Most types of immune cells are able to freely enter tissues, perform surveillance functions, and then leave them, while distinct cells are permanently located in non-lymphoid tissues. Such cells comprise tissue-resident populations (TR). Non-lymphoid tissues are home to a diverse community of innate and innate-like immune cells, such as tissue-resident macrophages (TRMφ), innate lymphocytes (ILC), γδT cells, NKT cells, MAIT cells, B1 cells, and marginal zone B cells. Previously, TR cells were thought to be derived from hematopoietic stem cells, but most TR cells are shown to be derived from erythromyeloid precursors of the yolk sac and fetal liver. TR cells have some features of “stemness”, they have the ability to self-renew, like classical hematopoietic stem cells. TR cells live in tissues due to trophic factors produced within these tissues, thus maintaining homeostasis at their microenvironment. Homeostatic factors for TRMφ are interleukin 34 (IL-34), monocyte and granulocyte-monocyte colony-stimulating factors; for ILC, γδT cells; for NKT and MAIT cells, IL-7 and IL-15; for B1 cells, IL-5. The concept of only 4 types of tissues (epithelial, connective, nervous and muscular) seems to be outdated, a more appropriate paradigm suggests existence of minimal tissue modules. In this case, each module consists of cell elements that interact with each other much more strongly than with elements outside the module. Cell associations within tissue modules provide homeostatic support to other cells that make up the module, being a niche for these cells, thus providing niche support for the former elements. Moreover, TR cells represent the first line of immune defense, since the vast majority of pathogens penetrate the body through barrier tissues. Repopulation of TR cells, that die in response to infection occurs by proliferation of the remaining TR cells, and due to migration of bone marrow-derived cells into the tissues. There are competitive relationships between these two repopulation pathways. At the same time, bone marrowderived TR cells are not capable of self-renewal and cannot fully reproduce all the functions of classical TR cells. TR cells ensure the removal of cellular debris and dead cells, regulate inflammation, remodel the extracellular matrix and produce tissue growth factors.

Our objective was to consider the adverse reactions associated with usage of immune checkpoint inhibitors (ICI). The literature review includes a search for scientific papers from the databases PubMed, Embase, eLibrary, CyberLeninka and Web of Science, CNKI and MEDLINE by the following keywords: “immune checkpoint inhibitors”, “immune-mediated adverse events”, “immune checkpoints”, “antitumor therapy”, “immune system”, “side effects”. Over the past decade, the discovery of immune checkpoints followed by development of appropriate inhibitors have provided breakthrough advances in cancer treatment. The ICI-based therapy has opened a new era of antitumor treatment and has really improved clinical prognosis in the cancer patients. The antitumor effect of ICI is based on the blockade of CTLA-4 and PD-1/PD-L1 signaling pathways, thus promoting antitumor activity of lymphocytes. However, inhibition of immune checkpoints may also provoke dysregulation of immune responses and appearance of a new type of adverse reactions associated with changed activity of immunocompetent cells in the host organism, i.e., immunerelated side effects (irAEs). The most common side effects concern skin, hepatobiliary, and endocrine systems. Of note, the frequency of adverse events affecting cardiovascular and nervous systems is relatively low among total number of cases, but the consequences lead to disability of patients and are often fatal. Currently, hormonal drugs, immunosuppressants, and cytokine antagonists are mainly used to treat adverse events of ICI. However, these treatments may cause suppression of the immune system in patients, thereby weakening their antitumor immune response. There are still many unresolved issues related to irAEs, such as unclear mechanisms and biomarkers, tools for early detection of these adverse events, and development of more advanced individual treatments for such complications. The researchers believe that the above problems can be solved with wider use of immunotherapy, deeper studies on ICI and related adverse immune reactions, thus enabling full-scale implementation of ICI potential in anticancer therapy and improving clinical outcomes. Accordingly, the topic is quite relevant and requires close attention from practitioners and scientists.

The aim of the present review is to analyze the behavioral strategies and mechanisms of antifungal activity of neutrophils against Candida and Aspergillus based on data published in open scientific sources. Invasive mycoses are systemic diseases caused by microscopic fungi, characterized by high morbidity and mortality in immunocompromised individuals, especially those with neutropeniA. Neutrophils have significant antifungal activity against Candida spp. and Aspergillus spp. C. albicans, the most common causative agent of invasive candidiasis, exhibits a pronounced morphological plasticity. When neutrophils are unable to phagocytize fungal hyphae, they choose another defense mechanism, forming NETs as a result of NETosis. The C. albicans biofilms cause active migration and adhesion of neutrophils, but, unlike planktonic forms, they suppress the release of NETs thus promoting survival of the pathogen. Clusters of C. albicans yeasts and A. fumigatus conidia induce neutrophil swarming, an LTB₄-mediated, coordinated, and tightly controlled process characterized by accumulation of neutrophils at the site of infection and aimed at its isolation from healthy tissues. Intravascular neutrophil swarming occurs in the lungs during candidemia, which is a specific defense response to fungal pathogens. In systemic candidiasis, a subpopulation of neutrophils is transformed to PMN-DCs, which demonstrate effective killing and induce an antigen-specific immune response against fungal pathogens. A. fumigatus conidia induce human neutrophils to release extracellular vesicles with potential fungicidal activity. Spores of fast-growing A. fumigatus strains stimulate an influx of neutrophils, facilitating rapid clearance of the fungal pathogen; conidia of slower-growing strains are capable of long-term persistence due to lower neutrophil attraction and survival inside macrophages. Interaction of neutrophils with growing A. fumigatus hyphae results in swarming, NETosis, and ROS generation; the degree of hyphal branching affects their susceptibility to neutrophil-mediated killing: the most branched hyphae are more vulnerable and die first. A. fumigatus hyphae cause activation of NADPH-oxidase and myeloperoxidase in neutrophils with ROS generation which exert a cytotoxic effect and induce the formation of NETs with a predominantly fungistatic effect. Thus, the available data and further study of the mechanisms of neutrophil antifungal activity may provide the basis for development of new pathogenetic concepts, preventive, therapeutic and diagnostic approaches to the causative agents of invasive mycoses.

The major histocompatibility antigen (HLA) complex is among the most polymorphic genetic systems in humans. The distribution of HLA alleles and haplotypes differs within ethnic groups and geographical regions. Russian populations evolving in different regions of Russia may have distinct immunogenetic characteristics due to the influence of internal and external factors (vast territories, multinational population, interethnic contacts). The aim of this study was to evaluate the genetic distances between Russians from different regions of Russia, and other populations. The results of this study show that the Russians living in St. Petersburg, Nizhny Novgorod and Rostov-on-Don had a similar distribution of HLA allele groups. The pan-European HLA haplotypes A*01-B*08-C*07-DRB1*03-DQB1*02 and A*03-B*07-C*07-DRB1*15-DQB1*06 were most common in Russians from all regions. When comparing 10 most common HLA haplotypes, nine of them were similar for the residents of St. Petersburg and Nizhny Novgorod. In addition, we have registered the following haplotypes: A*02-B*13-C*06-DRB1*07-DQB1*02, A*03-B*35-C*04-DRB1*01-DQB1*05, A*02-B*07-C*07DRB1*15-DQB1*06, A*02-B*18-C*07-DRB1*11-DQB1*03, A*25-B*18-C*12-DRB1*15-DQB1*06, A*02B*41-C*17-DRB1*13-DQB1*03, A*30-B*13-C*06-DRB1*07-DQB1*02. The A*02-B*15-C*03-DRB1*04DQB1*03 haplotype was one of the most common among Russians of St. Petersburg, but its frequency was less in Russians from Nizhny Novgorod (0.0119 vs. 0.0034, p = 0.03) and it was not found among Russians of Rostov-on-Don. The residents of Rostov-on-Don had the more significant differences of HLA haplotype profile. In particular, the following HLA haplotypes were among the most common in Russians living in Rostov-on-Don: A*23-B*44-C*04-DRB1*07-DQB1*02, A*02-B*57-C*06-DRB1*07-DQB1*03, A*24-B*35C*04-DRB1*11-DQB1*03, A*01-B*52-C*12-DRB1*15-DQB1*06, A*11-B*35-C*04-DRB1*01-DQB1*05, A*02-B*27-C*02-DRB1*01-DQB1*05, A*02-B*44-C*02-DRB1*16-DQB1*05. Two of these haplotypes (A*24B*35-C*04-DRB1*11-DQB1*03 and A*02-B*44-C*02-DRB1*16-DQB1*05) were not detected in Russians of Nizhny Novgorod, the frequency of other haplotypes was < 0.01. Frequency of these haplotypes in Russians of St. Petersburg was also less than 0.01. The haplotype A*23-B*44-C*04-DRB1*07-DQB1*02 was less common in Russians of St. Petersburg (0.0246 vs. 0.0062, p = 0.01). An analysis of genetic distances between populations showed that Russians of Nizhny Novgorod, as well as Russian residents of Moscow and Belarus were the closest to Russians living in St. Petersburg. The genetic distance between Russians living in St. Petersburg and the residents of Rostov-on-Don and Chelyabinsk Region is a bit greater. Comparison of genetic distances between the various Slavic populations showed that the Eastern (Belarusians, Russians) and Western (Poles, Slovaks, Czechs) Slavs are closest to each other. The Southern Slavic folks (Serbs, Croats, Macedonians) are more genetically remote. The results of present research can be used to study the processes of ethnogenesis, searching for associations between HLA and diseases, and also being applied in practical activities of hematopoietic stem cell donor registries.

The importance of cytokines, including TNF, in development of uterine fibroids (UF) or leiomyomas (LM) is well proven. The number of polymorphic sites in promoter region of TNF gene is established, and their relationship with the gene expression level has been shown, thus potentially affecting the evolution of the disease. The aim of our research was to analyze the distribution of TNF-238, TNF- 308 and TNF-863 structural variants at the regulatory region of the TNFA gene in a representative group of Caucasian patients with UF compared with a matched group of healthy women followed by assessment of personalized prognostic significance of suggested differences. 180 patients diagnosed with uterine fibroids and 98 practically healthy women were examined. Genotyping of TNF gene polymorphisms (-863 C/A, TNF- 308 G/A, TNF-238 G/A, IL1B-31 T/C, IL4-590 T/C, IL6-174 C/G, IL8-251 T/A, IL10-592 A/G, IL10-1082 A/G and IL17A-197 G/A) was performed by RT-PCR using the SYBR Green intercalating dye. Statistical processing was carried out using multifunctional programs – IBM SPSS Statistics 23, SNPStats. We did not reveal significant differences between the compared groups when analysing distribution of TNF allelic variants and their combinations in genotypes. When comparing the combined SNP variants of the TNF gene at the studied nucleotide positions with the polymorphisms of other genes encoding proinflammatory cytokines, an increased frequency of TNF-238 GG:TNF-308 GG:IL17A-197 AA complex was found in the group of patients with uterine fibroids. The diagnostic specificity of this index was 100%, and the predictive value of this quotient reached 13.3, thus implying a 99.9% probability of a correct prediction. At the same time, the combination of TNF-863 CC genotype with IL-6-174 GG and IL-17-197 GG was significantly reduced in the patients. The frequencies of the anti-inflammatory cytokine genes IL4-590 T/C, IL10-592 A/G and IL10-1082 A/G analyzed n our study did not differ in the both compared groups and they were not considered either predisposing or protective for the disease. The magnitude of the revealed differences in occurrence of these allelic combinations reaches a significant level, thus assuming these traits as potential genetic factors for predicting a predisposal or resistance of women with a certain genotype to development of uterine fibroids, being prognostic criteria for early detection of this disorder.

The aim of our research was to study the features of activation receptor expression on various subsets of blood monocytes in patients with acute pancreatitis (AP). 69 patients aged 37-62 years with moderateand severe-grade AP were examined. The diagnosis of AP was based on the results of clinical, laboratory and instrumental examination. Phenotype and subpopulation composition of monocytes were studied by flow cytometry. Alterations in blood monocytes phenotypes and increased expression of activation receptors were noted in patients during the initial period of AP. Thus, an increased proportion of monocytes in the blood of patients with AP with co-expression of CD45RO and CD62L was detected, along with increased number of cells expressing CD25 receptor. An increased level of migratory monocyte activity in AP could be linked with CXCR4 and CCR5 receptors. Altered subset composition during the acute period of AP was linked with 2-fold increased levels of “non-classical” monocytes. The proportion of cells with expression of chemokine receptors in the subset composition of monocytes changed in AP. Thus, the number of “classical” and “nonclassical” monocytes with CXCR4 was increased within total monocyte subset in the patients. Meanwhile, the content of cell subsets with CCR5 receptor expression was almost uniformly increased. The changed expression levels of activation receptors also characterized the activation features of various monocyte subsets in patients during the initial period of AP. Elevated CCR5 was detected in AP only on “classical” monocytes, whereas increased CD64 was found only on “non-classical” monocytes. Elevated HLA-DR expression was detected on “classical” and “intermediate” monocytes of patients with AP but a high level of CXCR4 expression was found on all monocytes subsets. The registered changes in phenotype and subset composition of monocytes in patients during the initial period of the disease seem to characterize the mode of monocyte involvement into the inflammatory process in AP thus revealing not only pro-inflammatory reaction of monocytes, along with increased activity of monocyte subset with anti-inflammatory function.

The development of simple and accessible tools for improvement of dental health over active period of orthodontic treatment with fixed arch appliances (bracket system) is a pressing issue in clinical dentistry. The aim of this study was to investigate the effects of regular usage of oral care products on mucosal immunity in young people undergoing active period of orthodontic treatment using fixed arch appliances. The study involved 39 persons (17 men, 22 women), aged 18 to 28 years, suffering from dentoalveolar anomalies without concomitant somatic pathology. The patients were divided in 2 groups: the comparison group (1) and the main group (2). Patients in Group 1 (16 subjects, 7 men and 9 women), used their usual personal hygiene products throughout the study. Patients in Group 2, (23 persons, 10 men and 13 women) were recommended to use a new domestic low-abrasive toothpaste for sensitive teeth with a triple mechanism of tooth and gum protection, containing copper chlorophyllin at a concentration sufficient to inhibit periodontopathogenic bacteria, calcium glycerophosphate, calcium hydroxyapatite suspension, potassium chloride, silicon dioxide, magnesium chloride and xylitol (R.O.C.S. PRO SENSITIVE). The control age-matched group consisted of 15 people (6 men, 9 women) without dental anomalies and not requiring orthodontic treatment. The biological material was the patients’ oral fluid. The salivary contents of secretory immunoglobulin A, as well as some pro-inflammatory and anti-inflammatory cytokines were determined using the enzyme immunoassay method. The study has revealed unfavorable dynamics in terms of secretory immunoglobulin A, concentrations of pro- and anti-inflammatory cytokines in salivary fluid among young patients using braces at the active stage of orthodontic treatment. The usage of recommended dental and oral care products allowed us to optimize mucosal immunity and normalize the cytokine balance within a month, as well as to maintain it for a long time in complex cases of orthodontic treatment. To maintain dental health during the active period of orthodontic treatment with braces, an algorithm of individual oral care should be kept, by usage of oral hygiene products containing plant-based components with antimicrobial action.

Recently, the relationship between autoimmune diseases and atopy is one of the important areas of scientific studies. There is evidence of a relationship between atopy and psoriasis (PS). Thus, the study of sIgE concentration to 44 causally significant allergens was performed using PROTIA™ Allergy-Q test system (atopic panel) by the immunoblotting method being of particular diagnostic relevance. Objective of our study was to conduct a comparative analysis of the presence of allergen-specific IgEs to the common food, fungal, pollen, household and epidermal allergens in the blood serum samples from patients with PS using the immunoblotting method (Allergy-Q® system). The study included patients with PS (group 1, n = 51). The comparison group was patients with atopic dermatitis (AD, group 2, n = 20). The average age of patients in group 1 was 40.0±1.8 years, in group 2 – 25.0±2.0 years. The control group consisted of practically healthy individuals matched by gender and age with patients (group 3, n = 19). All patients underwent a specific allergological examination, including medical history of allergy, determination of total immunoglobulin E (IgE) level in the blood serum and the sensitization spectrum based on measurable concentration of allergen-specific IgE (sIgE) to 44 most common allergens in blood serum by immunoblotting technique using the Allergy-Q® test system (atopic panel, Korea). Statistical processing of the obtained results was carried out using the application program “Statistica 8.0”. Sensitization of atopic origin was noted in 35.3% (n = 18) of patients with PS and in 90% (n = 18) of cases with atopic dermatitis. In the group of patients with AD, the most significant food allergen was peach compared to the group of patients with PS and the control. Sensitization to potato, rice, peanut, peach was significantly higher among patients with PS compared to the control. In the group of patients with AD, sensitization to ragweed, wormwood, alder-birch mixture pollen was statistically significantly higher if compared to the control group. In PS, the highest frequency of sensitization to ragweed pollen was found in comparison with the group of patients with AD and control group. In the group of patients with PS, a statistically significant increase in the frequency of sensitization to staphylococcal enterotoxin B, Candida albicans was noted when compared with the group of patients with AD and the control persons. An increased frequency of sensitization to cat and dog epithelium was noted in the groups of patients with PS and AD in comparison with the control group. Thus, our study substantiates the need for specific allergological examination of patients with PS in order to establish causative allergens, especially in the cases of a severe course of the disease.

Contact dermatitis is a disease characterized by skin inflammation caused by external agents, most commonly, allergens. Patients with contact dermatitis have impaired skin barrier function, causing permeability of the epidermis layer. Haptens, including oxazolone, are the small molecules that easily penetrate the epidermal barrier. When oxazolone binds to the tissue proteins, new antigenic conformations are formed, triggering an immune response and, subsequently, the development of allergic contact dermatitis. The pathogenic role of interleukin-6 in the development of contact dermatitis has been previously described in various murine models. Dendritic cells (DC), along with keratinocytes, are an important source of IL-6 in the skin. Moreover, DC as an antigen-presenting cells are involved in the development of allergic reaction. To establish the functional role of IL-6 from DC in development of allergic contact dermatitis, we induced dermatitis in the knockout mice with deficiency of IL-6 in dendritic cells (CD11c-IL-6 KO), and in wild-type control mice by applying oxazolone to the abdominal skin and then to the skin of the ears. Mice with deficiency of IL-6 from dendritic cells had more pronounced symptoms of skin inflammation than wild-type mice after sensitization with oxazolone. Thus, IL-6 produced by dendritic cells seems to have protective and regulatory functions in allergic contact dermatitis. Implementation of these functions may be mediated by TGF-β, whose expression was reduced in mice with tissue-specific IL-6 knockout in dendritic cells. TGF-β is an important regulatory cytokine that controls the balance of effector and regulatory T cell populations. Moreover, TGF-β is important for the resolution of inflammation and tissue healing. At the same time, the lack of difference in IL-4 and IL-17a expression between CD11c-IL-6 KO and wild type mice suggests that the Th2 and Th17 branches of the cellular response were not affected in highly susceptible mice with IL-6-deficiency in dendritic cells. The effects of systemic IL-6 deficiency shown in various models of dermatitis suggest a predominantly pathogenic role of this cytokine in the development of allergic contact dermatitis. Our data suggests that dendritic cells may serve as sources of “protective” IL-6 activity, participating not only in the development of the immune response but also in repair and maintenance of skin barrier functions.

Over 85% of patients with bronchial asthma are sensitized to mites from the Pyroglyphidae, Acaridae, Glycyphagidae families. The aims of our study were to analyze the sensitization profile of patients with allergies to allergens of Pyroglyphidae, Acaridae, Glycyphagidae mites and appropriate molecules. Blood serum samples have been taken from 923 patients aged 5 to 58 years with a previously established allergic status, IgE antibodies to 300 allergens (120 whole extracts and 180 molecular components), along with total IgE antibodies being simultaneously measured using allergochip ALEX² (MacroArrayDX (MADx, Austria)). In 26% (241 of 923) of the patients, IgE antibodies to allergens of synanthropic mites and their molecules was detected. 87% (210 of 240) of these subjects exhibited sensitization to allergens of house dust mites (HDM), and 60% (145 of 241), to storage mites (SM). IgE antibodies was most often detected for single molecules of mite origin (33.3% of patients). IgE antibodies was simultaneously detected for 2-11 molecules in 0,9-22,9% of patients, respectively. Sensitization to the complex of major allergens (Der p 1, 2, 23 and/or Der f 1 and 2) and minor allergenic molecules (Der p 5, 7, 21) reached 36%. Sensitization to major allergens only (Der p 1 and/or, 2 and/or 23) was found in 25% of cases. 67 variants of sensitization profiles (patterns) to allergens of synanthropic mites were revealed among patients. The detection frequency of IgE antibodies to clinically significant allergenic molecules has been increased by 2.4-4.6 times over the past ten years.

Severe bronchial asthma in children is an actual current problem, due to high risk of severe and/ or frequent exacerbations, decreased quality of life in patients and their families, as well as significant costs of socio-economic and medical resources. Personalized medicine suggests the need to search for specific objective indexes of the bronchial asthma severity in children. Biomarkers characterizing the inflammatory process may serve as indexes of the bronchial asthma severity. Aim of the study was to examine the amounts of surfactant protein A (SpA), Clara cell protein (CCP), interleukin-4 (IL-4), interleukin-6 (IL-6) and transforming growth factor β1 (TGF-β1) in induced sputum in children with severe bronchial asthma. 70 children took part in the study. The patients were grouped as follows: group 1, severe bronchial asthma (n = 24); comparison group 2 with mild bronchial asthma (n = 26). The control group 3 consisted of 20 healthy children. IS collection was performed according to standard methods. The concentrations of pneumoproteins and cytokines were determined in the induced sputum using ELISA techniques. In the group of patients with severe bronchial asthma, a statistically significant increase of SpA, CCP, IL-6 and TGF-β1 concentrations in induced sputum and a significant decrease of IL-4 levels was detected, when compared with mild asthma group and healthy persons (Kruskal-Wallis test, p < 0.05). Strongly positive correlations have been found between bronchial asthma severity and sputum proteins: for SpA (Spearman quotient r = 0.893814, p < 0.05); IL-6 (r = 0.827230, p < 0.05), and TGF-β1 (r = 0.886062, p < 0.05). The contents of studied pneumoproteins and cytokines reflect the severity of respiratory inflammatory process in children with bronchial asthma. The data on the IL-4 and IL-6 cytokine production in the group with severe bronchial asthma demonstrate involvement of other immune response types into allergic inflammation. The studied immunological parameters can serve as biomarkers of the asthma severity in children.

The prevalence of allergic diseases, including rhinitis and allergic asthma, is increasing in the modern world based on the Hygiene theory. Avoidance of allergens and using drugs to relieve clinical symptoms in these patients are not sufficient and efficient. Currently, allergen-specific immunotherapy is the only stable treatment approach. Previous studies in Iran have investigated the efficiency of this treatment. However, they had not performed a simultaneous follow-up of treatment status, with respect to patients’ recovery and side effects. In the present study, we addressed these issues together. After obtaining informed personal consent, a standard questionnaire form was completed for the selected patients according to the study’s entry conditions. The results were analyzed using SPSS, a statistical software program. Of the 64 patients in the present study with an average age of 34.48 (±10.46) years, 25 were women. Immunotherapy against antigens from trees, grass, weeds, and mites was performed, respectively for 57, 49, 53, and 1 allergy cases in the study, The median (IQR) asthma score in these persons before and after immunotherapy was 8 (5-9) and 2 (1-3), respectively. After immunotherapy, the scores of asthma, wheezing, shortness of breath, and cough in the studied subjects were shown to be significantly decreased (p < 0.0001 for entire group). The median (IQR) score of allergic rhinitis in these people before and after immunotherapy was 16 (12-20) and 2 (1-4), respectively. The scores of allergic rhinitis, sneezing, runny nose, nasal itching, nasal congestion, itchy eyes, watery eyes, and red eyes in these patients were significantly decreased after immunotherapy (p < 0.0001 for the total group). Local, extensive, and systemic complications were reported in 10, 2, and 3 cases, respectively. This study demonstrated that standard immunotherapy using common native allergens can improve significant clinical symptoms in patients with moderate to severe allergic rhinitis and mild-to-moderate allergic asthma who have not responded adequately to conventional therapy. An effective treatment approach should be suggested for these patients.

Evaluation of clinical effect is used as a marker of efficiency in patients wwith allergic rhinitis (AR) subjected to allergen-specific immunotherapy (AIT). This assessment is subjective and may be influenced by individual perception, expectations, and fluctuations in pollen concentrations. Therefore, development of objective markers is necessary to monitor therapy outcomes. A single-center, cross-sectional study was conducted in 26 patients with AR sensitized to birch, having been divided in two groups: those who had not yet received ASIT (AIT0) and those who had completed two courses of treatment (AIT2). The treatment was performed in two courses of birch allergy immunotherapy with the Staloral allergen, administered for, at least, 5 months at a dose of 120–240 international units (IR) per day. After two courses of AIT, a significant decrease in medication usage was observed. Moreover, a marked improvement in AR severity was noted, with 85% of patients exhibiting mild grade, and only 15% experienced a moderate course of the disorder, compared to the AIT0 group (p = 0.001). The median total IgE level before therapy was 455.1 IU/mL (154.8-537.4), and after two courses of ASIT it was 136.2 IU/mL (88-484.7), p = 0.27. According to Bayesian analysis, it is likely that the total IgE will be lower after therapy, at a moderate probability (BF = 4.9). The median IgE level specific to Bet v1 before therapy was 100 kU/L (36.5-100), with high levels (> 100, beyond the range of test) detected in more than a half of the patients. Patients in the AIT+2 group had a median sIgE of 53.5 kU/L (38.8-100), p = 0.71. Bayesian analysis suggests that IgE levels decrease with a weak probability (BF = 3.4). In the total group of patients with allergic rhinitis, IgG4 Bet v1 was determined. In the group without ASIT, the median IgG4 level was 0.60 (0.16-1.0) mg/L, after ASIT, the specific IgG to birch was significantly increased to 2.16 (1.44-3.00) mg/L, p = 0.02, with moderate probability for increase (BF = 4.41). After ASIT, specific IgG to birch significantly increased to 2.16 mg/L (1.44-3.0), p = 0.02 and a moderate increase probability (BF = 4.41). ROC analysis of “IgG4 with repeated AIT course” model showed a good diagnostic potential, with AUC value of 0.87 and p = 0.018. Measurement of sIgE levels and IgG4 may be useful for assessing the efficacy of ASIT and understanding the immune changes. Further research and standardization of diagnostic technique may enhance the significance of these markers in clinical practice.

In 2023, 3,545 cases of viral hepatitis A (HA) were reported in the Russian Federation, with an incidence rate of 2.42 per 100,000 population. Acute HA accounted for the largest share in the structure of acute viral hepatitis morbidity – 61%, and in comparison, with 2010, its specific weight increased 1.3 times (55% – in 2010). Currently, there is no specific treatment for HA. Vaccination remains the most effective method to eliminate viral hepatitis A in the population. In 2023, 423,855 people were vaccinated in the country, including 171,161 children up to and including 17 years of age. The aim of our work was to assess the seroprevalence of IgG antibodies to hepatitis A virus in the population of St. Petersburg and Leningrad Region depending on the infection-vaccine status and socio-demographic characteristics. In a population-based study, 6773 volunteers from St. Petersburg and Leningrad Region aged 1 year to 70+ years were examined. Volunteers were stratified into 9 age groups: 1-5 years (n = 370), 6-11 years (n = 511), 12-17 years (n = 538), 18-29 years (n = 792), 30-39 years (n = 838), 40-49 years (n = 914), 50-59 years (n = 900), 69-69 years (n = 930), and 70+ years (n = 980). ELISA testing was performed using reagent kits manufactured by Vector-Best (Russia) according to manufacturer instructions: “Vectohep A-IgG” for the presence of antibodies to hepatitis A virus. In the course of the study, anti-HAV IgG antibodies were detected in 38.1% of people. A direct correlation between the frequency of anti-HAV IgG antibodies and increasing age was shown. High frequency of anti-HAV IgG antibodies was found among workers in the scientific, transport and medical spheres. The lowest frequency of anti-HAV IgG antibodies was found among office and IT workers, and civil servants. The proportion of vaccinated persons in St. Petersburg was significantly lower than in Leningrad Region. Among unvaccinated volunteers from St. Petersburg and Leningrad Region, anti-HAV IgG antibodies were detected in 37.3% of people; however, those examined were sure that they had never had HA. The proportion of vaccinated persons among educational and medical workers was 10.1% and 12.0%, respectively. It should be noted that these groups are among the risk groups for whom vaccination against HAV is recommended.It is shown that residents of St. Petersburg and the Leningrad Region continue to be in contact with HAV, and risk groups are not sufficiently covered by vaccination. Given the increasing seroprevalence of anti-HAV IgG antibodies with age, the issue of HA prophylaxis remains highly relevant.The study of herd immunity to HAV in different regions to obtain a more reliable picture of the pathogen distribution in the Russian Federation, as well as to identify hidden foci, will further improve the effectiveness of specific immunisation.

The worldwide trend towards increasing life expectancy makes relevant the studies on aging and ageassociated pathology. The pathophysiologic mechanisms underlying geriatric syndromes remain insufficiently studied. It is hypothesized that chronic sterile inflammation (inflammaging) may be a key factor that links senile asthenia and sarcopenia. Several scientific teams are searching for biomarkers associated with different aging phenotypes. IL-1β, IL-6, TNFα, and C-reactive protein are among the most studied immunologic markers of aging. The study is devoted to a comprehensive evaluation of expression leveld of TLR2 patternrecognizing receptor gene as well as IL-1β, IL-6, IL-10 cytokine genes, and the contents of IL-1β, IL-6, IL-10 cytokines in long-livers with senile asthenia and sarcopenia. We included 219 nonagenarians who underwent a comprehensive geriatric evaluation according to current clinical guidelines. A subgroup including 161 patients meeting the homogeneity criteria for comorbidity was assessed by the Charlson comorbidity index. Further on, the clinical groups of long-livers were identified according to geriatric syndromes with the presence of senile asthenia (n = 77) and absence of frailty (n = 84); with sarcopenia (n = 130), and free of sarcopenia (n = 31). It was shown that the frailty is accompanied by increased expression of TLR2 gene, genes of proinflammatory cytokines IL-1β and IL-6, increased concentration of serum cytokine IL-6 compared to the group without this syndrome. It was found that sarcopenia is combined with increased IL6 gene expression, IL-1β and IL-6 cytokine production, and decreased gene expression and production of anti-inflammatory cytokine IL-10 compared to the group without sarcopenia. The ratio of IL-6/IL-10 cytokine concentration was found to be 5 times higher in long-livers with sarcopenia than in nonagenarians without sarcopenia, being 3.4 times higher in patients with senile asthenia than in nonagenarians without this syndrome. Increased IL-6/IL-10 ratio was associated with high probability of developing frailty and sarcopenia. Hence, the results of our study confirm the involvement of inflammatory aging in pathogenesis of geriatric syndromes in long-livers. The IL-6/IL-10 ratio, which characterizes the imbalance of pro- and anti-inflammatory factors in blood serum of nonagenarians, may be considered a potential marker of inflammation severity, evolving frailty and sarcopenia.

The incidence of mast cell activation syndrome (MCAS) has increased since first definition as a mastocytosis-like phenotype. Despite well-described criteria developed by the MCAS consortium, its growing rates have occurred in the context of multiple alternative criteria for MCAS diagnostics. The Vienna Consensus has defined clear diagnostic criteria for MCAS, which include, first of all, a clinical criterion characterized by severe recurrent symptoms involving two or more organs and meeting the criteria for anaphylactic response. Secondly, a laboratory criterion, has been established where the most specific and golden standard marker is a significant increase in tryptase levels, determined in blood serum for several hours (up to 4 h) after the event, being calculated as 120% of the basal tryptase level plus 2 ng/mL. Determination of other biomarkers is currently not recommended due to their lower specificity and lack of clearly set cut-off values. Third, the therapeutic response criterion, which implies that the drugs targeting mast cells, should reduce the frequency and severity of MCAS episodes. There is a classification of MCAS, which discriminates primary (clonal) and secondary (non-clonal) response from idiopathic MCAS. Primary MCAS is defined by clonal expansion of mast cells and proceeds in confirmed systemic mastocytosis, or two minor criteria for mastocytosis. Secondary MCAS is diagnosed when the mast cells are activated by known triggers. Most often, it is associated with IgE-mediated or other hypersensitivity reactions (e.g., drug-, food-, or insect-induced anaphylaxis). If neither clonal expansion, nor a trigger event for mast cell activation can be identified, the condition is classified as idiopathic MCAS. Consensus 2 clinical criteria are not specific enough to diagnose MCAS, and the use of less specific (or non-specific) laboratory tests may lead to overdiagnosis of this condition. Recent studies confirm that MCAS is quite rare. However, patients with unspecified MCAS exhibit non-specific symptoms without a clear pathogenic significance, do not respond to standard mast cell-targeted therapy, thus leading to a reduced quality of life, as well as to social stigmatization. However, it is important to understand that false diagnostics of MCAS may lead to missing the diagnosis of underlying disease not associated with mast cell activation, and appropriate treatment will be not administered to the patient.

The issues of effective treatment of malignancies are, mainly, related to the problems of tumor cell recognizing, which have only minor differences from healthy cells. A search for treatment approaches based on stimulation of tumor cell recognition by the host immune cells is one of the main tasks of oncoimmunology. The differentiation-related testicular antigens (TAG) in healthy adults are expressed only in testicular cells, being, however, specific markers of tumors of various origins. They play an important role in maintenance of high growth rates and invasive activity of tumor cells. DNA, mRNA and peptide vaccines are currently being developed to induce specific antitumor reactions and generate tumor-specific TAGs in vivo. Xenogeneic variant of TAG, if applied as a vaccine, may enhance immunogenicity of the cell material and is aimed at forming an effector link of immunity, being oriented on TAGs present on the host tumor cells. In our study, a xenogeneic variant of TAG was used to induce antitumor reactions and to enhance immunogenicity. Purpose of the present work was to evaluate the effectiveness of induction of antitumor response in mice having been preliminary immunized with sheep TAGs. In this study, a xenogeneic variant of TAG was used to enhance immunogenicity and induce antitumor response. The survival rate of mice was evaluated using the Kaplan–Meier method. Production of IFNg and IL-10 was assayed by ELISA technique. Phenotyping of CD4⁺CD25⁺FoxP3⁺ and CD4⁺CD44⁺CD62L⁺ cells was performed by multicolor flow cytometry, as well as counting the number of lymphocytes containing intracellular Perforin. Survival rate of mice with preceding TAG vaccination proved to be significantly higher than the parameters obtained with syngeneic TAG vaccination, whereas in some animals a tumor did not grow at all. There was a significant increase in the number of cells carrying Perforins (both CD3⁺ and CD8⁺) during xenogenic vaccination and an increased level of IFNg in serum of LLC tumorbearing mice, while the number of CD4⁺CD25⁺FoxP3⁺T regulatory cells, on the contrary, decreased. Using of xenogenic TAG for immunization has shown that induced immune reactions are directed not only at injected antigens, but also, in a cross-sectional manner, at tumor cells present in a body if they carry any TAGs on their surface. Preliminary immunization with xenogenic TAGs leads to increased life expectancy of mice carrying LLC carcinoma, being accompanied by induction of protective antitumor response directed, in a crosssectional manner, against the own tumor-associated antigens.

Primary adrenal insufficiency is a disease resulting from bilateral destruction of the adrenal cortex. The most common etiological factors are autoimmune disorders and infectious diseases, which indicates the key role of the immune system in the development of this pathology. Activation of innate immune receptors leads to transcription of genes for pro-inflammatory cytokines and type I interferons, which contributes to the further development of the inflammatory process, activating both adaptive and innate immunity. The role of pattern recognition receptors and type I interferons has been previously shown in many autoimmune pathologies, but their significance in primary adrenal insufficiency is still not well understood. To gain a broader understanding of the occurring processes, innate immune receptors are being studied at both the molecular and genetic levels. Thus, the purpose of our work was to study polymorphic markers in the genes of interferon, NOD- and RIG-like receptors and their association with the risk of developing primary adrenal insufficiency. The biomaterial was collected from patients with primary adrenal insufficiency and from healthy individuals and was examined using real-time polymerase chain reaction. It was found that among the six polymorphic markers (rs2257167 in the IFNAR1 gene, rs2229207 in the IFNAR2 gene, rs2075822 in the NOD1 gene, rs8057341 and rs3135499 in the NOD2 gene and rs1990760 in the IFIH1 gene), there are only two sufficient predictors of the risk of developing primary adrenal gland disease: rs2257167 (IFNAR1) and rs2229207 (IFNAR2). The association of heterozygous genotypes of the polymorphic markers rs2257167 (IFNAR1) and rs2229207 (IFNAR2) with the risk of developing pathology, as well as the protective role of the CC genotype of the polymorphic marker rs2257167 (IFNAR1) was shown. The results obtained can be used for early diagnostics of the disease. These data can contribute to a better understanding of the pathogenesis of primary adrenal insufficiency and serve as the basis for further research in the field of personalized medicine. These markers can also be studied in connection with the severity of primary adrenal insufficiency, complications, as well as in connection with the effectiveness of the therapy.

The condition of patients following new coronavirus infection (NCI) is accompanied by a number of pathophysiologic changes that aggravate the course of the patient’s existing pathology, which is especially manifesting by cardiovascular and respiratory disorders. Cardiovascular risk after NCI is increased many-fold as compared to the patients who did not suffer with this infection. A decreased bronchial asthma (BA) control was reported in patients within post-NCI period. Many changes remain latent for a long time without clinical manifestations but increase the risk of adverse events. Earlier laboratory detection of these abnormalities would significantly accelerate clinical decision-making to reduce the likelihood of severe changes in the future. Transforming growth factor-beta (TGF-β) plays role in the regulation and resolution of inflammatory processes. Polymorphism of the gene encoding TGF-β is known to be associated with the development of BA and atopy, development and progression of remote NCI consequences. The aim of the present study was to investigate the effect of TGF-β Arg25Pro polymorphism on laboratory markers of systemic inflammation, intestinal permeability and vascular regulation in patients with BA who underwent NCI. The study included 72 patients with BA including 52 women (72.22%) and 20 males (27.78%), at a mean age of 64.9±6.86 years) who had a history of NCI. All patients underwent testing to determine the genotype of TGF-β Arg25Pro polymorphism by allele-specific polymerase chain reaction (Litech, Russia). Immunoassay kits (Cloud Clone Corp., China) were used to determine plasma concentrations of C-reactive protein (CRP) (mg/L), zonulin (ng/mL), angiotensin-2 (pg/mL), and TGF-β. Patients with AA genotype of TGF-β Arg25Pro polymorphism had higher level of CRP (3.59; 2.95-3.88) mg/l compared to PP genotypes (1.91; 0.54-3.37) mg/l (p_1-2 = 0.028) and AP (2.45; 0.48-2.88) mg/l (p_1-3 = 0.005). Plasma zonulin levels were also higher in the group with AA genotype, compared to study groups 2 and 3 (p_1-2 = 0.023 and p_1-3 = 0.032). The group with AA genotype displayed higher TGF-β levels compared to PP genotype (p_1-2 = 0.009). The lowest angiotensin-2 concentration was found in group 1. Conclusion: TGF-β Arg25Pro polymorphism may be associated with development of systemic inflammation and increased intestinal permeability in patients with BA over the post-COVID period.

SLAMF1 (CD150) is a receptor expressed on various hematopoietic cells and involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). This disorder is a chronic autoimmune inflammatory disease characterized by dysregulation of B lymphocytes, production of a large number of autoantibodies, and various abnormalities in immune regulation, such as changes in the number and functions of T helper cells and T regulatory (Treg) lymphocytes. Expression of SLAMF1 on T helper cells and B lymphocytes is increased in patients with active SLE. Impaired interaction of SLAMF1 receptors on T and B lymphocytes reduces the production of IL-6 and differentiation of plasmablasts in SLE. In the present work, we performed a functional analysis of single nucleotide promoter polymorphisms rs2295614(A>T) and rs2295613(G>A) of the SLAMF1 gene in the models of T-regulatory lymphocytes (MT-2 cell line) and T helpers (Jurkat cell line). Previously, an association of the rs2295614(A)/rs2295613(G) haplotype with the risk of developing SLE was shown, and it was also demonstrated that the risk haplotype in the promoter region of the SLAMF1 gene increases promoter activity in the Jurkat T cell line. Using reporter analysis, we have shown that the activity of the SLAMF1 promoter containing the minor variant rs2295613(A) increases in MT-2 cells and decreases in Jurkat cells. Based on the analysis of transcriptomes of these cell lines, we suggest that such a differential effect of the protective minor rs2295613(A) variant on promoter activity may be mediated by differential binding of transcription factors: activating MYC/MAX heterodimer in MT-2 cells and repressor MAX/MXD4 in Jurkat cells. Furthermore, both the increased expression of SLAMF1 in regulatory T cells and its decreased expression in T helper cells are likely to impact SLE pathogenesis similarly. These changes could reduce the efficiency of activating signal transmission from T helper cells to B lymphocytes, thereby weakening the autoreactive response of B lymphocytes. Thus, we propose a molecular mechanism mediating the protective role of the minor rs2295613(A) allele in the development of SLE.

Current knowledge about vaccine prevention provides the basis for searching a way to unravel the causes of unfavorable disease outcomes and reinfection with COVID-19, both in cases with natural and hybrid immunity observed in patients infected with genetic variants of the SARS-CoV-2 virus. Our aim was study the effect of vaccination on the timing of reinfection with variant strains of the SARS-CoV-2, and to evaluate the differences in Ct values (threshold cycles in PCR test) between primary COVID-19 infection and reinfection cases. The study included 67 patients treated at the St. Petersburg City Hospital No. 40, aged 22-75 years, from April 2020 to August 2023, who were repeatedly infected with the SARS-CoV-2. The criteria for including patients in the study were as follows: a confirmed COVID-19 diagnosis in the initially and repeatedly infected persons with SARS-CoV-2 virus, age from 22 to 75 years, availability of vaccination data between the primary and repeated episodes of the new coronavirus infection. The study did not include pregnant women, patients with mental disorders, cancer, and respiratory infections caused by other respiratory viruses. As a test system for determining Ct values (threshold number of PCR cycles), we used a diagnostic real-time PCR kit for detecting SARS-CoV-2 coronavirus RNA (RealBest RNA SARS-CoV-2, Vector-Best JSC, Russia). Statistical evaluation was carried out using the STATISTICA 13.0 program. The group differences were considered statistically significant at p < 0.05. Analysis of the data obtained revealed a statistically significant difference between (p < 0.05) group A and other groups (B, C, D) in the number of days between the primary and repeated incidence of COVID-19. In the groups A, B, C, D who had a primary viral infection, the Ct levels had no statistically significant differences (p > 0.05). When comparing the results obtained in each group for Ct during primary disease and reinfection with COVID-19, a statistically significant difference was found in group B (p < 0.05). When comparing Ct values during primary and reinfection between group A and other groups, no statistically significant differences were found (p > 0.05). Vaccine prevention is the main strategic task for the near future, but the use of various vaccines for these purposes requires continuous analysis by the medical community.