinical analyzer (Cormay, Poland). Statistical studies of the data were performed in the Windows 10 operating environment (Microsoft Corp., USA); the computer program Statistica v. 12.5 (StatSoft, USA) was used. The normality of the data distribution was also evaluated. Kruskal–Wallis one-way analysis of variance (pk-w) was used as criterion for assessing differences between the compared groups at a significance level of differences p < 0.017 (between three unrelated groups), as well as Wald–Wolfowitz test (pw-w) with a significance level of differences p < 0.05. Factor analysis was performed.
We have found that the presence of pulmonary tuberculous granuloma is accompanied by a decrease of NK-cells number by 33%, a two-fold decrease in the number of NKT-cells, a 34.3% decrease in the population of CD3-HLA-DR+-cells, and a 21.7% decrease in the number of CD3-CD16+CD56+CD11b+-cells. Coinfection with HIV in cases of pulmonary tuberculous granuloma was associated with a three-fold decrease in the leukocyte numbers, significant variability in lymphocyte counts, e.g., 3-fold decrease in NK-cell counts, with NK-cells expressing α-chain of the CD8 antigen decreased by 2.3 times; 6-fold drop of NKT-cell, CD3-HLA-DR+-cells decreased by 42.9%; 2.3-fold decline in CD3-CD16+CD56+CD11b+-cells. Decreased control of M. tuberculosis infection was observed both in patients with pulmonary tuberculous granuloma, and in presence of HIV infection as associated comorbidity.

Russian Journal of Immunology. 2021;24(3):363-372
pages 363-372 views

Altered expression of cell membrane HLA-G molecules in mothers of children with inborn heart defects upon exposure to plasma gamma-globulin from multiparous women

Shabaldin A.V., Deeva N.S., Sukhikh А.S., Vavin G.V., Kryukov P.M.


High incidence of newborns with inborn heart defects (HD) and sufficient contribution of this disorder into perinatal, infant and pediatric mortality, as well as disability levels, even after radical surgical treatment determine significance of search for novel methods of prediction and prevention of appropriate HD risks at the stage of pregnancy planning. HLA-G is among key molecules participating in immune interactions between maternal microenvironment and embryos. Maximal antibody titers for HLA antigens is detected in multiparous women. However, the question remains open, which HLA molecules participate in blockage of immune inflammation in the mother-embryo system: either by maternal antibodies, or by donor immune globulins. Hence, the aim of our study was to obtain enriched γ-globulin preparation from blood of multiparous women and evaluation of its activity towards female HLA-G molecules. The γ-globulin fraction (GGF) was obtained from blood plasma of muliparous women by means of affine chromatography using DEAE Affi-Gel Blue system (BioRad, USA). We have formed 2 groups: a control group (14 healthy males), and experimental group of 14 women who gave birth to the children with inborn heart defects.
The changes of HLA-G expression on lymphocytes exposed to GGF were evaluated according to a flow cytometry protocol with calculation of percentage values using appropriate quotients. Evaluation of functional activity exerted by the GGF concentrate in control group showed inhibition of HLA-G expression on CD3+ and CD--lymphocytes against effects of autologous serum. GGF effects in experimental group upon HLA-G expression were differently directed, e.g., GGF sufficiently inhibited membrane HLA-G expression on the CD3-negative lymphocytes, compared to control group. Meanwhile, GGF showed stimulatory effect upon CD3+-lymphocytes, or it did not show any inhibitory action. The preparation obtained may serve as prototype for intravenous infusion. Moreover, in future one may use such immunoglobulin preparations, both for immune prophylaxis of non-syndromal sporadic HDs at the pregragravidary stage, as well as at early terms of pregnancy. The therapeutic effect will achieved due to blockage of embryoblast HLA molecules available to recognition. 

Russian Journal of Immunology. 2021;24(3):373-376
pages 373-376 views

Features of polymorphic site combinations of Toll-like receptor (TLR) genes in children with ventricular septal defects

Shabaldin A.V., Tsepokina A.V., Shmulevich S.A., Ponasenko A.V.


Congenital heart disease is the leading cause of the childhood disability and mortality. The development of new technologies has made it possible to advance in diagnosis and treatment of congenital heart disease, but its etiology is poorly understood. Considering multifactorial origin of this disease, a search for biomarkers having fundamental and practical importance is of current interest. Study of the genetic component is one of the areas of research. E.g., Toll-like receptors (TLR) are important regulators of susceptibility to infectious and non-infectious diseases. Polymorphic variants with single nucleotide substitutions in these genes may be accompanied by changes in the structure and expression of the encoded proteins, thus affecting functional activity of these receptors. Our aim was to study some genetic predictors of congenital heart defects in children. Materials and methods. We examined 47 children (21 girls and 26 boys) with congenital heart defects: 23 children had a ventricular septal defect (VSD); 24 children, atrial septal defect (ASD). The patients in the main group were 1 to 9 years old. As a control group, 96 conditionally healthy age- and sex-matched children were examined. Real-time genotyping was carried out with Viia7 real-time PCR system (Applied Biosystems, USA) using TaqMan probes of four TLR genes (TLR1 rs5743611, rs5743551, TLR2 rs5743708, rs3804099, TLR4 rs4986791, rs4986790, TLR6 rs3775073, rs5743810). Results. The distribution of all studied polymorphic variants corresponded to the HardyWeinberg equilibrium. It was revealed that sporadic nonsydromal VSD are associated with G allele of the TLR2 gene (rs5743708) and T allele of the TLR6 gene (rs3775073). According to ROC analysis, the combination of these alleles is a significant parameter showing high degree of sensitivity (82.4%). Both TLR2 (rs5743708) and TLR6 (rs3775073) gene variants define amino acid substitutions (missense mutations) in TLR molecules. Thus, we concluded that genetic testing can be used to identify risk groups at the early stages.

Russian Journal of Immunology. 2021;24(3):377-380
pages 377-380 views

Study of relationships between maternal HLA-G gene polymorphism and intrauterine infection with risk of congenital malformations

Gordeeva L.A., Voronina E.N., Gareeva Y.V., Polenok E.G., Mun S.A., Glushkov A.N.


This study aims for assessing relationships between maternal HLA-G gene polymorphisms (rs41551813, rs12722477, rs41557518) and intrauterine infection with the risk of congenital malformations (CM) in infants. We studied 331 women who had offspring with CMs, and 408 women with one or more healthy children. Influence of the intrauterine infection was analyzed on the basis of laboratory tests. Diagnostics of bacterial vaginosis and vulvovaginal candidiasis by microscopic examination were conducted. Viral infections (herpes simplex virus type 2, cytomegalovirus, human papilloma virus type 16/18) as well as Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum, Gardnerella vaginalis; Trichomonas vaginalis and Toxoplasma gondii were detected by enzyme-linked immunoassay or polymerase chain reaction (PCR) techniques. The data were obtained from the medical cards of the surveyed women. The gene polymorphisms were typed for Thr31Ser (rs41551813, HLA-G*01:03) in exon 2, Leu110Ile (rs12722477, HLA-G*01:04) and 1597 delС (rs41557518, HLA-G*01:05N) in exon 3 HLA-G using real-time PCR followed by melting analysis. The study showed that maternal age was not a significant risk factor for CMs in the fetus/newborns. Meanwhile, the maternal intrauterine infections were shown to be a significant risk factor for CMs in their infants (OR = 1.57 (1.08-2.29); p = 0.002). It was found that the 110 Ile allele (HLA-G *01:04) was a risk factor for CMs incidence in the fetus/newborns (OR = 1.57 (1.08-2.29), p = 0.01). No association was found between the maternal rs41551813 and rs41557518 HLA-G genetic polymorphisms and CMs in the infants. Hence, intrauterine infections and maternal 110 Ile allele (HLA-G *01:04) may be suggested as risk factors for birth defects in the children. Our results will be useful in understanding the molecular mechanisms of immune disorders in feto-maternal interface.

Russian Journal of Immunology. 2021;24(3):381-386
pages 381-386 views

Sperm DNA fragmentation and total antiradical activity of sperm in men with exaggerated anamnesis

Dolgikh O.V., Dianova D.G., Krivtsov A.V.


Various intracellular and extracellular stimuli can promote excessive accumulation of reactive oxygen species and lead to detrimental effects on sperm function, in particular, damage to sperm DNA, thus often resulting into infertility. The aim of the study was to assess the degree of sperm DNA fragmentation by flow cytometry and to study total antiradical activity of sperm in men with infertility and chronic prostatitis using spectrophotometric technique. A total of 75 men were examined. The comparison group consisted of 45 men with chronic prostatitis beyond exacerbation. The observation group included 30 men with chronic prostatitis in remission state. We have found that in the subjects during the period of acute inflammation, pathological fragmentation of sperm DNA was revealed, being statistically significant (p = 0.004). It was registered 1.7 times more often than in the examined men during the remission of chronic prostatitis. Increased fragmentation of the sperm DNA was noted in 50% of men from comparison group. In the patients from observation group, the degree of sperm DNA fragmentation over reference ranges was observed in 80% of the subjects. In men diagnosed with chronic prostatitis at the exacerbation stage, there is a statistically significant (p <0.05) relationship between sperm DNA fragmentation and development of acute inflammatory process. It was shown that in the subjects from observation group, the mean value of antiradical sperm activity did not show statistically significant differences (p = 0.378) compared with results found in men from the comparison group. The presented results suggest a higher degree of sperm DNA fragmentation in the examined patients with chronic prostatitis at the stage of decompensation, which may point to excessively increased production of free radicals during the acute inflammatory process. Obviously, exacerbation of chronic prostatitis contributes to imbalance in the redox homeostatic system in men, thus creating prerequisites for excess of reactive oxygen species and significant fragmentation of sperm DNA. The identified changes, i.e., an increased sperm DNA fragmentation levels and a deficiency of total antiradical activity of sperm in men with chronic urogenital diseases, may play a pathogenetic role in occurrence and further development of infertility. The degree of sperm DNA fragmentation and markers of redox processes may serve as informative activity indices of the inflammatory process.

Russian Journal of Immunology. 2021;24(3):387-390
pages 387-390 views

Cytokine profile of seminal plasma and effectiveness of assisted reproductive technology programs

Arefieva A.S., Babayan A.A., Kalinina E.A., Nikolaeva M.A.


Increasing evidence shows that seminal plasma is among the most important immunoregulatory factors in female reproductive function. We suggest that the favorable effect of the partner’s seminal plasma (SP) upon pregnancy occurence in women during the cycle of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) may be provided by the balanced content of Th1/Th2-dependent seminal cytokines. Otherwise, in case of pathologic changes in SP composition, it may negatively affect the IVF efficiency. Our aim was to determine whether the levels of seminal IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-18, IFNγ, TNFα, TNFβ and TGF-β1 are associated with pregnancy establishment in female patients exposed to seminal plasma during IVF/ICSI cycle.
Twenty-eight female patients were exposed to seminal plasma via sexual intercourse before the day of oocyte retrieval, and also underwent intravaginal application of seminal plasma just after transvaginal puncture and oocyte retrieval. Quantitative measurement of seminal cytokines was performed by FlowCytomix™ technology. IL-1, IL-18 and TNFβ concentrations were significantly higher in non-pregnant group (p = 0.011; p = 0.030 and p = 0.008, respectively). The contents of IL-2, IL-6, IL-18 and TNFβ per ejaculate were also significantly higher in non-pregnant group (p = 0.020; р = 0.042; р = 0.030 and р = 0.004, respectively). We conclude that elevated concentrations of proinflammatory cytokines in seminal plasma, as well as their total excessive content per ejaculate may have an adverse effect on implantation and pregnancy establishment. 

Russian Journal of Immunology. 2021;24(3):391-398
pages 391-398 views

Macrophage inhibiting factor in women with habitual miscarriage in pregnancy following immunocytotherapy

Vtorushina V.V., Krechetova L.V., Inviyaeva E.V., Tetruashvili N.K.


The aim of our study was to evaluate the macrophage inhibitory factor (MIF) content of in peripheral blood serum, as well as MIF production by mitogen-stimulated cells from whole peripheral blood during pregnancy in women with idiopathic recurrent miscarriage who received immunocytotherapy both prior to and in the first trimester of pregnancy. The study involved 51 women 20 to 40 years old: 10 fertile healthy females beyond pregnancy, 23 women with idiopathic recurrent miscarriage (IRM), 18 women with a physiological course of pregnancy at different stages of gestation (12, in the first trimester; 12, in the second; 9, in third trimester). MIF content was assessed by multiplex analysis using flow fluorometry. Of 23 women with IRM, six lost their pregnancy in the first trimester, 14 women prolonged pregnancy to the full-term resulting into birth of a healthy child; three had premature births at 24 to 35 weeks with a live fetus. There were no intergroup differences in the serum MIF level in control women and in patients with IRM, both beyond and during pregnancy. However, the dynamics of this index during pregnancy, was similar with increase during the II and III trimesters in both groups of women (control and with IRM). During pregnancy, the dynamics of MIF production by mitogen-activated cells from peripheral blood was also similar, except for values in the II trimester: in this period, MIF production in women with IRM was significantly lower, although it was still increased 3 times compared to the 1st trimester (5-fold to controls). In women with physiological pregnancy, the serum MIF levels at 5 to 6 weeks were lower than in women in both IRM subgroups, but there was no difference in MIF content for women with miscarriage and full-term pregnancy. Similarly, there were no differences of MIF contents in the supernates of activated whole blood cells of women at the time of study within groups and between the groups at the same time of examination. It has been shown that ICT has a positive effect on the course and outcomes of pregnancy in women with pregnancy prolonged to full-term. The serum MIF content in women with full-term pregnancy is higher than in women with miscarriage, which is consistent with results of other authors about adverse developmental effects of low serum MIF levels at early pregnancy terms. The results obtained indicate that immunocytotherapy do not regularly promote pregnancy to full term in women with IPV. Therefore, further research is required to find out criteria for administering ICT in treatment of idiopathic recurrent miscarriage.

Russian Journal of Immunology. 2021;24(3):399-408
pages 399-408 views

Role of apoptosis disturbances in external genital endometriosis

Avanesova T.G., Levkovich M.A., Ermolova N.V., Krukier I.I., Dudareva M.V.


External genital endometriosis (EGE) is currently considered one of the most common disorders in women at their reproductive age. EGE is a chronic disease that affects about 10% of women of reproductive age, leading to functional and structural changes in reproductive system, infertility, pelvic pain, and affects their quality of life. Moreover, the patients with endometriosis often suffer from depression, especially, due to pain syndrome. Endometriosis is associated with dysregulation of T-cell immune response, which presents as altered interactions between T-cells, macrophages, NK (natural killer cells), B-cells, thus allowing ectopic implantation of endometrial cells. The pronounced negative effect of EGE on the quality of life of patients, their reproductive function, impaired adaptation of the patients in community, and growing costs of treatment determine social significance of the disease and importance of appropriate studies. It is obvious that disorders of the immune system play a significant role in IGE development. However, despite extensive research in this area, the processes of apoptosis in IGE have not been sufficiently studied. Therefore, the aim of our study was to assess the origin of apoptosis disorders in women with stage I-II and III-IV of external genital endometriosis. We examined 71 patients with EGE which were divided into 2 groups: group 1 included the patients with EGE stage I-II (n = 31), and group 2, the patients with stage III-IV EGE (n = 40). The control group included 24 patients without EGE. The population profile of peripheral blood lymphocytes was determined by laser flow cytometry using Immunotex reagents, i.e., FITC-labeled CD8+, CD16+, and PE-labeled CD95+ antibodies. The number of lymphocytes entering apoptosis was detected using a diagnostic kit for AnnexinV+ (FITC) and PI+ from Caltag. The results were read on a BECKMAN COULTER EPICS XL-II flow cytometer using standard protocols.
An imbalance between activation and apoptosis of immunocompetent cells may be a significant cause of EGE. Induction of apoptosis by the Fas-FasL pathway in patients with external genital endometriosis leads to decreased cytotoxicity mediated by T-lymphocytes and NK-cells. A statistically significant decrease in the content of AnnexinV+ presenting lymphocytes suggests impairment of their receptor-dependent apoptosis.
Altered apoptosis processes may be responsible for the development of IGE by promotion of proliferation and growth of endometrioid implants.

Russian Journal of Immunology. 2021;24(3):409-412
pages 409-412 views

Detection frequency and duration of lupus anticoagulant circulation in COVID-19 patients

Beznoshchenko O.S., Shpilyuk M.A., Ivanets T.Y., Krechetova L.V., Pyregov A.V., Kodatsky D.S., Tavluyeva E.V., Melkumyan A.R., Gorodnova E.A., Dolgushina N.V.


The aim of the work was to determine frequency of lupus anticoagulant (LA) detection in patients at various degrees of COVID-19 severity as well as duration of LA circulation after the infectious disease. The study included 103 patients with COVID-19. The patients were observed during the hospital care and in ambulance, if required. The patients were admitted to the departments of infectious diseases arranged at the V.I.Kulakov National Medical Research Center for Obstetrics, Gynecology, and F.I. Inozemtsev City Clinical Hospital. Treatment schedules and stratification of the patients by clinical severity was carried out in accordance with Interim Guidelines issued by the Ministry of Health of the Russian Federation for the prevention, diagnosis and treatment of new coronavirus infection (version 9). The following groups were formed: mild (n = 27), moderate (n = 55) and severe (n = 20). The patients were tested for LA positivity in the course of disease: on the day of starting medical care (with outpatient observation), or on the day of hospitalization; repeated tests were made before discharge (inpatients), and later, 1-2 months and 7 months after recovery. Lupus anticoagulant was determined by two independent tests (dRVVT and SCT), i.e., as a screening test and a confirmation test. At initial examination, LA was found in 50 patients (49%). The effect of LA in 98% of cases was observed with dRVVT test, as an increase of normalized ratio (NR). The maximum median value of NR was 1.54 (0.97: 2.1) was revealed in patients with severe course of COVID-19 (p < 0.0001) compared with other groups and correlated with severity of the infectious process (r = 0.491, p < 0.0001). In mild cases of COVID-19, LA was detected less often (4 cases, 14.8%) than in moderate severity cases (27, 49.1%), and severe patients (19, 95%) (p < 0.05). Re-examinations of the patients before discharge from the hospital and 1-2 months later revealed high frequency of LA (p < 0.05). However, no LA-positive test was found 7 months after discharge. In patients with COVID-19, high frequency of circulating LA was registered, depending on severity of the infectious process. In addition, we have first shown that persistence of the circulating LA over post-infectious period does not exceed 7 months. 

Russian Journal of Immunology. 2021;24(3):413-418
pages 413-418 views

Glycoarrays for diagnosis and therapy of the disorders of the female reproductive system

Shilova N.V., Bovin N.V., Nokel A.Y., Ziganshina M.M., Khasbiullina N.R., Vuskovic M., Huflejt M.E.


The development of effective methods for prediction, diagnostics and treatment of female reproductive disorders is an urgent task. Natural antiglycan antibodies (AGAT) are of great interest in both diagnostic and therapeutic aspects, since AGATs are very diverse, and their specificities were selected in the course of natural evolution. In this work, we investigated the possibility of using glycoarray technique, as well as the signature approach to predict effectiveness of therapy in breast cancer (BC), as well as a targeted search for natural antibodies with therapeutic potential.
We studied blood serum samples of apparently healthy female donors (n = 27), and patients with established diagnosis of metastatic breast cancer prior to starting therapy (n = 29). The median age of the patients was 48 years, 41% had “ER/PR+”-status, 59% – “ER/PR-“-status. The median age of healthy subjects was 50 years. The patients received combined therapy with doxorubicin and herceptin with different outcomes: 11 patients did not respond to treatment and 18 patients showed clinical response (the tumor was not revealed). For the study with AGAT, glycoarray was used, on which more than 200 different glycans were printed. The antibodies bound to the ligands were detected using biotinylated goat antibodies against human Ig (G+M+A). To search for a combination of diagnostically significant AGATs (signatures), the previously developed calculation tool “Immunoruler” was used.
An opportunity of using glycoarray to predict efficiency of therapy was studied in breast cancer patients. The study included patients receiving combination therapy with doxirubicin and herceptin, with clinical response monitored at 18-24 weeks. A signature consisting of 10 AGATs with high sensitivity and specificity (90 and 91%, respectively) proved to predict efficiency of the administered therapy.
The possibility of breast cancer diagnosis using AGAT has been further confirmed. The specified signature included five antibodies: the level of two AGATs was significantly higher in patients than in donors, which could be adaptive antibodies developed in response to emerging malignancy. For three other antibodies, the registered signals in patients were lower than in healthy controls, thus, probably, indicating depletion of humoral immunity during the development of breast cancer. Hence, such AGATs may have some therapeutic potential, and, by usage of glycoarray screening technology, they could be searched in purposeful manner.

Russian Journal of Immunology. 2021;24(3):419-424
pages 419-424 views

Outcomes of IVF programs with intrauterine administration of autologous mononuclear cells in women with repeated implantation failure

Vtorushina V.V., Krechetova L.V., Perminova S.G.


Frequency of the repeated implantation failure (RIF) in assisted reproductive technology programs remains to be high, reaching 50-75%. Intrauterine administration of autologous mononuclear cells before embryo transfer is a technique for the RIF immunocorrection being used in assisted reproductive technology programs. Direct effect of mononuclear cells upon implantation was first studied in 2006 and showed that intrauterine administration of autologous mononuclear cells prior to embryo transfer proved to significantly increase implantation frequency, as well as incidence of clinical pregnancy, and frequency of delivery in the patients with a history of RIF. The aim of this study was to evaluate the effect of intrauterine administration of autologous peripheral blood mononuclear cells prior to embryo transfer upon the results of assisted reproductive technology programs in women with a history of RIF, and to evaluate cytokine profile of the supernates from the injected cultures of peripheral blood mononuclear cells.
The study included 129 women with RIF included into the assisted reproductive technology programs. The patients were divided into three groups with intrauterine administration before embryo transfer in a stimulated cycle and in a cryocycle: group 1, treated with mononuclear cells activated by human chorionic gonadotropin; group 2, with mononuclear cells without activation by human chorionic gonadotropin; group 3 who received saline solution (placebo). Clinical and anamnestic data of the women from these groups did not differ. The age of women in all three groups was also similar. The number of RIFs in their anamnesis was comparable for the 3 groups. Analysis of the embryological parameters also showed that there were no significant differences in the number of transferred embryos, including those of good quality.
The levels of IL-2 (p = 0.006), IL-4 (p = 0.012), IL-5 (p = 0.012), IL-12p70 (p = 0.011), IFNγ (p = 0.012), GM-CSF (p = 0.026), and TNFα (p = 0.021) were found to be higher in the supernatants of human chorionic gonadotropin-activated mononuclear cells of women with advanced cryocycle implantation, than in supernatants of inactivated chorionic gonadotropin mononuclear cells. Frequencies of implantation and clinical pregnancy were significantly higher in the groups with intrauterine administration of autologous mononuclear cells, both in stimulated cycle and the cryocycle compared to the placebo groups.
The cytokine profile of the mononuclear cell culture supernates upon intrauterine administration affects the efficiency of assisted reproductive technology programs in the women with RIF. Hence, the data obtained may allow us to develop a personalized approach to usage of various immunotherapies in assisted reproductive technology programs for the patients with a history of repeated implantation failure.

Russian Journal of Immunology. 2021;24(3):425-434
pages 425-434 views

Relationship between the level of antiglycan antibodies in the blood and clinical and laboratory parameters of patients with normal pregnancy and pregnancy complicated by moderate preeclampsia

Ziganshina M.M., Shilova N.V., Khasbiullina N.R., Tyutyunnik N.V., Kan N.E., Naumov V.A., Tyutyunnik V.L.


One of the new trends in the study of the pathogenesis of preeclampsia (PE) is the study of the development of glycopathology in the functional mother-placenta-fetus system. Given the importance of carbohydrate-protein interactions for the morphogenesis of the placenta, interactions in the immune system, and the formation of tolerance to fetal alloantigens, anti-glycan antibodies (AgAbs), which can interfere with these interactions, changing them, may play a special role in the pathogenesis of PE. Since the production of antibodies occurs against the background of existing natural antibodies, as well as adaptive ones acquired during life, it is obvious that there are a significant number of factors that are interrelated with AgAbs, which is important for the pathogenesis and identification of risk factors for the disease. Objective: to determine the relationship between the content of AgAbs in the blood and clinical and laboratory parameters in patients with physiological pregnancy and PE.
The study includes 146 pregnant women: the main group I consisted of 51 patients with moderate PE, the comparison group – 95 conditionally healthy pregnant women. Clinical and anamnestic data, peculiarities of the course of pregnancy, data of laboratory examinations, data of a representative spectrum of AgAbs were studied. AgAbs (IgG and IgM) were studied in serum using a glycoarray containing 473 glycans and 216 polysaccharides. To determine the relationship between the variables, the nonparametric Spearman rank correlation method was used for the analysis of quantitative data, and the Wilcoxon T-test for the analysis of qualitative data.
It was found that in the main group there were more correlations between the level of AgAbs of various specificities and clinical and laboratory parameters than in the comparison group. A burdened gynecological and infectious history, complications during pregnancy are associated with changes in the profile of AgAbs of both classes in patients whose pregnancy is complicated by moderate PE, which indicates the pathogenetic significance of these antibodies. In healthy pregnant women, the level of antibodies to a number of glycans is reciprocally related to the number of lymphocytes, platelets, and ALT, which may indicate the regulatory role of these antibodies, since lymphocytosis, thrombocytopenia, and increased transaminases in the blood are pathological conditions.
The revealed relationships between the AgAbs level and clinical-anamnestic and laboratory parameters indicate different patterns of correlation relationships in health and disease, which apparently indicates the pathogenetic

Russian Journal of Immunology. 2021;24(3):435-444
pages 435-444 views

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