Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. represent ESKAPE group, which is characterized by the greatest resistance to antibiotics. Due to the wide spread of pathogens and their danger to the health care system, the search for new ways to treat bacterial infections remains relevant.

Antibiotics were first obtained in the early twentieth century, but their widespread use began during the Second World War. To date, the range of antibacterial drugs is wide, but despite this, the problem of bacterial resistance to them is acute.

An urgent task of modern science is considered to be the search for overcoming the resistance of bacteria to antibacterial drugs. Since the search for new classes of substances is a long and expensive process, combined drug regimens are used, methods of delivering antibiotics to the source of infection in the body are modified, the structure of the active substance molecules is changed, and adjuvants are used.

NK cells are traditionally considered as part of antitumor or antiviral immunity. However, due to the appearance of data indicating the presence of antibacterial proteins in them and the ability to exhibit cytotoxicity against cells infected with intracellular prokaryotic organisms, today they can be considered as a component of antibacterial immunity.

NK-92 cells reproduce the characteristics of NK cells and have similar properties. In addition, the possibility of their use as a component of antitumor therapy is being actively studied, and clinical trials are being conducted at different stages. In combination with the antibacterial properties of NK cells and the facts described above, it becomes possible to use NK-92 cells as an adjuvant in the antimicrobial therapy of infections caused by antibiotic-resistant bacteria.

The review presents data on the possibility of using the NK-92 cell line and the microvesicles produced by them to combat antibiotic-resistant bacteria of ESKAPE group. Currently, there is not enough research in this area, but data on NK cells presented in the review allow us to propose a cell line reproducing their characteristics and the MV produced by them as a promising adjuvant of antibacterial therapy.

Angiogenesis refers to the formation of new blood vessels from existing ones and is considered a crucial stage in vascular development. Two distinct types of angiogenesis have been identified: branching and non-branching angiogenesis. This process is involved in both normal physiological and pathological conditions, making it an area of significant interest for biomedical research. The development of angiogenesis involves a series of six stages, each controlled by various microenvironmental factors, such as cytokines and growth factors. These factors can either stimulate (pro-angiogenic) or inhibit (anti-angiogenic) the angiogenesis process. Additionally, ligand-receptor interactions between cells in the vicinity of the site of vessel formation play a role in regulating this intricate process. To date, the precise molecular mechanisms underlying the effects of cytokines, growth factors, and intercellular interactions in angiogenesis have not been fully elucidated. However, studies have demonstrated that signals received by endothelial cells during angiogenesis trigger a series of reactions within these cells, leading to alterations in gene expression and affecting the cellular phenotype and function. These changes influence the nature of vascular formation. The purpose of this review is to summarize current understandings of angiogenesis and its associated molecular mechanisms. The review presents data on the characteristics of endothelial cell populations in growing vessels, the stages of angiogenesis, and the factors that control vascular formation. It highlights the latest findings on signaling pathways such as PI3K/Akt, MARK/ERK, mTOR, RhoA, Ras, Notch, Smad2/3, Smad1/5/8, STАT3, STАT5, NF-κB, and molecules induced in endothelial cells during their interactions with cytokines and growth factors, as well as activation of certain endothelial surface receptors (VEGFR1, VEGFR2, VEGFR3, Tie1, Tie2, FGFR, PDGFR-α, PDGFR-β, TNFR1, TNFR2, VE-cadherin, and TßRI and TßRII. Special attention is given to the interaction between TGF-β signaling and other pathways during angiogenesis. Special attention is given to the description of the interaction between TGFβ signaling and other signaling pathways in angiogenesis. The review also provides current data on inhibitors of these signaling pathways, which can be used in the study of angiogenesis and, if necessary, in its correction during therapy. The review summarizes information on 29 such inhibitors at various stages of development – from in vitro research to clinical applications.

The review is a comprehensive analysis of current scientific data on Duhring's dermatitis herpetiformis. The main attention is paid to an in-depth understanding of the immunopathogenesis of the disease, in which autoantibodies of the IgA class play a key role, primarily directed against epidermal transglutaminase. Duhring's dermatitis is a specific skin manifestation of gluten-dependent enteropathy, which explains its inextricable link with celiac disease. Even in the presence of a classic clinical picture, including polymorphic itchy rashes, verification of the diagnosis requires mandatory morphological confirmation. The "gold diagnostic standard" is the direct immunofluorescence of a biopsy of the affected skin, which makes it possible to detect IgA deposits in the papillary layer of the dermis. Serological diagnostics, including the determination of antibodies to transglutaminase and endomyelium of the IgA class, is a highly sensitive and specific noninvasive method. It is of key importance not only for the confirmation of Duhring's dermatitis, but also for the detection of concomitant celiac disease, which is often asymptomatic or latent. In this regard, the review highlights the need for mandatory screening of all patients with Duhring's dermatitis for celiac disease, including, if indicated, esophagogastroduodenoscopy with biopsy of the small intestine mucosa. The work focuses on current therapy algorithms, which are based on two main strategies.: strict gluten-free diet and prescription of drug therapy. A gluten-free diet is a pathogenetic treatment method that leads to remission of the skin process, a decrease in autoantibody levels, and resolution of intestinal pathology. However, its effect may be delayed, which requires the appointment of drug therapy. The first-line drug for the control of skin manifestations remains dapsone, the effectiveness of which is due to the suppression of neutrophil activity. The review analyzes in detail the schemes of its administration, safety monitoring, including monitoring of the total blood count, glucose-6-phosphate dehydrogenase and methemoglobin levels, as well as potential side effects. For patients with refractory course or dapsone intolerance, the article analyzes generally accepted methods and fundamentally new therapeutic strategies. Among them, rituximab, a monoclonal antibody to CD20, JAK kinase inhibitors, and the interleukin–4 and -13 blocker dupilumab were considered. Of particular practical value of the review is a systematic step–by-step algorithm for patient management that combines all the aspects considered, from primary diagnosis using highly specific serological markers to long-term remission control. This algorithm serves as a ready-made tool for the clinician, allowing him to optimize diagnosis and treatment based on the latest achievements of evidence-based medicine, minimize the risks of therapy and significantly improve the quality of life of patients.

T lymphocytes play a central role in adaptive immunity. Helper, cytotoxic, regulatory T cells (Treg), unconventional T cell types (γδT cells, natural killer T (NKT) cells), as well as T cell subtypes such as invariant T cells, mucosal-associated T cells (MAIT) and CD8αα intraepithelial lymphocytes (lEL) help develop the humoral immune response, destroy infected and cancer cells, regulate specific and targeted immune reactions, while avoiding long-term inflammation and autoimmunity. (The development of T lymphocytes occurs in several stages, the most important of which is the formation of T cell self-tolerance in the thymus. As the source of RTE (Recent Thymus Emigrant) T cells, the earliest and most antigenically naive T cells emerging from the thymus and phenotypically detectable in human peripheral blood, the thymus creates the necessary environment for T cell differentiation and selection. The development of central immune tolerance is determined by the interaction of naive T cells with the thymic microenvironment in the medullary, cortical, and perivascular spaces. A sufficient number of specific and self-tolerant naive RTE cells, having undergone selection, are continuously exported to the periphery, facilitating the establishment of adaptive immunity and central tolerance.

The complex mechanisms of thymus function that prevent autoimmune diseases affect the structural matrix (cortex and medulla) of the thymus. The results of this impact depend on both the environment with which the body is exposed and the structural and functional stability of thymus components, the deficiency of which can lead to organ dysfunction and disease, with devastating consequences for the body. Despite the difficulties in studying the pathogenesis of autoimmune diseases, it is now known that they are based on disturbances in the structures that form central autotolerance. The contribution of the gradual accumulation of genetic mutations, changes in gene expression, and structural and functional abnormalities of thymus components is also being studied. Understanding the molecular mechanisms of these processes is necessary for identifying diagnostic biomarkers, potential checkpoints, and clarifying the pathogenesis of autoimmune diseases. It also identifies possible approaches to maintaining or restoring thymus function and helps develop strategies to mitigate complications associated with involution.

Chronic hepatitis C (CHC) represents a significant public health concern. In the majority of cases, the infection progresses to a chronic form, which is characterised by the development of fibrosis and cirrhosis of the liver. A plethora of cytokines and chemokines are generated as a consequence of inflammatory processes within the liver. These can exert a dual effect, both protective and damaging, particularly in relation to the death of hepatocytes and the progression of liver fibrosis. Furthermore, a number of growth factors have been identified as playing a role in the pathogenesis of CHC. The objective of the study was a comprehensive evaluation of a wide range of cytokines, chemokines and growth factors in the blood plasma of patients with CHC at varying stages of liver fibrosis. The study cohort comprised 63 patients diagnosed with CHC, who were divided into three groups according to the stage of liver fibrosis. The control group comprised healthy individuals (n=32). Concentrations of the following cytokines were determined in plasma: Interleukins and some cytokines (IL-1α, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IL-17-E/IL-25, IL-17F, IL-18, IL-27, IFNα, IFNγ, TNFα, TNFβ); chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROα, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine) and growth factors (EGF, FGF-2, Flt-3L, G-CSF, M-CSF, PDGF-AA, PDGF-AB/BB, TGFα, VEGF-A) by multiplex analysis based on xMAP technology. Nonparametric statistics methods were used for statistical analysis. As a result of the study, increased concentrations of cytokines IL-12 (p40), IL-15, IL-17E/IL-25, IL-27, IFNγ, TNFα, chemokines CXCL9/MIG and CXCL-10/IP-10 and growth factors FGF-2 and M-CSF were found at all stages of liver fibrosis. Elevated concentrations of cytokines IL-1α, IL-1β, IL-2, IL-6, IL-9, IL-10, IL-17F, IFNα, TNFβ, chemokines CCL2/MCP-1, CCL11/Eotaxin, CCL22/MDC and growth factors G-CSF, TGFα, Flt-3L were found in severe liver fibrosis/cirrhosis. Correlation analysis revealed a relationship of high significance between the severity of liver fibrosis and the content of cytokines IL-6, IFNγ, TNFα, IL-7, chemokines CCL2/MCP-1, CCL11/Eotaxin, CXCL9/MIG, CXCL10/IP-10, CXCL1/GROα, growth factors TGFα, PDGF-AA, PDGF-AB/BB. Thus, a certain profile of cytokines characteristic for CHC was revealed, cytokines, chemokines and growth factors significant for liver fibrosis in CHC were found. 

Recently, one of the important areas of scientific research is the relationship between autoimmune diseases and atopy. There is evidence of a relationship between atopy and psoriasis. Our studies have shown that in some cases psoriasis and atopy (in particular, food allergy) have a cause-and-effect relationship, which is proven not only by the establishment of sensitization, but also by the positive effect of elimination against the background of elimination therapy. Thus, the study of the concentration of sIgE to 44 causally significant allergens using the PROTIA™ Allergy-Q test system (atopic panel) by the immunoblotting method in this study is of particular relevance.
Objective: to conduct a comparative analysis of the presence of allergen-specific IgE to food, fungal, pollen, household and epidermal allergens in the blood serum of patients with psoriasis using the immunoblotting method using the Allergy-Q® test system.
Materials and methods. The study included patients with psoriasis (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 comparable with patients by gender and age (group 3, n=19). All patients underwent a specific allergological examination, including collection of an allergological anamnesis, determination of the level of total immunoglobulin E (IgE) in the blood serum and the sensitization spectrum based on the analysis of the concentration of allergen-specific IgE (sIgE) to 44 most common allergens in the blood serum by immunoblotting 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".
Research results. The concentration of total immunoglobulin E in the blood serum was statistically significantly higher in the group of patients with AD compared to PS and the control. Sensitization of atopic genesis was noted in 35.3% (n=18) of patients with psoriasis and in 90% (n=18) of patients 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 statistically significantly higher in the group of patients with PS compared to the control. In the group of patients with AD, the most common pollen allergen was wormwood pollen. In the group of patients with AD, sensitization to ragweed, wormwood, alder-birch mixture pollen was statistically significantly higher compared to the control group. In psoriasis, the highest frequency of sensitization to ragweed pollen was found in comparison with the group of patients with AD and the control group.
When analyzing the structure of sensitization to fungal allergens, it was found that sensitization to Candida albicans was determined statistically significantly more often in the group of patients with PS in comparison with the group of patients with AD and the control group. An increase in the 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. In the group of patients with PS, a statistically significant increase in the frequency of sensitization to Staphylococcal enterotoxin B was noted in comparison with the group of patients with AD and the control group.
Conclusion. Thus, our study should draw attention to the problem of skin damage in psoriasis from the position of an allergist-immunologist. This justifies the need for a specific allergological examination of patients with psoriasis in order to establish causative allergens, especially in the case of a severe course of the disease.

Our current knowledge on transcriptomic characteristics of monocytic populations in prostate cancer remains very limited. This is due to complexity of studying heterogeneous circulating immune cells, due to variability of cell phenotypes and antigen expression in malignant tumors. The use of single-cell sequencing provides an opportunity to study the transcriptional profile of monocytes, which may resolve many questions related to the role of different monocyte subpopulations in  formation of the tumor immune microenvironment in patients with prostate cancer. The aim of our study was to characterize the contribution of transcriptional features of monocyte subpopulations to the formation of the immune microenvironment in prostate cancer. Patients and methods: The study included 3 patients with acinar adenocarcinoma of the prostate and one patient with small acinar prostatic adenocarcinoma. The transcriptomic profile of peripheral blood monocyte cells was obtained using single-cell RNA sequencing (scRNA-seq). Counting matrices were obtained using Cell Ranger and analyzed in R/Seurat, taking into account duplicates (scDblFinder) and filtering low-quality cells. After normalization (SCTransform), integration (Harmony), and clustering (UMAP, PCA, FindClusters), clusters were annotated in Azimuth, and ligand–receptor interactions were explored using CellChat. Results: Transcriptome profiling of monocytic cells using single-cell RNA sequencing (scRNA-seq) revealed that among the highly expressed genes of classical monocytes, there is a network aimed at increasing the pro-inflammatory background of the immune environment (S100A8, S100A9, IL-6). Non-classical monocytes were characterized by increased expression of TRPC6, NO/cGMP signaling components (GUCY1A1/B1), and Sema3A, which are associated with angiogenesis, monocyte recruitment, and their polarization into immunosuppressive phenotypes. Intermediate monocytes demonstrated activation of regulatory-migratory programs (ETS1, CCL5) along with elements of T-cell interaction (CD3E, CD247, SKAP1) and IL signaling. The signaling profiles of monocyte subpopulations in prostate cancer show diversity in both outgoing and incoming pathways, reflecting their functional heterogeneity. Features associated with activation of TGFβ-, galectin-, and TRAIL-signaling are noted, thus suggesting involvement of different monocyte subtypes into arising intercellular interactions within tumor microenvironment. Hence, the performed analysis emphasizes an important role of transcriptional features of monocyte subpopulations in development of intercellular interactions and formation of the immune microenvironment in prostate cancer.

Phosphorylation of the STAT1 protein at serine 727 (pSTAT1_S727) is a key post-translational modification whose function in the anti-tumor immune response within malignant central nervous system (CNS) tumors remains insufficiently understood. This study aimed to determine the role of pSTAT1_S727 in immune modulation in the most aggressive brain tumor – glioblastoma. The results demonstrated that STAT1_S727 phosphorylation is closely associated with the activation of the anti-tumor immune system. A positive correlation was found between pSTAT1_S727 levels and the expression of genes encoding components of the major histocompatibility complex class I (MHC-I), as well as other genes involved in tumor antigen presentation. This indicates that pSTAT1_S727 plays an important role in enhancing the antigen-presenting capacity of glioblastoma cells, a critical step for tumor recognition by the immune system. Furthermore, high levels of pSTAT1_S727 were statistically significantly correlated with increased intensity of tumor infiltration by cytotoxic CD8+ T-cells. These observations were consistently confirmed both in data from glioblastoma patients and in experimental mouse models, underscoring the significance of the identified relationship. Thus, STAT1_S727 phosphorylation has been identified as an important molecular factor promoting the initiation of immune recognition of glioblastoma by enhancing antigen presentation and recruiting effector T-cells. However, despite this pro-inflammatory role, survival analysis of patients did not reveal an association between high pSTAT1_S727 levels and improved overall survival. This lack of clinical benefit is likely explained by the profoundly immunosuppressive environment characteristic of glioblastoma, where infiltrating T-cells are often functionally exhausted, and the tumor actively employs immune evasion mechanisms. Consequently, while activation of the pSTAT1_S727 signaling pathway is necessary for initiating an immune response, it is insufficient on its own to overcome immunosuppression and achieve a significant therapeutic effect. The obtained data highlight the need for combined strategies that simultaneously enhance the initiation of the immune response (e.g., through STAT1 activation) and block mechanisms of T-cell exhaustion within the tumor microenvironment.

Malignant tumors of the central nervous system (CNS) are poorly immunogenic, which limits the effectiveness of therapies and contributes to an unfavorable prognosis for patients with this pathology. Therefore, the development of new approaches to treating this group of diseases is becoming increasingly important. Atypical cyclin-dependent kinase 5 (CDK5) is involved in tumor progression and metastasis, as well as in the formation of immune escape by modifying the expression of MHC-I molecules and immune checkpoints, is an important candidate for regulating the molecular mechanisms of tumor growth. However, the influence of CDK5 on the functional state of T-cell subsets and the expression of key cytotoxic effectors in the microenvironment of primary and metastatic CNS cancers remains poorly understood. The aim of this study was to evaluate the effect of Cdk5 gene knockdown in tumor cells of mouse model on the functional status of cytotoxic T lymphocytes in the microenvironment of CNS cancers for comparation of experimental results with clinical data of patients diagnosed with CNS tumors. The objectives were to: (1) analyze the expression profile of genes associated with the T cell response using scRNA-seq in a mouse model of Cdk5 knockdown disease; (2) validate changes in infiltration and effector molecule expression using immunohistochemistry (IHC); (3) bioinformatically evaluate correlations between CDK5 expression levels and cytotoxic genes in cohorts of patients with brain metastases and primary glioblastoma using bulk- and scRNA-seq; and (4) analyze the impact of effector molecule expression on overall patient survival. Our results indicate that CDK5 expression levels influence the transcriptional activity of genes encoding key T cell effector molecules such as perforin or granzymes. The following of the analysis may be the possibility of formulating more accurate prognoses of patient survival based on the level of expression of CDK5 and effector molecules. Further studies are needed to elucidate the conditions and characteristics that mediate the immunomodulatory effect of CDK5.

The conducted studies have revealed the potential role of genetic variants of the main histocompatibility complex, which regulates the expression of human leukocyte antigen molecules (HLA) in the course of coronavirus infection (COVID-19). The aim: The aim - determine the relationship between HLA polymorphism and COVID-19, as well as the severity of the infection process in patients of the West Siberian of Russia. 260 patients with COVID-19 were examined after two months of convalescence. The comparison group included 372 residents of the Novosibirsk region. Genotyping alleles and alleles groups was performed using DNA-technology test-systems, Moscow. The IBM SPSS Statistics 23 and Arlequin 3.5.2 were used for statistical processing. An increase DRB1*15; DQA1*01:02 and decrease DRB1*03; DQA1*01:03; DQB1*05:03 frequency were detected in the COVID-19 patient relative control group. Differences remained only for DQA1*01:02 after Bonferroni correction. Three haplotypes were identified, which differed between the groups without Bonferroni correction. DRB1*07,15; DQA1*01:02,0201 and DQB1*02,06:02-08 frequency prevailed in patients relative control group. DRB1*07,15-DQB1*02,06:02-08; DQA1*01:02,02:01-DQB1*02,06-02-08 and DRB1*07,15-DQA1*01:02,02:01-DQB1*02,06:02-08 combinations prevailed in COVID-19 patients relative control group. Genotypes DRB1*07,11; DRB1*11,15 and combinations DRB1*07,11-DQA1*02:01,05:01; DRB1*11,15-DQA1*01:02,05:01; DRB1*11,15-DQB1*03:01,06:02-08, DRB1*11,15-DQA1*01:02,05:01-DQB1*03:01,06:02-08 were present only in patients with severe disease. DRB1*11, DRB1*07,11 and DRB1*07,11-DQA1*02:01,05:01 were higher in the combined group with severe plus moderate severity of the disease relative to the group of patients with mild disease. These results obtained make a definite contribution to clarifying the role of HLA- polymorphism in COVID-19 not only in Western Siberia, but also in the Russian Federation as a whole. Researches are needed with an increase in sample size, which is likely to overcome the threshold of significance when correcting for the multiplicity of alleles.

Abstract

In case of cardiac rhythm disturbance, factors related to the activation of the blood coagulation system and platelet aggregation have a significant contribution to the pathogenesis of thromboembolic complications, the researchers are closely focused on a joint study of congenital risk factors for the development of thrombosis and biomarkers that may be associated with the pathogenesis of thrombosis in atrial fibrillation.

Objective: to study the relationship of markers of inflammation and platelet activation with polymorphic variants of genes of the hemostasis system and platelet receptors in patients with non-valvular atrial fibrillation receiving anticoagulant therapy and having a history of thrombotic complications and patients with atrial fibrillation without thrombotic complications.

Materials and methods: the study included 60 patients diagnosed with atrial fibrillation, 21 patients developed thrombotic complications. All patients gave their written informed consent for inclusion in the study. The study of a panel of biomarkers, polymorphic variants of genes and platelet aggregation was conducted using the equipment of the Center for Collective Use "Medical Genomics" of the Tomsk National Research Medical Center.

Results: comparative analysis of polymorphic variants of plasminogen activator inhibitor PAI–1, platelet collagen receptor ITGA2, nitric oxide synthase NOS3, and beta-2 adrenergic receptor ADRB2 genes in patients with or without thrombotic complications did not reveal statistically significant differences in the studied groups. In the group of patients with thrombotic complications, compared with patients without thrombosis, there was a decrease in the levels of α-acid glycoprotein, fetuin A, L-selectin, thrombomodulin and an increase in CD40L and platelet factor 4 levels, a statistically significant difference was noted in subgroups with a high-risk genotype of thrombosis. The genotype of a high risk of thrombosis and the feasibility study of the PAI–1 and ITGA2 genes in the group with thrombotic complications is associated with increased platelet aggregation activity and increased platelet factor 4 content.

Conclusion: analysis of the relationship between markers of inflammation and platelet activation with polymorphic variants of hemostasis system genes and platelet receptors showed a link between the high-risk genotype and an increase in CD40L, platelet factor 4, and aggregation activity in patients in the group with thrombotic complications.

Previously, the associations were described between tumor proliferation rates (levels of Ki67 positive cells), and levels of IgA and IgG antibodies against estradiol (E2) and progesterone (Pg) (IgA₁-E2 and IgA₁-Pg, IgG₁-E2 and IgG₁-Pg) as well as corresponding antiidiotypic antibodies (IgG₂-E2 and IgG₂-Pg) in breast cancer patients (BCP). The purpose of the present work was to look for a combined influence of E2 and Pg, antibodies against benzo[a]pyrene (Bp), E2 and Pg, and antiidiotypic antibodies to E2 and Pg, searching for relations with Ki67 positive cells in tumors and metastatic disease in BCP. We performed studies in blood serum of 1245 BC patients before anticancer treatment (620 women with stage I BCP; 475, stage II; 150, with stages III+IV). Antibodies and antiantibodies were studied using ELISA technique with adsorbed haptens-BSA conjugates and monoclonal antibodies to E2 and Pg, respectively. The patients were divided into several groups with different individual levels of the studied factors. Low-proliferating tumors (Ki67≤20%) combined with metastases (Met+) were less frequent whereas tumors with Ki67>20% + Met- were more common among 143 BCP with IgG₂-Pg ≤1.95 conventional units (c.u.) than in 332 BCP with IgG₂-Pg>1.95 c.u. (10.0% vs 21.1% and 42.0% vs 26.2%, p<0.01). Tumors with Ki67>20% were revealed in 94 BCP with IgG₂-Pg>1.95 c.u. + IgG₁-Bp>14.3 c.u., more frequently than in 238 BCP with IgG₂-Pg >1.95 c.u. + IgG₁-Bp≤ 4.3 c.u. (69.2% vs 50.1%, p<0.01). Tumors with Ki67≤20% + Met- were diagnosed more frequently, and Ki67>20% + Met+ were less common in 102 BCP with IgG₂-Pg>2.1 c.u. + IgG₂-E2>3.3 c.u. than in 42 BCP with IgG2-Pg>2.1 c.u. + IgG₂-E2≤3.3 c.u. (33.3% and 16.7% vs 7.1% and 31.0%, p<0.01). 43 BCP had high levels of E2 (>166 pmol/L) combined with IgG₂-Pg>2.1 c.u. + IgG₁-Bp≤14.3 c.u. + Pg>869 pmol/L, and the most aggressive tumors (Ki67>20% + Met+) more frequent than 33 BCP with low levels of E2≤166 pmol/L combined with the same factors (55.8% vs 21.2%, p<0.01). Each of these immuno-hormonal phenotypes has been found equally common in BCP with I, II, and III+IV stages. In conclusion, individual features on the tumor proliferation and metastasis in II stage BCP were dependent on individual combinations of IgG₂-Pg, IgG₂-E2, IgG₁-Bp, E2, and Pg serum levels. Immuno-hormonal phenotypes during tumor growth did not change upon tumor progression.

Immunological changes in subpopulations of normal lymphocytes in the blood of patients with chronic lymphocytic leukemia (CLL) may play a negative role in the progression of the disease. The aim - to study the effect of immunochemotherapy on the subpopulation composition and immunophenotypic characteristics of normal lymphocytes in the blood of patients with CLL. The study included 37 men, 25 women with CLL in stages B, C according to Binet, median age 64 [50; 71] years old, who received 6 cycles of immunochemotherapy: RB (Rituximab+Bendamustine) or FCR (Rituximab+Fludarabine+ Cyclophosphamide). The subpopulation composition of polyclonal B-, T- (T helper cells, T regulatory cells, T cytotoxic cells), NK-lymphocytes, as well as the expression of PD1, PD-L1, LAG3 were studied in the blood of patients before and after treatment. The studies were performed using the method of flow cytometry (Navios 10/3, Beckman Coulter, USA). The statistical analysis is performed in Statistica 13.0. The study showed that all patients with CLL had significant quantitative and functional changes in the subpopulation composition of B-, T-, and NK-lymphocytes before and after therapy. The proportion of normal polyclonal B cells among all lymphocytes before treatment is reduced and is characterized by PD1 expression. The therapy leads to a partial restoration of the population of normal B-lymphocytes, which do not show expression of PD1, PD-L1, LAG3. Before and after treatment, CD4+ and CD8+ T cells show the highest expression of PD1, which indicates a violation of their antitumor functions. After treatment, the T-lymphocyte microenvironment tends to recover due to an increase in their number. However, the preservation of PD1 expression on T-cells apparently prevents the complete restoration of their functional activity, which, along with an increase in the content of T-regulatory cells and the preservation of PD1 and LAG3 expression on NK-lymphocytes, helps to suppress the antitumor immune response and reduce the possibility of long-term remission. In this regard, monitoring of immunological parameters during therapy is useful for detecting the degree of dysregulation of the immune response and, thus, for timely provision along with antitumor therapy and corrective immunotherapy.

Inflammatory bowel diseases (IBD), which are a heterogeneous group of pathologies with various clinical and morphological manifestations, are a significant problem in modern medicine. The aim of the study was to reproduce the signs of IBD in Macaca mulatta (Rhesus macaque) by oral administration of DSS and to assess the cytokine response to intestinal barrier damage and translocation of bacterial components into the vascular bed. Mature Macaca mulatta males (n=5), kept in the wildebeest nursery at the Scientific Research Institute of Experimental Pathology and Therapy of the Academy of Sciences of Abkhazia were selected as the object of the study. The induction of inflammatory bowel disease in Rhesus macaque was carried out by chemical exposure – oral administration of 5% sodium salt of sulfated dextran (DSS) with a molecular weight of 40 000 in volumes corresponding to the physiological needs of animals. Immunological and molecular genetic analysis methods were used to determine cytokines and a marker of microbial translocation. The results of the study showed that induction of IBD in Rhesus monkeys leads to a regular increase in the serum marker of 16S rDNA translocation from the second day after exposure to DSS, reaching maximum values on the sixth day. In parallel with the increase in the translocation marker, there was an increase in the cytokine response, manifested by a significant increase in the concentrations of IL-6 and IFN-γ. The stimulation of cytokine production in response to induction is observed in the early stages, starting from the first day, and reaches peak values on the 2nd to 6th day. It is important to note that after the discontinuation of DSS, the levels of inflammation markers remained high, although they showed a gradual decrease towards the end of the experiment. Thus, a model of chemically induced inflammatory process in Macaca mulatta has been developed, characterized by a clear, predominantly Th1-cytokine profile, accompanied by pronounced microbial translocation. The duration of inflammation induced by DSS is comparable to the time required for acute inflammation to transition into a chronic form. This model can be a valuable tool for further studying the pathogenesis and developing new treatments for IBD.

HLA alloimmunization, allergic rhinitis/atopic dermatitis, and tick-borne encephalitis serve as relevant models for investigating genetically determined immune responses to three types of antigens: alloantigens, allergens, and viral antigens. Previous research has primarily focused on individual HLA alleles, without considering haplotype-level interactions and potential synergistic effects among HLA genes. This study aimed to identify associations between three-locus HLA haplotypes (HLA-DRB1-DQA1-DQB1) and the risk of developing HLA alloimmunization, allergic rhinitis, atopic dermatitis, and tick-borne encephalitis. Twelve common European haplotypes were analyzed in 215 patients and 317 healthy controls. Alloimmunization risk was assessed in 61 recipients of blood components, atopic conditions were evaluated in 50 patients with persistent allergic rhinitis and atopic dermatitis, and the clinical course of tick-borne encephalitis was examined in 104 patients. Genotyping was performed using real-time PCR (DNA Technology, Russia) at the Laboratory of Immunohematology, Kirov Scientific Research Institute of Hematology and Blood Transfusion. Statistical analyses included chi-square. The haplotypes HLA-DRB104-DQA103:01-DQB1*03:02 and HLA-DRB103-DQA105:01-DQB1*02:01 were significantly associated with the development of HLA alloimmunization. Their complete overlap with genetic markers of autoimmune diseases suggests a shared mechanism by which HLA molecules mediate the presentation of both autoantigens and alloantigens. It has been shown that distinct HLA haplotypes are associated with specific clinical phenotypes of atopy. Specifically, HLA-DRB112-DQA105:01-DQB1*03:01 and HLA-DRB115-DQA101:02-DQB1*06:02 are linked to a selective predisposition toward respiratory sensitization, whereas HLA-DRB101-DQA101:01-DQB1*05:01 is associated with systemic atopy that includes a cutaneous component. These findings support the immunogenetic heterogeneity of atopic disorders, indicating that allergic rhinitis and atopic dermatitis are distinct endotypes within the broader “atopic continuum.” The analysis revealed that a prognostically favorable form of tick-borne encephalitis—the fever form, characterized by an intact humoral antiviral immune response—was found to be associated with the HLA-DRB109-DQA103:01-DQB1*03:03 haplotype. More severe forms involving central nervous system damage and dysfunction in both humoral and cellular immunity were linked to distinct haplotypes: the meningeal form was associated with HLA-DRB108-DQA104:01-DQB1*04:01/04:02, while the focal form correlated with HLA-DRB116-DQA101:02-DQB1*05:02/05:04. These findings have important implications for clinical practice, particularly in guiding patient stratification, forecasting disease progression, and informing the selection of targeted preventive and therapeutic strategies.

This review provides a definition of secondary immunodeficiency (SID), substantiates its role within the framework of multimorbidity, and examines the clinical consequences of multimorbidity when SID is present. The article summarizes the limited available epidemiological data on the prevalence of SID, analyzes the most common risk factors and causes of immunodeficiency, and highlights the expanding spectrum of these factors in light of recent advances in understanding disease pathogenesis and the pharmacodynamics of modern drugs that may adversely affect immune cells and mediators.

A structured clinical pathway for medical management is proposed, starting with the identification of risk factors and early clinical manifestations of SID—particularly severe and recurrent infections as key clinical markers—and culminating in the diagnosis of immunodeficiency. These recommendations are based on expert consensus statements developed by multidisciplinary teams of clinicians and immunologists.

The review also presents a detailed diagnostic algorithm for patients with suspected secondary immunodeficiency, including comprehensive medical history taking and clinical assessment to guide appropriate laboratory evaluation, including immunological testing. It is emphasized that normal immune parameters do not exclude the diagnosis of SID in patients with severe or recurrent infections.

Approaches to differentiated anti-infective prophylaxis across various risk groups are discussed, along with the main therapeutic strategies for SID, including vaccination and immunoglobulin therapy. At the same time, the limited evidence regarding the efficacy and safety of vaccines and immunoglobulins in the treatment of SID is highlighted. The article concludes that optimal management of patients with SID requires a multidisciplinary clinical team, with mandatory involvement of a clinical immunologist.

Аsthma remains one of the most common chronic respiratory diseases in children, with about half of children with asthma experiencing uncontrolled disease progression. Markers of the eosinophilic endotype of asthma are well studied, but the neutrophilic endotype, especially in children, has not been sufficiently researched, and reliable serum/plasma markers of the neutrophilic pattern of inflammation in asthma are unknown. Objective: To determine the diagnostic significance of plasma concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in relation to asthma control in children. Materials and methods: 132 children with asthma aged 6-17 years (mean age 12.5±3.5 years; 81 boys/51 girls) were examined. The degree of asthma control was assessed using the Asthma Control Test questionnaire. The following groups were identified: controlled asthma (n=21), partially controlled asthma (n=47), and uncontrolled asthma (n=64). NGAL concentration in blood plasma was determined using an automated immunoassay. Statistical analysis included the Kruskal-Wallis test, Mann-Whitney U test, Spearman's correlation analysis, and ordinal logistic regression. Results: In children with uncontrolled asthma, NGAL levels were statistically significantly higher compared to the controlled and partially controlled asthma groups (p=0.043). NGAL correlated positively with the absolute number of peripheral blood neutrophils (r=0.272; p<0.001) and showed no association with markers of eosinophilic asthma endotype (total IgE, eosinophils). At the same time, we did not find any differences in NGAL concentration depending on the asthma severity (Kruskal-Wallis test p = 0.420) and the phase of the disease (remission (n = 46) – 103 (63-185) ng/ml, exacerbation against the background of viral infection (n = 14) – 105 (66.8-156) ng/mL, exacerbation without signs of viral infection (n = 72) – 138 (90.5-207) ng/mL; Kruskal-Wallis test p = 0.310). Ordinal logistic regression showed that an increase in NGAL by every 10 ng/ml increases the likelihood of worsening asthma control by 5% (OR=1.05; 95% CI: 1.01-1.09; p=0.022) regardless of gender, age, and disease severity. Conclusion: Plasma NGAL concentration is an independent biomarker of uncontrolled asthma in children, reflecting a predominantly neutrophilic inflammation pattern. NGAL may be used as a screening tool for the early identification of children at risk of losing asthma control and requiring treatment adjustment.

Background. Chronic rhinosinusitis (CRS) is a serious medical and social problem due to its high prevalence worldwide. According to the literature, approximately 5–12% of the world's population is susceptible to this disease. Particularly complex pathogenetic variants of CRS include polypous rhinosinusitis (PRS) and chronic hyperplastic rhinosinusitis (CHRS).

The significant reduction in quality of life, prolonged periods of disability, and the prevalence of these pathologies necessitate further research into their pathogenesis. Most PRS phenotypes follow the T2 type, but there are also T1, T3, and mixed variants. A dominant endotype has not been established for CHRS.

We believe that patients with PRS and CHRS will have different immune responses. Cytokine profiles and immune response characteristics may vary, specifically influencing mucosal proliferation in the nasal cavity and paranasal sinuses.

The aim of this study was to investigate cytokine regulation in polypous rhinosinusitis and chronic hyperplastic rhinosinusitis.

Materials and Methods: 68 individuals with rhinosinusitis and 43 healthy individuals were examined. The study included patients with polypous rhinosinusitis (PRS, n=33), chronic hyperplastic rhinosinusitis (CHRS, n=35), and a control group (n=43) consisting of apparently healthy individuals. This case-control study was conducted in the Clinical Pathophysiology Laboratory of the Research Institute of the Ministry of Railways. Blood serum and nasal secretions were used for the study. Levels of IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-13, and IL-17A were determined by ELISA using Vector-Best reagents (Novosibirsk) and a Muitiskan FC spectrophotometer. Statistical analysis was performed using Statistica 10.0. Sample description included calculation of the median and interquartile range (IQR) at the 25th and 75th percentiles, the Mann-Whitney test, and a significance level of <0.05.

Results.

A study of cytokine concentrations revealed significant intergroup differences at the local and systemic levels. Patients in the control group had low levels of all studied cytokines, both locally and systemically. Consistent changes were identified for each CRS phenotype. Thus, high concentrations of IL-4, IL-5, and IL-13 were detected locally and systemically in PRS compared to the control group and the chronic hyperplastic rhinosinusitis group. For chronic hyperplastic rhinosinusitis, increased levels of IFN-γ, IL-2, IL-10, IL-17A, IL-8, and IL-1β were detected locally and systemically compared to the control and PRS.

Conclusions.

A T2 immune response was detected locally and systemically in PRS, while a mixed T1/T3 immune response was demonstrated locally and systemically in PRS.

The multifunctionality of neutrophilic granulocytes (NG) is associated with the presence of various subsets and phenotypes. Previously, in children with severe purulent inflammatory diseases, a correlation was found between the severity of disease and the number of CD66b⁺CD16⁺CD33⁺HLA-DR⁺NG (APC-NG) subset. Thus, the determination of the APC-NG subset can serve as a valuable diagnostic tool and an indicator of the effectiveness of complex therapy in severe purulent-inflammatory diseases.

Goal: to assess the dynamic changes in APC-NG level in children with AHO in comparison with the dynamics of indicators of clinical effectiveness during immunomodulatory therapy with a synthetic thymic hexapeptide (HP).

Materials and methods. The study group (SG) included children aged 10-15 years with AHO (n=15), the comparison group (CG) consisted of 13 conditionally healthy children. In the peripheral blood (PB) of children, the content of NG expressing CD66b, CD16, CD33, HLA-DR (FC500, Beckman Coulter) and the expression density of these molecules was evaluated. The PB was collected before surgery, on the 10th day of therapy, and before discharge. The immunological parameters of children with CG were studied once.

Results: It was found that the amount of APC-NG, which was increased by 18 times in SG before treatment, decreased by 1,9 times on the 10th day after the beginning of treatment and by 3,8 times by the time of discharge (20-25th day). However, the content of APC-NG after treatment did not reach the CG indicators. In addition, a decrease in the number of APC-NG correlated with positive clinical dynamics: there was an earlier regression of general and local symptoms. A delay in the positive changes of APC-NG was observed in the absence of clinical effectiveness, which required a revision of therapeutic tactics and the need to change antibacterial therapy.

Conclusion: The study demonstrated the high clinical efficacy of HP in the complex treatment of children with AHO and the possibility of using the content of the APC-NG subset as a diagnostic marker for monitoring efficacy of postoperative treatment of children with AHO. This marker can also serve as a tool that allows for timely adjustment of the treatment of patients with AHO.

The aim of this study - to investigate the associations of blood serum idiotypic and antiidiotypic antibodies specific to estradiol (IgA₁-E2 and IgG₂-E2) with genes polymorphisms of DNA-repairing enzymes in breast cancer patients (BCP) according to Ki-67 positive cells in tumor.  

Idiotypic and antiidiotypic antibodies in the blood serum of BCP (360 at the I stage and 376 at the II–IV stages) were measured by enzyme-linked immunosorbent assay. Prevalence of hOGG1 (rs1052133), XRCC1 (rs25489), XPD (rs13181), APEX1 (rs1130409) were determined by allele-specific polymerase chain reaction. High levels of Ki-67 positive cells in tumors (>30%) were revealed in 47.9% and 58.9% BCP II–IV stages with low and high IgA₁-E2 levels (p = 0.035); in 61.2% and 46.9% BCP II–IV stages with low and high IgG₂-E2 levels (p = 0.001). High Ki-67 tumor levels were found in 55.6% BCP with low levels both IgA₁-E2 and IgG₂-E2; in 67.6% BCP with high IgA₁-E2 levels combined with low IgG₂-E2 levels; in 43.2% BCP with low IgA₁-E2 levels combined with high IgG₂-E2 levels; in 52.2% BCP with high both IgA₁-E2 and IgG₂-E2 levels. So IgG₂-E2 inhibited the tumor proliferation but IgA₁-E2 blocked this effect. There were no revealed any associations of hOGG1, XRCC1, XPD, APEX1 genes polymorphisms with Ki-67 positive cells tumors levels. High IgA₁-E2 levels were found in 39.9% BCP with CC hOGG1 genotype and in 47.8% BCP with CG hOGG1 genotype (p = 0.049). High IgG₂-E2 levels were revealed in 65.3% and 53.7% correspondingly (p = 0.003). High IgG₂-E2 levels in combination with low IgA₁-E2 levels were revealed in 40.6% BCP with CC hOGG1 and in 27.2 % BCP with CG hOGG1 genotypes. The other combinations of low and high levels of IgA₁-E2 and IgG₂-E2 were found more frequent in CG hOGG1 BCP. The differences between CC and CG hOGG1 BCP according to prevalence of anti-proliferative and pro-proliferative immunological phenotypes were statistically significant (p = 0.003).

It was shown for the first time that the formation of antibodies that modulate the proliferative activity of a tumor may be associated with variants in the genes for DNA repair enzymes. In particular, the formation of idiotypic and antiidiotypic antibodies specific to estradiol were associated with hOGG1 gene polymorphisms in BCP. IgA₁-E2 and IgG₂-E2 immunoanalysis may be used in BCP I stage for tumor proliferation prediction.

The presence of FcᵧRIIIb (CD16) on the surface of neutrophil granulocytes (NG) in human blood endows these cells, through interaction with IgG, with a key property of adaptive immunity: an antigen-specific cellular  response. The purpose of the work was to compare the ex vivo reaction of human neutrophil FcᵧRIIIb in response to the addition in blood the live cells of  opportunistic (Escherichia coli, Staphylococcus aureus) and pathogenic (Yersinia pestis, Brucella abortus) bacterial species. Materials and methods. The density of CD16 expression on NG was determined by flow cytometry in arbitrary fluorescence intensity units (MFI) after staining leukocytes with CD45-FITC and CD16-PE reagents (Backman Coulter, USA) when immunophenotyping them in the blood according to the Lyse/No-Wash protocol. To model  bacteremia, we used attenuated (vaccine) strains B. abortus 19BA and Y. pestis EV NIIEG, as well as strains S. aureus ATCC 6538 (209-P) and E. coli ATCC 25922. Blood was obtained from healthy donors (n= 10), who were not vaccinated against plague and brucellosis. Bacteria of 4 species were added to the blood samples of each donor in the same dose of 10⁸ mc/ml and the results were taken into account according to the studied indicator after 30 minutes, 1, 2 and 6 hours of incubation. Results. Opportunistic bacteria, in contrast to Y. pestis and B. abortus, caused a sharp decrease in the density of FcᵧRIIIb expression on human blood NG after 2 hours of incubation, which was a marker for the development of ex vivo IgG-mediated anaphylaxis, caused by the presence in the blood of all healthy adults IgG to specific antigens of E. coli and S.aureus. Changes in the CD16 marker induced in NG by opportunistic bacteria preceded degranulation and lysis of these cells under ex vivo conditions, while in the presence of Y. pestis and B. abortus neutrophils did not undergo degranulation and cytolysis within 6 hours. Conclusion. The experimental data obtained in the work reflect the known fact of the participation in the neutralization of E. coli and S. aureus of the phenomenon of extracellular antibody-dependent cytotoxicity of NG, which is realized in the bloodstream using the NETosis mechanism and plays a decisive role in the prevention of sepsis. The absence of a reaction of the molecular trigger CD16 NETosis to Y. pestis and B. abortus indicates that in the human body not vaccinated against plague or brucellosis, this protective antibody-dependent bactericidal mechanism does not work. Evaluation of FcᵧRIIIb reactivity by flow cytometry in an ex vivo bacteremia model is promising from the point of assessing the intensity of post-vaccination immunity in humans. 

Despite its economic importance and health benefits, strawberries (Fragaria × ananassa) can cause IgE-mediated allergic reactions, primarily manifesting as oral allergy syndrome. The primary sensitizing factor is the allergen Fra a 1. This protein is a member of the PR-10 (pathogenesis-related proteins) family and is structurally homologous to the major birch pollen allergen Bet v 1. This study assessed the allergenic potential of the strawberry allergen Fra a 1 and analyze the effect of heat treatment on its structural and functional properties. A recombinant allergen, Fra a 1, was obtained. Fluorescence spectroscopy demonstrated the protein's ability to bind a wide range of fatty acids, confirming the functional activity of the recombinant analogue. Circular dichroism demonstrated that heating to 98°C causes irreversible changes in the protein's secondary structure. Enzyme-linked immunosorbent assay demonstrated that pre-boiling (99°C, 15 min) leads to a statistically significant but partial (up to 30%) reduction in the ability of Fra a 1 to bind cross-reactive polyclonal anti-Bet v 1 IgG, while binding to specific IgE from sera of patients with pollen and food allergy decreased in only half the cases. A study of proteolysis kinetics revealed rapid degradation of the allergen by pepsin in vitro, which was not accelerated by preheating. Furthermore, Fra a 1 exhibited relative resistance to digestion by lysosomal enzymes of human macrophages in vitro compared to birch Bet v 1 and soybean Gly m 4. These data indicate partial thermal stability of the Fra a 1 allergen, its ability to retain IgE-binding activity in some sensitized individuals after heating, and characteristics of proteolytic degradation that may modulate its immunogenicity. The results of the study are important for assessing the risks associated with the consumption of heat-treated strawberries and developing strategies to reduce allergenicity.

Edwards syndrome (trisomy 18) is recognized as the second most common autosomal trisomy after Down syndrome and is characterized by pronounced multiorgan pathology affecting virtually all body systems, including the organs of the immune system. Although immune disturbances in this chromosomal anomaly occur frequently and may substantially influence the clinical course of the disease, the morphological diagnosis of these changes in pediatric pathology practice has traditionally received insufficient attention. As a result, important structural alterations in immune organs are often underestimated and rarely considered as a distinct and clinically relevant component of the underlying pathogenesis.

The aim of this study was to conduct a detailed analysis of morphological changes in the organs of the immune system in children diagnosed with Edwards syndrome. The investigation was carried out at the Sverdlovsk Regional Pathology Bureau (SOPAB) in Yekaterinburg, Russia, and included an examination of autopsy materials from ten children who died between 2019 and 2025. A review of their medical records demonstrated that, despite comprehensive clinical evaluations, none of the patients received a premortem diagnosis of immunodeficiency, and this condition was not reflected in the final clinical diagnoses.

Postmortem morphological analysis revealed significant abnormalities in immune organs in 70% of the children. The thymus showed various pathological changes, including hypoplasia (30%), hypoplastic dysplasia with areas of fatty degeneration and lymphoid depletion (10%), and large-cystic hypoplastic dysplasia (10%). The spleen also exhibited alterations in both the quantity and architecture of its lymphoid components. Infectious complications were identified in six children (60%), either as competing conditions or as the direct cause of death. One child presented only with prolonged recurrent pneumonia, while in the remaining cases the infections were generalized. In all instances, infectious processes were associated with severe congenital malformations of organs and systems and/or pronounced structural abnormalities of the thymus.

The findings highlight the importance of further research into immunopathology in patients with chromosomal abnormalities, aiming to enhance diagnostic accuracy at both clinical and pathological stages.