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.

Herpesvirus infections caused by herpes simplex viruses types 1 and 2 represent a major global healthcare challenge due to their widespread prevalence and ability to establish lifelong persistence. Current estimates indicate that approximately 3.752 billion people under the age of 49 are infected with herpes simplex virus type 1, while herpes simplex virus type 2 affects approximately 491.5 million people in the same age group. In the Russian Federation, despite a reported decline in incidence rates, experts suggest that this may reflect limitations in disease registration. The true prevalence of herpesvirus infections is difficult to determine because infections are frequently asymptomatic and many cases remain undiagnosed. Clinical manifestations range from localized lesions of the skin and mucous membranes to severe conditions such as herpetic encephalitis, keratitis, and neonatal herpes. herpes simplex viruses type 2 also increases the risk of acquiring human immunodeficiency virus infection three to four times by recruiting target cells to sites of inflammation. The immunopathogenesis of herpesvirus infection involves interactions between innate and adaptive immune mechanisms. Innate immunity provides the first line of defense, with Toll-like receptors recognizing viral components and activating signaling pathways. Adaptive immunity subsequently controls the pathogen through T and B lymphocytes. Cytotoxic T-lymphocytes are particularly important because they persist in sensory ganglia and suppress viral reactivation from latency. However, herpes simplex viruses employ multiple mechanisms to evade the immune response. Viral proteins suppress interferon production and inhibit protein synthesis in host cells, while viral glycoproteins facilitate entry into host cells and interfere with humoral immune responses. The interferon system connects innate and adaptive immunity. Type I and III interferons provide local mucosal protection, whereas type II interferon coordinates cellular immune responses. The interaction between the host’s multilayered immune defenses and viral mechanisms of immune evasion contributes to lifelong herpes simplex viruses persistence and makes herpesvirus infections a significant unresolved medical challenge. Elucidation of these molecular mechanisms underlying virus–host interactions is essential for the development of innovative therapeutic strategies aimed at restoring effective immune control.

Inborn errors of immunity, also known as primary immunodeficiencies, are a group of genetic disorders that affect the development and functioning of the immune system. Recently, researchers have identified a subgroup of inborn errors of immunity with an atopic phenotype. Hyper-IgE syndromes occupy a prominent place among these. Fundamental research, particularly in the last decade, has convincingly demonstrated the link between severe forms of atopic dermatitis (and other allergic diseases) and monogenic disorders—mutations in various gene exons. It has been established that several different inborn errors of immunity are phenotypically similar to classic hyper-IgE syndrome (Jow's syndrome), but the genotypes of these disorders differ significantly. As is known, genes can be inherited through such mechanisms as gain of function (GOF), loss of function (LOF), dominant-negative effects (DN), as well as autosomal dominant, autosomal recessive, X-linked pathways, or de novo development of the disease can occur. Thus, to date, more than 10 monogenic disorders with a phenocopy of hyper-IgE syndrome associated with a deficiency of such genes as LOF and DN in the STAT3 gene, DOCK8; TYK2; IL6R; IL6ST; ZNF341; ERBIN; TGFBR (Loeys-Dietz syndrome); phosphoglucomutase 3 (PGM3), CARD11; STAT6GOF. It should be borne in mind that many of them have a number of distinctive features (clinical, immunological and non-immunological), which can be unique. To diagnose such conditions, the clinical manifestations of the disease should be taken into account (primarily severe atopic dermatitis refractory to traditional therapy, often accompanied by complications of the skin, respiratory tract, and other systems, as well as skeletal muscle abnormalities, autoimmune involvement, etc.). However, genetic testing is always required to confirm the diagnosis, which is also crucial in the selection of modern targeted therapy (and/or small molecules, etc.). This review aims to increase physician awareness of this connection. Furthermore, this knowledge will assist physicians in correctly differentiating between severe atopic dermatitis and inborn errors of immunity with an atopic phenotype, given the similarity of clinical symptoms, elevated IgE levels, and eosinophilia in the blood. Soon, several new variants of inborn errors of immunity with an atopic phenotype will likely expand the genetic spectrum of hyper-IgE syndromes

Community-acquired pneumonia is one of the most common infectious diseases. According to the World Health Organization, lower respiratory tract infections are a leading cause of death. Identifying predictors of severe pneumonia and its fatal outcome is of great interest to practical medicine. Predicting the course of the disease allows us to develop an appropriate treatment strategy for the patient and ensure timely hospitalization. The aim of this study was to analyze the scientific literature to identify predictors of severe pneumonia and its fatal outcome. The following databases were used: Elibrary, Cyberleninca, Pubmed, and Google Scholar. Determining the number of leukocytes and their populations in the blood is the most accessible diagnostic method, reflecting immune responses. A link has been established between eosinopenia and the severity of inflammatory lung diseases. According to researchers, an increase in the relative neutrophil count and the neutrophil-to-lymphocyte ratio can be used to predict the outcome of pneumonia, while a decrease in the absolute lymphocyte count below 0.724*10^9/L is an independent predictor of 30-day mortality. Determining biochemical markers allows for a comprehensive assessment of the patient's condition. For example, blood albumin levels help determine the patient's nutritional status; it also has immunomodulatory activity and is involved in the fight against pathogens. In severely ill patients, hypoalbuminemia is observed, as well as elevated creatinine and blood urea nitrogen levels. Clinical studies have also demonstrated a link between brain peptide levels and mortality in patients with concomitant cardiovascular disease. C-reactive protein, along with procalcitonin, is one of the main indicators of community-acquired pneumonia severity used in clinical practice. Pentraxin-3 has received considerable attention as an indicator of severe progression and a predictor of mortality. Cytokines, whose levels change in response to the development of an inflammatory reaction, play a key role in regulating the immune response to pathogens. However, a comprehensive assessment of a patient's condition requires the use of prognostic scales. The large number of existing and newly proposed scales reflects the lack of a methodology that would fully meet the requirements of practical medicine. A complete assessment in prognostic scales requires consideration of immunological parameters.

Allergic diseases represent a complex social and medical problem due to their increasing prevalence in the population. Studying their pathogenesis is crucial for developing new diagnostic and treatment methods. The difficulty of managing patients with this pathology is exacerbated by the complexity of diagnosing triggers, the variety of possible mechanisms for developing reactions, and the difficulty of choosing optimal treatment regimens. Despite the fact that allergic diseases of the female genital tract are poorly documented in the literature, they represent an important clinical problem that combines elements of dermatological, infectious, and immunological disorders. The aim of this study was to summarize the data on the immunopathogenesis of allergies in the context of the new concept of hypersensitivity, focusing on reactions in the female genital tract. The article provides a systematic review of current knowledge about the types of hypersensitivity according to the EAACI-2023 classification, including possible triggers, cells involved in allergic inflammation with initiating, differentiating, and effector functions, as well as significant humoral factors, taking into account the main stages of an allergic reaction. Any type of hypersensitivity, as well as a combination of them, can be involved in the development of allergic reactions in the female genital tract. An analysis of possible mechanisms of development of hypersensitivity reactions in allergic contact dermatitis of the vulva, allergic dermatitis of the anogenital area and vulvovaginitis, irritant contact dermatitis of the vulva, Candida vulvovaginitis. It is emphasized that an effective treatment requires a comprehensive approach, including the obstetrician-gynecologist's awareness of potential causes of allergic discomfort, the use of an optimal set of tests to identify triggers, and appropriate recommendations for eliminating provoking factors and prescribing therapy. In the applied aspect of studying the pathogenesis of allergic diseases, possible new diagnostic biomarkers and targets for reducing excessive inflammation using targeted drugs are considered. Thus, the expanded concept of immunopathogenesis of allergy offers a theoretical basis for the personalization of diagnosis and treatment, taking into account the prevailing hypersensitivity mechanism. The use of pathogenetically justified laboratory tests will optimize the diagnosis and treatment of various allergic diseases, improving the quality of life for patients.

The clinical picture of immune-mediated inflammatory rheumatic diseases (IMIRD) is characterized by polymorphism. Currently, the theoretical platform allowing to understand the pathogenesis of IMIRD is the concept of a systemic sterile inflammatory process in connective tissue caused by the release of proinflammatory DAMPs, the interaction of DAMPs with PRR of dendritic cells   and macrophages, the induction of a destructive DAMP-specific immune response in the form of production of multiorgan DAMP-specific auto-antibodies, hyperproduction of proinflammatory cytokines, expansion of DAMP-specific autoreactive Th1 and Th17 lymphocytes and inhibition of regulatory T lymphocytes (Treg). The source of intracellular proinflammatory DAMPs in IMIRD are necrosis, apoptosis, pyroptosis, and necroptosis of inflammatory infiltrate cells, as well as PANoptosis. Activation of PANoptosis leads to a massive release of DAMPs and proinflammatory cytokines, creating a self-sustaining vicious cycle. Extracellular connective tissue DAMPs - biglycan, decorin, lumican, fibromodulin, hyaluronan, versican, aggrecan, etc. actively participate in the progression of sterile inflammation in IMIRD. The paper presents an analysis of molecular and cellular processes that make it possible to substantiate the formation of a self-sustaining vicious circle in IMIRD: “probable etiological factors in IRR (auto-antigen, microorganisms, UVR, etc.) → cell death → release of pro-inflammatory DAMPs → PRR-DAMPs interaction → induction of PANoptosis → release of new pro-inflammatory DAMPs by PANoptotic cells → progression of sterile inflammation.” There is every reason to believe that PANoptosis activation of sterile inflammation in IMIRD can be used as a criterion for disease activity and a prognostic marker for resistance to therapy. Studies of signaling pathways, adaptor molecules, and transcription factors, including PRR-DAMP interactions, have allowed us to identify "checkpoints" for targeted therapy in IMIRD. These may include Z-DNA binding protein 1 (ZBP1), receptor-interacting serine/threonine kinases 1 and 3 (RIPK1 and RIPK3), the NLRP3 inflammasome, and caspase-8, which acts as a "molecular regulator" of cell death that promotes PANoptosis. Thus, pathogenetically based therapy for IMIRD, based on knowledge of the molecular and cellular processes involved in inflammatory cell death, is becoming feasible. Implementation of this concept opens up prospects for the development of new diagnostic tests, targeted drugs, and personalized treatment protocols for IMIRD. 

Inborn errors of immunity (IEI) are severe, genetically determined, chronic diseases resulting from the loss, reduction, or malfunction of parts of the immune system. The clinical presentation and lifestyle circumstances of individuals with IEI make this category of patients particularly vulnerable to the development of mental disorders. Once mental health problems have developed, they can, in a vicious cycle, worsen physical conditions, increase hospitalization rates, and place additional strain on the healthcare system. A patient diagnosed with IEI requires lifelong immunoglobulin replacement therapy, which creates additional specific iatrogenic and sociopsychological challenges: regular medical visits, multiple infusion procedures, "needle phobia," dependence on medication, "medication anxiety," etc. Furthermore, immune system dysfunction can play an etiological role in the development of mental disorders through post-infectious microglial activation and microbial dysbiosis. In the Russian Federation, the average time from the onset of symptoms to diagnosis of IEI is approximately 17 years. This prolonged period of time not only leads to a significant deterioration in the patient's health but also to a comprehensive decline in quality of life. The aim of this study was to analyze accumulated domestic and international scientific publications on the psychological well-being of patients with inborn errors of immunity to determine the role of psychological support in the comprehensive treatment of adults with Inborn errors of immunity (primary immunodeficiencies) and the main areas of clinical psychologist work with this group of patients. This study provides an overview of the psychosocial aspects of the lives of patients with IEI, as well as research on their mental disorders and satisfaction with their quality of life. The study also examines the key principles and possible areas of clinical psychologist work with patients with IEI. Adherence to these principles will enable systematic and consistent work, an individualized approach tailored to each patient's needs, and long-term interventions. Based on the results of this study, it is concluded that the specific psychosocial factors of the disease, as well as the close relationship between mental and immune system functioning, create a unique psychological profile in patients with IEI that requires description and clarification through multidisciplinary scientific research.

Glioblastoma is the most aggressive primary brain tumor with a dismal prognosis. Despite standard protocol (surgery, radiotherapy, temozolomide), median overall survival remains approximately 16 months, and relapse is almost inevitable. Immunotherapy based on Natural killer cells is a promising avenue due to their ability to eliminate tumor targets without prior sensitization and the lack of graft‑versus‑host disease risk when using allogeneic products.

The objective of this review is to systematize and critically analyze current data on the development NK‑cell and CAR‑NK‑based therapies for glioblastoma and to identify key barriers to clinical application.

The research includes the analysis of publications in PubMed and ClinicalTrials over the past decade, focusing on preclinical studies and phase I‑II clinical trials. A total of 25 preclinical and 10 clinical studies were included.

In preclinical studies, alongside immortalized lines U87, U251 and 3D spheroids, orthotopic xenografts in NSG mice with patient-derived glioma stem cells have become the standard. The model captures heterogeneity, microenvironment, and interpatient variability. CAR‑NK cells targeting GD2, CSPG4, and EGFRvIII show the highest efficacy with local intratumoral or intraventricular administration.

Clinical trials are dominated by allogeneic NK cells and local delivery. The best median overall survival of 22.5 months was achieved using allogeneic NK cells from peripheral blood with multiple intravenous infusions.

Preliminary data are limited and require confirmation in controlled trials. Three major obstacles were identified: the blood‑brain barrier; the immunosuppressive microenvironment (TGF‑β, NKG2A, PD‑L1); and the lack of standardized protocols and phase III evidence. Strategies to overcome these barriers include genetic engineering (CAR, TGF‑βR2/NKG2A knockout, IL‑15 expression), combination with checkpoint inhibitors, and targeted drugs.

Recommendations are provided for optimizing preclinical modeling and designing future clinical trials to assess the potential of NK‑cell therapy using integrated engineering approaches and local delivery.

As one of the two central organs of the body's immune system, the thymus is the only place where T lymphocytes are produced. It has been established that, in fact, after the pineal gland, the thymus is the second organ in humans that undergoes involution, starting from the first year of life, when a sufficient number of CD4+, CD8+, and Treg cells migrate from the thymus to the periphery on a daily basis. However, it has been discovered that the organ's migration activity does not end there. It has been established that during ontogenetic development, the thymus is an organ into which immunocompetent cells from the periphery constantly migrate. First of all, these include thymocyte precursors that migrate from the bone marrow. Other immunocompetent cells, including dendritic cells and B-lymphocytes, also migrate from the periphery to the thymus. Of particular interest is the migration of T cells from the periphery to the thymus, which had previously migrated from the thymus to the periphery. These re-emigrants contribute significantly to the overall cellularity of the organ as we age. These re-emigrants carry a whole functional load, and are not passive residents of the thymus. It has been shown that they take part in both positive and negative selection processes. Memory T cells continue to remain in the thymus for an indefinite period of time after migration. They provide support for the functional activity of thymic epithelial cells. Mature Treg cells that re-emigrate to the thymus inhibit the production of new regulatory cells, thereby also participating in the process of thymic involution. There is no doubt that reverse thymic reemigrants contribute to the immunopathogenesis of many immunocompromised diseases.

Endometriosis remains a complex clinical problem due to underdiagnosis and limited treatment options. Current scientific theories do not fully explain the causes and mechanisms of this disease, highlighting the importance of in-depth study of its pathogenesis. Immune mechanisms are increasingly recognized as key drivers of pathological changes in endometriosis. Particular focus is placed on γδT-cells, which participate in both innate and adaptive immunity. The diversity of γδT-lymphocyte subpopulations determines their participation in a wide range of biological processes with individual subpopulations exhibiting both synergistic and antagonistic functions, potentially influencing the course of the disease. These cells secrete cytokines, execute cytotoxic reactions, and modulate other immune cells, forming a complex interaction network within the endometriotic lesion microenvironment. This review provides a detailed analysis of the cellular composition of endometriotic lesions, focusing on the expression of surface receptors and molecules providing intercellular interactions. It also compares the immunopathogenesis of three reproductive tract disorders: endometriosis, uterine fibroids, and tumours. This comparative approach helps distinguish common and disease‑specific immunological mechanisms and clarifies the contribution of particular cell populations. Systematized data on γδT‑cell subpopulations cover their tissue distribution and ratios, age‑related variations, phenotypic and functional traits, and expression of immune control points. It is noted that the balance of activating and inhibitory signals mediated by immune checkpoints can determine the direction of the immune response and influence the progression of endometriotic lesions. Current insights into γδT‑lymphocytes’ role in endometriosis and reproductive tumors provide a foundation for identifying diagnostic markers, discovering therapeutic targets, and refining endometriosis treatment strategies by accounting for its immunological underpinnings. The review enhances understanding of immune cells’ involvement in endometriosis and related conditions, pointing to new avenues for clinical and basic research.

This descriptive review analyzes the available literature on the characteristics the immune system and its role in the pathogenesis of long COVID. The review examines proposed definitions of long COVID, its prevalence, the heterogeneity of clinical manifestations, the challenges of timely diagnosis in the absence of reliable biomarkers, and known risk factors. The pathophysiological mechanisms underlying long COVID remain incompletely understood. One of the leading hypotheses suggests that persistent clinical symptoms are driven by interactions between viral persistence and an altered immune system.
Analysis of available data on innate immunity indicates predominantly proinflammatory alterations involving phagocytic cells, mast cells, components of the complement system, and cytokines. These alterations appear to be more pronounced in certain long COVID phenotypes, particularly neurological and cardiopulmonary phenotypes. Another important mechanism underlying persistent inflammation involves alterations in adaptive immunity, including sustained activation of SARS-CoV-2-specific T lymphocytes in patients with long COVID for up to six months after infection, together with a reduced CD4+ T-cell response in recovered individuals and an increased proportion of memory T cells in patients with long COVID. Persistent inflammation, combined with tissue alterations and chronic stress responses, may contribute to immune dysfunction and impaired clearance of residual virus, thereby creating a vicious cycle.
Quantitative assessment of T-lymphocyte subsets expressing activation markers is not consistently associated with long COVID, whereas biomarkers directly associated with SARS-CoV-2 antigens appear to be more informative. Data regarding the presence of autoantibodies remain contradictory and depend on detection methods, the analyzed biological material, and clinical differences among patient populations. Several large-scale studies have demonstrated a significantly increased incidence of newly diagnosed autoimmune diseases following COVID-19 compared with uninfected controls.
The identified immune alterations are believed to be associated with latent persistence of SARS-CoV-2 and reactivation of other viruses. Overall, patients with long COVID represent a heterogeneous and typically multimorbid population characterized by chronic inflammation and diverse immunopathogenetic features. Further advances in understanding long COVID will likely depend on identifying distinct phenotypes and endotypes, which may provide the basis for personalized therapeutic approaches.

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.

Pregnant women are vulnerable to SARS-CoV-2 infection due to physiological features of the immune system. The aim of the research was to evaluate the levels of interleukin-1β (IL-1β) in the peripheral blood of pregnant women during SARS-CoV-2 infection with mild to moderate forms of the disease. We examined 60 pregnant women with COVID-19, including 14 women in the first trimester, 17 in the second trimester, and 29 in the third trimester. The comparison group consisted of 20 pregnant women without clinical and laboratory signs of acute respiratory infections. IL-1β concentrations were determined in serum using enzyme-linked immunosorbent assay. Statistica 10.0 (StatSoft, USA) was used for statistical data processing. The statistically significant error level was considered to be p≤0.05. The study results showed higher levels of IL-1β in the blood of SARS-CoV-2-infected pregnant women compared to pregnant women without clinical and laboratory evidence of acute respiratory infections (p=0.005). COVID-19 is characterized by a decrease in the level of IL-1β in the blood in the third trimester of gestation compared to the first trimester (p=0.01). Pregnant women with COVID-19, compared with pregnant women without clinical and laboratory signs of acute respiratory infections, had higher levels of red blood cells (p=0.043), total protein (p=0.006), direct bilirubin (p=0.02), high-sensitivity C-reactive protein (p<0.001), ferritin (p=0.016), prothrombin time (p=0.018) and international normalized ratio (p=0.013). COVID-19 in pregnant women is associated with lower levels of lymphocytes (p=0.004), serum iron (p<0.001) and transferrin (p=0.003), transferrin saturation coefficient (p=0.026) and total iron-binding capacity of serum (p=0.021) in the blood. IL-1β in SARS-CoV-2-infected pregnant women had an inverse correlation with biochemical and coagulation blood parameters: transferrin (p=0.006), total iron-binding capacity of serum (p=0.03), latent iron-binding capacity of serum (p=0.009), fibrinogen (p=0.002). IL-1β in the blood of SARS-CoV-2-infected pregnant women is associated with the level of direct bilirubin (p=0.045) in moderate COVID-19, C-reactive protein (p=0.047) and alanine aminotransferase (p=0.024) in mild forms of the disease. Moderate COVID-19 in pregnant women is associated with a decrease of  leukocyte count (p=0.038) and an increase in prothrombin time (p=0.046). Thus, a relationship was established between the concentration of IL-1β in the blood and coagulation and biochemical parameters in women with COVID-19 at different stages of pregnancy and depending on the clinical course of COVID-19.

Objectives: This study aimed to evaluate the levels of tumor necrosis factor-alpha (TNF-α), receptor activator of nuclear factor-κB ligand (RANKL), and calprotectin in GCF, as well as serum C-reactive protein (CRP), in periodontitis patients with and without T1DM compared with periodontally healthy controls.

Materials and Methods: A total of 90 participants were enrolled and divided into three groups (n = 30 each): healthy controls, periodontitis patients without diabetes, and periodontitis patients with T1DM. Clinical periodontal parameters, including probing depth (PD), clinical attachment loss (CAL), plaque index (PI), and bleeding on probing (BOP), were recorded. GCF samples were analyzed for TNF-α, RANKL, and calprotectin using ELISA, while serum CRP and HbA1c levels were measured using automated analyzers. Statistical comparisons were performed using ANOVA and post-hoc tests.

Results: Periodontal clinical parameters were significantly worse in both periodontitis groups compared with controls (PD: 3.00 ± 0.00 vs. 4.53 ± 0.51 and 4.63 ± 0.49 mm; CAL: 2.00 ± 0.00 vs. 3.53 ± 0.51 and 3.63 ± 0.49 mm; p < 0.0001). TNF-α levels were significantly elevated in periodontitis patients with T1DM (15.11 ± 2.98 pg/mL) and without diabetes (13.90 ± 2.91 pg/mL) compared with controls (8.72 ± 2.35 pg/mL; p = 0.000). RANKL levels were highest in the diabetic periodontitis group (314.98 ± 74.65 pg/mL) compared with controls (270.46 ± 35.89 pg/mL; p = 0.021). Calprotectin levels showed a significant increase in periodontitis patients with T1DM (0.285 ± 0.149 ng/mL) compared with controls (0.223 ± 0.018 ng/mL; p = 0.017). A strong positive correlation was observed between TNF-α and RANKL in both periodontitis groups (r = 0.812, p < 0.001).

Conclusion: Periodontitis is associated with significant elevations in local inflammatory and bone-resorptive biomarkers, with T1DM further amplifying neutrophil-mediated inflammation and osteoclastogenic activity. GCF biomarkers, particularly TNF-α, RANKL, and calprotectin, may serve as valuable adjunctive tools for periodontal disease assessment in diabetic patients.

Background: Gingivitis is a common inflammatory condition of the gingiva initiated by dental plaque biofilm. The progression from health to early and acute gingivitis involves activation of local immune responses, particularly chemokines that regulate leukocyte recruitment. CXCL8 (IL-8) plays a key role in neutrophil attraction, while CCL2 is important for monocyte/macrophage recruitment. However, the relationship between these local mediators and systemic inflammatory marker C-reactive protein (CRP) remains unclear.

Aim: This study aimed to evaluate the levels of CXCL8, CCL2, and CRP in gingival crevicular fluid (GCF) and serum across health, early gingivitis, and acute gingivitis, and to analyze their correlations during disease progression.

Materials and Methods: A case-control study was conducted on 90 participants divided into three groups: healthy, early gingivitis, and acute gingivitis. Gingival crevicular fluid samples were collected to measure CXCL8 and CCL2 levels, while serum CRP was assessed as a systemic marker. Statistical analysis included comparison between groups and correlation analysis among biomarkers.

Results: CXCL8 levels showed a significant increase from health to acute gingivitis (approximately 1.8-fold increase, p<0.05). CCL2 demonstrated a marked elevation, reaching nearly 15-fold higher levels in acute gingivitis compared to healthy subjects (p<0.001). In contrast, CRP levels did not show a significant difference between healthy and gingivitis groups (p=0.588). Correlation analysis revealed weak, non-significant associations among biomarkers in early gingivitis. In acute gingivitis, a significant negative correlation was observed between CXCL8 and CRP (r=-0.381, p=0.038).

Conclusion: The findings suggest that gingivitis progression is characterized by increased local chemokine production, reflecting neutrophil and monocyte recruitment, without significant systemic CRP elevation. Local inflammatory regulation appears more prominent than systemic involvement in gingivitis.

 

The aim of this study was to investigate the dynamics of maturation of the humoral immune response to the receptor-binding domain (RBD) of SARS-CoV-2 in the context of accumulated population immunity during the period 2020–2025, encompassing both pandemic and post-pandemic phases.

Serum samples from 817 volunteers collected between 2017 and 2025 were analyzed. Five groups were delineated: post-infection immunity (2020, n=36), post-vaccination immunity following Gam-COVID-Vac administration (2021, n=83), hybrid immunity following infection and primary vaccination (2021, n=140), hybrid immunity following booster vaccination (2022, n=58), and a post-pandemic cohort obtained during circulation of Omicron subvariants (2024–2025, n=338). Quantification of IgG antibodies to SARS-CoV-2 RBD and determination of their avidity were performed using solid-phase enzyme-linked immunosorbent assay (ELISA) calibrated against the WHO International Standard (NIBSC code: 20/136).

When 4 M urea was employed as a chaotropic agent, a gradual increase in the proportion of samples exhibiting high avidity index (AI >80%) was observed from Group I to Group IV (11.5% → 82.9%); in groups with hybrid immunity, 70% of samples demonstrated AI ≥80%. However, upon application of a more stringent denaturing agent—8 M urea—the avidity index practically did not exceed 50% in nearly all samples from Groups I–IV, indicating incomplete antibody maturation: only 8.7% of samples reached the threshold of AI ≥50%. In the post-pandemic Group V (2024–2025), the proportion of samples with AI ≥50% increased to 16.3%, with the median avidity index differing significantly from pandemic-period values (Mann–Whitney U test, p < 0.0001).

Based on the study results, it can be hypothesized that the high antigenic variability of SARS-CoV-2 accompanying viral variant succession induces novel primary immune responses to mutant epitopes concomitantly with reactivation of pre-existing memory to conserved regions. This results in the circulation of a heterogeneous antibody pool comprising high-avidity antibodies directed against "legacy" epitopes and low-avidity antibodies targeting "novel" epitopes, thereby impeding the attainment of a high cumulative avidity index (>60–70%) characteristic of mature immunity in infections conferring lifelong protection.

Background: Peri-implantitis is an inflammatory condition that damages the tissues surrounding dental implants. It develops when the body's immune response to bacterial biofilm and implant-related factors becomes dysregulated. Key signaling proteins called chemokines as CXCL8, CXCL1, CCL5 and CCL2orchestrate the recruitment of immune cells like neutrophils and macrophages. Shifts in the balance between these chemokines may reflect an underlying immune disturbance around implants.

Aim: This study aimed to measure and compare the levels of CXCL8, CXCL1, CCL5, and CCL2 and their relative ratios in the peri-implant sulcular fluid of three groups: individuals with healthy implants, patients diagnosed with peri-implantitis, and a control group with no implants.

Materials and Methods: In a case-control study, a total of 80 participants were divided into three groups: healthy controls without implants (n=30), patients with healthy osseointegrated implants (n=30), and patients with peri-implantitis (n=20). We recorded demographic data and clinical parameters including probing depth (PD) and plaque index. PISF samples were collected using PerioPaper strips and stored at -80°C until analysis. Chemokine concentrations were determined using ELISA.

Results: Probing depth and plaque index were significantly higher in the peri-implantitis group compared to the healthy implant and control groups (p<0.005). All four chemokines were elevated in peri-implantitis compared to both healthy groups: CXCL8 (773.9 ± 112.7 pg/mL), CXCL1 (327.1 ± 188.4 pg/mL), CCL5 (243.5 ± 48.8 pg/mL), and CCL2 (729.3 ± 86.9 pg/mL) (p<0.005). The ratios between chemokines revealed distinct patterns: (CXCL8/CCL5) was highest in healthy implants, (CXCL1/CCL2) increased progressively from controls to peri-implantitis, (CXCL8/CXCL1) declined across groups, and (CCL5/CCL2) dropped in healthy implants before rising slightly in peri-implantitis (p<0.05).

Conclusion: Peri-implantitis is associated with deeper pockets, more plaque and higher levels of neutrophil and macrophage related chemokines. Importantly, composite ratios (CXCL8/CCL5) and (CXCL1/CCL2) distinguished between health and disease more clearly than individual chemokine levels alone pointing to a shift in immune signaling. These ratios could potentially serve as useful biomarkers for early identification and tracking of peri-implant inflammation.

Pregnancy is characterized by the establishment of a unique immunotolerant microenvironment that supports fetal development. Trophoblast cells and natural killer (NK) cells cooperate to establish the microenvironment essential for successful embryo implantation. Potential participants in this process include the activating NK cell receptor NKG2D and its ligands (NKG2D-Ls): MICA, MICB (MIC), and the family of UL16-binding proteins (ULBPs 1-6). The aforementioned ligands may enhance the cytotoxic activity of lymphocytes. There is also a mechanism that involves the secretion of NKG2D-L as soluble forms (sMIC, sULBPs). This feature allows NKG2D-L-expressing cells to evade immune recognition and generally suppresses the functional activity of NK cells. To date, the contribution of NKG2D-L molecules to interactions between placental and immune cells remains insufficiently studied. Currently, it is unknown which specific placental cell types are the primary producers of MIC molecules. Trophoblast cells represent likely candidates. These cells express a wide spectrum of ligands specific to NK-cell receptors, and their interaction facilitates the implantation process. The expression levels of genes encoding NKG2D-L can change depending on environmental conditions. Expression of NKG2D-L is regulated by external factors, including histone deacetylase inhibitors (HDACi). In this study, we aimed to investigate the effect of SAHA on NKG2D-L expression in trophoblast cells and to evaluate changes in NK cells following their interaction with trophoblast cells treated with SAHA. We showed that suberoylanilide hydroxamic acid (SAHA) modulates NKG2D-Ls expression on trophoblast cells in a dose-dependent manner. At high concentrations, SAHA increased the proportion of MICA-expressing trophoblast cells, whereas low concentrations resulted in reduced expression intensity of ULBP2, ULBP5, and ULBP6. Co-culture with NK cells also altered trophoblast expression of MICA and ULBP molecules; however, this effect was abrogated at high SAHA concentrations. Notably, high-dose SAHA enhanced trophoblast susceptibility to NK cell-mediated cytotoxicity, which correlated with an increased frequency of MICA-positive trophoblast cells. These findings indicate that the NKG2D–NKG2D-L interaction represents a potential regulatory axis in modulating trophoblast–NK cell crosstalk during pregnancy.

Specific genetic traits that could be considered biomarkers of predisposition to the development of uterine fibroids (UF) have not been identified. One of the candidates for this role could be quantitative trait loci (QTL), the complex of which controls the intensity of production of cytokines with proinflammatory, chemotactic and neoangiogenic properties. The aim of the study: to conduct qualitative (SNP genotyping) of TNF-α, IL-1β, IL-4, IL-6, IL-8, IL-10, VEGF, MMP2, MMP3, MMP9 and quantitative (determination of cytokine concentrations) analysis of the level of production of the most studied cytokines: TNF-α, IL-1β, IL-4, IL-6, IL-8, IL-10, VEGF, in the blood serum of healthy individuals and patients with diseases associated with impaired immune system function (uterine fibroids). The analysis results showed that patients with UF had statistically significantly elevated levels of IL-1b, IL-4, IL-6, IL-8, and TNF-a compared to the control group. VEGF levels in patients were significantly lower, while IL-10 levels did not show a statistically significant difference between the groups. In the control group, 16 significant associations of individual genotypes with IL-1b, IL-8, and VEGF levels were identified. In patients with UF, 9 significant associations were found. When comparing significant associations between genetic polymorphisms and regulatory factor levels, no association was found to be significant in both the control group and patients with UF. The analysis revealed 567 significant associations between SNP complexes and regulatory factor levels in the group of patients with UF and 1323 significant associations in the control group. The IL6-174 CG genotype is associated with IL1-β and VEGF levels in healthy women, while it is associated with IL6 and IL10 levels in patients. These findings suggest that the selective nature of the disease's development is linked to genetic factors predisposing individual women to its development, which are associated with the production of certain cytokines.

Coxsackievirus A6 (CVA6) is one of the predominant pathogens causing outbreaks of enterovirus exanthema worldwide including the Russian Federation. In 2025 in the Russian Federation the share of people with CVA6 infection exceeded 38.62% of the hospitalized patients. However, the state of population immunity against CVA6 has not been studied. The aim of this retrospective study was to determine anti-CVA6 – antibody (IgG, IgA, IgM) frequencies in the residents of the Nizhny Novgorod region. A plasmid vector containing the recombinant capsid CVA6 VP1 protein was obtained. CVA6 VP1was synthesized in E. coli cells, purified by affinity chromatography, and used to determine IgG, IgA, and IgM antibodies in the enzyme immunoassay method developed by us. Anti-CVA6 – antibodies were identified in 314 blood serum aliquots obtained from volunteers living in the Nizhny Novgorod region in the spring and summer of 2022. The serum positive rate for CVA6 antibodies was 57.0% The IgM antibody-obtained data evidence that in 2022 almost one in every ten-study participant (8.9%) was infected with CVA6 virus. The highest IgM antibody detection rate was observed in children under 18 years of age and amounted to 12.5%. Seasonal patterns of IgM antibody occurrence were also identified: in summer (13.2%), IgM antibody was detected 2.5 times more often than in spring (4.9%). IgG antibody was detected in a quarter of those tested (25.8%), which indicates the formation of long-term immunity against CVA6. The largest proportion of IgG-positive samples was recorded in the group of volunteers aged 19 - 45 years and amounted to 29.3%. IgA antibody was detected in one of three (35.7%). A detailed analysis of anti-CVA6 – antibody detection frequency in children revealed pronounced trends towards an increase in IgM and IgG antibody detection frequencies with age, which reached the highest values in the group of children aged 12 - 18 years (19.4% and 33.9%, respectively). The revealed dynamics of the anti-CVA6 – antibody detection frequencies may be associated with increased social activity and, as a result, with an increased likelihood of contact with CVA6 infected persons.

Primary open-angle glaucoma (POAG) is a chronic progressive disease of the optic nerve, which is one of the leading causes of irreversible blindness in the world. POAG includes several clinical and pathogenetic forms, such as pseudoexfoliation (PEG), primary simple (PPG), low-pressure glaucoma, and pigmented glaucoma. The question of the genetic factors role in differentiation of these clinical forms remains open. Taking into account that POAG reveals elevated values of IL-4 and IL-10 in blood, tears and eye fluids, we conducted the comparative study of the prevalence of SNP IL10 (rs1800896, rs1800872), IL4 (rs2243250) in groups of patients with PEG and PPG from seven branches of S. Fyodorov Eye Microsurgery Federal State Institution of Minzdrav of Russia: Novosibirsk, Irkutsk, Orenburg, Volgograd, Khabarovsk, Leningrad and Chuvash regions. DNA isolation and genotyping of IL10 (rs1800872, rs1800896), IL4 (rs2243250) were performed by RT-PCR on a single instrument and reagent database. The results were statistically processed using SPSS Statistics 23. It was shown that the frequency of IL10-592, IL10-1082, and IL4-590 genotypes in both groups corresponded to the Hardy–Weinberg. An almost twofold increase in the frequency of the IL4-590 TT was found among patients with PFG form, as well as differences between both forms of POAG in the distribution of complex genetic traits in three positions. Thus, in the group of PFG patients, IL4-590 CC + IL10-1082 AG; IL4-590 CC + IL10-592 CA and IL4-590 CC + IL10 -1082 AG + IL10-592 CA was with a higher frequency. When analyzing the frequency of three SNPs and their combinations among patients with PFH in seven regions of Russia, a number of differences were found for Leningrad Region and the Chuvash Republic, which are probably related with different ratios of representatives of the main ethnic groups of the Russian Federation in these regions.

Introduction. Impaired immune tolerance and dysregulation of programmed cell death pathways are central mechanisms in the pathogenesis of autoimmune rheumatic diseases. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important immunoregulatory molecule involved in the elimination of autoreactive lymphocytes and modulation of innate and adaptive immune responses. In addition to its proapoptotic activity, this ligand may activate non-apoptotic signaling pathways associated with cytokine production, cell survival, and chronic inflammation. However, its contribution to immune dysregulation in rheumatic diseases remains insufficiently characterized. Objective. To evaluate serum levels of TRAIL in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS), and to investigate its associations with clinical and immunological disease characteristics. Materials and Methods. This pilot study included 73 participants: 18 patients with RA, 29 with SLE, 16 with AS, and 9 healthy controls. Serum levels of TRAIL were measured by enzyme-linked immunosorbent assay. Immunological assessment included determination of rheumatoid factor, antibodies to cyclic citrullinated peptides, antibodies to double-stranded deoxyribonucleic acid, and complement components. Statistical analyses comprised comparative, correlation, and receiver operating characteristic curve analyses. Results. Patients with RA exhibited significantly elevated serum levels of TRAIL compared with healthy controls and patients with SLE or AS. A trend toward higher concentrations was observed in antibody-positive rheumatoid arthritis, suggesting a relationship between this mediator and autoimmune activation. In SLE, increased ligand levels were associated with joint involvement, potentially reflecting enhanced type I interferon-driven immune activation. Receiver operating characteristic analysis demonstrated high diagnostic performance of the biomarker for identifying RA. Conclusions. Elevated serum levels of TRAIL are associated with RA and may reflect disturbances in apoptosis-mediated immune regulation and persistence of autoimmune inflammation. These findings support the involvement of this mediator in the immunopathogenesis of rheumatic diseases and highlight its potential utility as a component of immunological biomarker panels for rheumatoid arthritis.

Implantation of fertilized blastocyst depends on adequate interaction with endometrium. After attachment and penetration of blastocyst into uterine endometrium, a gestational sac forms and uterine pregnancy develops. During cycle of assisted reproductive technologies (ART), if ultrasound visualization does not confirm clinical pregnancy, the embryo implantation failure is considered. The absence of clinical pregnancy after repeated cycles of ART is referred as repeated implantation failures (RIF). Immune mechanisms, especially disruptions in NK cell functions, may contribute to RIF. Currently, to assess the contribution of immune cells, a wide range of analysis is used, including assessment of NK cell quantitative and qualitative characteristics. However, the relationship between peripheral blood NK (pNK) cells and endometrial NK cells remains unclear. Aim: to perform a retrospective correlation analysis of pNK cell characteristics to the expression of NK cell receptors CD56, CD16, CD107a and NKG2D in endometrium of women experiencing infertility. Materials and Methods. We divided patients into two groups: women with RIF (I, n=69) and women with successful ART outcomes (II, n=33). Control group included healthy fertile women (III, n=19). Samples (peripheral blood and endometrial biopsy) were collected in the second phase of menstrual cycle, during presumed period of maximum endometrial receptivity. Peripheral blood and endometrial samples were obtained on the same day. Results. In group I, we found a positive correlation between the number of CD56+ cells in endometrium and the relative number of pNK cells. We identified a negative correlation between the number of CD16+ cells in endometrium and the pNK cell cytotoxic activity against JEG-3 trophoblast cells. The presence of CD16+ cells in endometrium appears to reflect proinflammatory cellular microenvironment, without specifying individual NK cell populations. In group II, we observed a positive correlation between CD107a expression in endometrium and the number of CD107a+ pNK cells. Additionally, we found a negative correlation between the number of CD107a+ pNK cells and the number of CD56+ cells in endometrium. Conclusion. The quantitative and functional characteristics of pNK cells are associated with endometrial NK cell profile and reflect their condition. Each group exhibits some differences in patterns of interrelations among these characteristics.

Introduction. Familial Mediterranean fever (FMF) is a monogenic autosomal recessive autoinflammatory disease caused by MEFV gene pathogenic variants. Heterozygosity remains a clinically challenging issue: while two variants are classically required for disease manifestation, individuals with one pathogenic variant are only carriers. However, there are a lot of cases of FMF clinical picture in heterozygous carriers of MEFV variants.

Aim. To study the features of the cytokine profile in patients with detected MEFV variants, taking into account molecular-genetic features such as zygosity and aggressiveness of pathogenic variants.

Materials and Methods. The study included 275 patients referred for MEFV genetic testing. Genomic DNA and EDTA-plasma were obtained from all subjects. Sanger sequencing of exons 2, 3, 5, and 10 of the MEFV gene was performed. Plasma levels of CRP, IL‑1β, IL‑6, IL‑8, and IL‑18 were measured by ELISA. A control group comprised 24 healthy donors from the laboratory biobank. Statistical analysis was carried out using GraphPad Prism 8.

Result. Based on genotyping results 275 samples were divided into groups: wild-type genotype – WT (n=60); FMF group includes homozygous (n=28), compound heterozygous (n=71), heterozygous (n=86), carriers of combination of pathogenic and variants of unknown significance (VUS) (n=15); for 15 samples of only VUS carriers’ cytokines’ levels were not measured. In the result of ELISA was shown an increase of CRP, IL-1, IL-6 and IL-18 levels in FMF compared to HD (P<0.0001), as well as an increase of IL-6 (P<0.05) and IL-18 (P<0.0001) was found in FMF compared to WT. There was shown no differences in IL-8 level between FMF, WT and HD groups. An increased levels of CRP (P<0.01) and IL-18 (P<0.0001) were shown in the subgroups with aggressive homozygous variants compared to low-aggressive ones, as well as an increased IL-18 level was obtained in aggressive heterozygous compared to low-aggressive ones (P<0.05). An increased level of IL-1β (P<0.05) was shown in the subgroup with two aggressive pathogenic variants compared to subgroup with one aggressive and one low-aggressive pathogenic variant.

Conclusion. The genotype and aggressiveness of detected variants influence the activity of the inflammatory process in patients with FMF.

Introduction. The C1-INH defect in addition to causing edema due to disruption of the kallikrein/kinin system, it also affects the pathways of coagulation and fibrinolysis, and the regulation of the innate immune response. It is possible to assume the contribution of changes in the immune response under conditions of chronic impairment of the complement system in maintaining the development of concomitant pathology in patients with HAE. Aim. To analyze the main parameters of the functioning of adaptive and innate immune response factors in patients with HAE, depending on the presence or absence of concomitant pathology. Material and methods. 24 people were examined, suffering from type 1 HAE, and they were divided into two groups: 10 patients with HAE with gastrointestinal diseases, and 14 patients with HAE without concomitant pathology. Between the period of seizure and in the absence of exacerbations of somatic pathology the activity of angioedema (AAS28) and control over their development (AEST), the quality of life AE-QoL were evaluated, and the factors of innate and adaptive immunity were investigated. The comparison group consisted of 10 blood donors. Results. When comparing the results of the immunological examination of patients with type 1 HAE and the indicators of the immune status of the comparison group of practically healthy ones, it was shown that the patients with HAE demonstrated an inhibition of the reserve resources of neutrophilic phagocytosis, a decrease in the proportion of NK containing granzyme B granules, an increase in the number of B lymphocytes, increased differentiation of T lymphocytes towards the cytotoxic subpopulation with increased lytic properties and an increase in the number of T-regulatory cells. In patients with HAE and concomitant pathology compared with patients without concomitant diseases, against the background of a more severe course of HAE, the functional parameters of innate immunity cells are more suppressed with an increase in the number of peripheral B cells. Conclusion. Concomitant somatic pathology makes its negative contribution to the dysfunction of the immune response, leads to aggravation of functional and regulatory disorders of both the innate and adaptive immune response, and aggravates the course of HAE.

Hereditary angioedema (HAE) is a rare inherited disorder characterized by recurrent episodes of edema involving the skin, mucous membranes, and internal organs. It results from dysregulation of the kallikrein–kinin system and excessive bradykinin production. The most common form, HAE type I, is caused by quantitative C1 inhibitor deficiency due to pathogenic variants in the SERPING1 gene. Although molecular diagnosis mainly focuses on SERPING1, the contribution of additional variants in other genes regulating the kallikrein–kinin pathway remains insufficiently investigated.

Objective. To evaluate the potential pathogenic significance of rare variants in the KNG1, MYOF, and HS3ST6 genes in patients with HAE type I using bioinformatic approaches.

Methods. Whole blood samples collected outside acute attacks from 24 patients with clinically confirmed HAE were analyzed. Diagnosis was established using clinical, laboratory, and genetic findings. Whole-genome sequencing was performed to identify additional variants, including variants of uncertain significance, in genes associated with regulation of the kallikrein–kinin cascade. The functional impact of variants detected in KNG1, MYOF, and HS3ST6 was assessed using multiple computational prediction tools (ConSurf, PrimateAI, CADD, PolyPhen-2, SNPs&GO, PhD-SNP, MutationTaster2021, PredictSNP, MuPro, MutPred2, Michelanglo-VENUS, I-Mutant2.0, and MolProbity). Structural validation was performed in ChimeraX.

Results. Whole-genome sequencing identified four unrelated patients carrying additional variants alongside pathogenic SERPING1 mutations: KNG1 NM_001102416.3.758-7C>G, HS3ST6 NM_001009606.4.542G>A, and MYOF NM_013451.4.3499T>C and NM_013451.4.6058G>A. All variants were classified as variants of uncertain significance. Among them, the HS3ST6 variant NM_001009606.4.542G>A demonstrated the strongest evidence of potential pathogenicity based on in silico analyses, whereas predictions for the remaining variants were inconsistent across algorithms.

Conclusions. These findings support the hypothesis that rare variants in genes involved in regulation of the kallikrein–kinin system may contribute to the clinical variability of hereditary angioedema. Nevertheless, segregation studies and functional experiments are required to determine their clinical relevance.

Introduction. Polypous rhinosinusitis (PRS) is often associated with bronchial asthma (BA), which complicates the course of both diseases and requires a differentiated approach to treatment.

Objective: To evaluate serum and nasal secretion cytokine concentrations (IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-1β, IL-8), as well as the intensity of subjective symptoms using a visual analog scale (VAS) in patients with different phenotypes of PRS and BA to determine the type of immune response.

Materials and Methods: Eighty patients with PRS (31 with isolated PRS, 26 with PRS combined with atopic BA (PRS+ABA), and 23 with PRS combined with non-atopic BA (PRS+NBA)) and 46 healthy volunteers were examined. Cytokine concentrations were determined by ELISA. Statistical analysis was performed using the Mann-Whitney U test.

Results. Isolated PRS was found to be characterized by a Th2-type immune response (high levels of IL-4, IL-5, and IL-13) in both the blood and nasal secretions. PRS+ABA demonstrated a mixed Th1/Th2 profile (elevated IFN-γ, IL-2, IL-4, IL-5, and IL-13). PRS+NBA was characterized by a Th1/Th2/Th3 response in the blood (maximum levels of IFN-γ, IL-2, IL-17A, IL-1β, and IL-8) and a Th1/Th3 response in nasal secretions. The highest severity of subjective symptoms (especially pain and nasal congestion) was observed in the PRS+ABA group (mean VAS score 7.43), while the lowest was observed in isolated PRS (3.33).

Conclusion. PRS phenotypes differ in the nature of the immune response and clinical presentation. The obtained data substantiate the need for personalized therapy aimed at correcting cytokine imbalance and can serve as a basis for prognosticating the disease course.

The study seeks to characterize the clinical relevance of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) in immunosenescence, i.e., whether their emergence is a physiological manifestation of aging or a marker for latent pathology. Also it investigates the interaction between age-related neutrophil dysfunction, C-reactive protein (CRP) and body mass index (BMI). A cross-sectional sample of 200 healthy volunteers aged 20 to 60 years was employed. The volunteers were divided into 10-year age groups. Serum p-ANCA levels were measured by (ELISA), and CRP levels were measured by automated nephelometric immunoassay. The (BMI) was calculated using the anthropometric measurements. The results revealed that the increase in the concentrations of p-ANCA and CRP with age was highly significant (P=0.000) and the highest levels were found in the age group of 50-60 years for p-ANCA (32.74 ± 12.01ng/mL) and CRP (11.25 ± 3.83mg/L). Conversely, there was no significant difference in body mass index (BMI) across age groups (P = 0.282). Linear regression analysis revealed that older age was a strong predictor for higher levels of p-ANCA (R2 = 0.47, P = 0.000) and CRP (R2 = 0.56, P = 0.000). In addition, raised p-ANCA was a significant predictor of increased CRP levels (R2 = 0.32, P = 0.000). BMI was not associated with either immune marker. The findings imply that the development of systemic tissue inflammation and autoimmune manifestations is linked to biological immunosenescence regardless of adiposity and body mass. The results demonstrate that p-ANCA are an independent predictive biomarker of immunosenescence and chronic inflammation in healthy subjects and are not affected by body mass. The study shows that intrinsic immunosenescence due to declining peripheral immune tolerance mechanisms, rather than metabolic stress, is the major driver of age-related inflammaging, and provides novel scientific insights establishing this biomarker as a direct measure of aging irrespective of obesity.

Cytokines, in particular IL-17 and TNFa, which are important mediators of inflammation in COVID-19, are known to play an important role in the immunopathogenesis of COVID-19. The analysis of the frequency distribution of alleles and genotypes of the IL-17A(-197)*G/A, IL-17F(7488)*T/C and TNFA(-308)*G/A genes in Russians of the Chelyabinsk region with COVID-19 was shown separately by us earlier, the purpose of this study was to evaluate the distribution features the frequency of occurrence and coupling parameters of intergenic haplotypes formed by single-nucleotide polymorphic sites of the above genes in Russians of the Chelyabinsk region with COVID-19. We suggest that analysis of the haplotypic frequencies of the proinflammatory cytokine genes IL-17A(-197)*G/A, IL-17F(7488)*T/C and TNFA(-308)*G/A may significantly increase the significance of these genes in the development and course of COVID-19. Thus, in the course of our work, haplotypes were identified that can be considered as immunogenetic factors of resistance to COVID-19 (IL-17A(-197)*G~IL-17F(7488)*C, IL-17A(-197)*G~IL-17F(7488)*C~TNFA(-308)*G and IL-17A(-197)*G~IL-17F(7488)*T~TNFA(-308)*A) and haplotypes that increase susceptibility to COVID-19 in the russian population of the Chelyabinsk region (IL-17A(-197)*G~TNFA(-308)*G, IL-17A(-197)*G~IL-17F(7488)*T and IL-17A(-197)*G~IL-17F(7488)*T~TNFΑ(-308)*G). The study included 2 groups of Russians from the Chelyabinsk region: COVID-19 patients (those who were treated in anti-covid clinics in Chelyabinsk during the epidemic period from December 2019 to April 2021 had a laboratory-confirmed test for COVID-19 and had no concomitant diseases) and a control group (individuals from the Chelyabinsk Regional Blood Transfusion Station who do not have antibodies to the SARS-CoV-2 pathogen, vaccinations against COVID-19 and are not included in the Federal Register of Persons Infected with COVID-19). Polymorphic variants of the genes we studied were determined using an allele-specific polymerase chain reaction followed by electrophoretic detection of the results in a 3% agarose gel. Statistical processing of the obtained data was carried out by evaluating the X² criterion, the odds ratio criterion and 95% confidence intervals. The frequency of occurrence of haplotypes was determined using the Arlequin program (ver. 3.5), taking into account the mean error and the parameters of the nonequilibrium coupling of alleles at loci. The results obtained were considered statistically significant at p<0,05.

Introduction. Modern clinical immunology is shifting towards systemic analysis of multidimensional functional interactions, viewing the female body as a dynamic system where homeostasis is sustained through interplay of metabolic factors, barrier resistance, and cellular surveillance. The growing prevalence of metabolic disorders, which act as triggers of low-intensity systemic inflammation, leads to phenotypic neutrophil inversion and premature depletion of functional immune reserve, underscoring the relevance of this study. Objective. To assess the influence of metabolic and barrier factors on formation of individual immune system patterns in reproductive-age women using nonlinear principal component analysis. Materials and Methods. A total of 84 conditionally healthy women were examined. Immunophenotyping included extended immunogram analysis and neutrophil subpopulation assessment performed by flow cytometry; additionally, functional activity of neutrophils was evaluated. Statistical processing was carried out using nonlinear principal component analysis with optimal scaling of variables to identify independent vectors of immune adaptation. Results. Three principal components were identified. The first component reflects metabolic-associated inflammation: increased body mass index correlates with quantitative expansion of leukocytes and lymphocytes but is accompanied by reduced bactericidal potential and accumulation of senescent and immunosuppressive neutrophil forms. The second component characterizes barrier deficiency, where a critical decrease in immunoglobulin A levels leads to compensatory mobilization of aging neutrophils and activation of innate lymphoid cells, creating risk of hyperergic reactions. The third component represents an optimal surveillance model based on harmonious combination of mature segmented neutrophils and cytotoxic lymphocytes, ensuring effective antiviral protection and cellular homeostasis. The age of 33 years was identified as a critical threshold beyond which cumulative metabolic influences override physiological mechanisms, shifting the immune profile from maximum plasticity towards immunological aging. Conclusions. The immune system of women functions as a multidimensional network in which metabolic stress, barrier protection, and cytotoxic surveillance dynamically interact. Body mass index serves as key modulator that transforms the system from state of qualitative surveillance to functional fragility. Integrative assessment of these factors enables precision health monitoring and detection of hidden signs of immunological degradation long before clinical symptom onset, opening new avenues for personalized predictive medicine.

Introduction. We are developing a new line of research exploring the role of soluble Tas2R receptors in bronchial asthma (BA). Soluble Tas2R receptors are viewed through the prism of the functions of the corresponding membrane receptors. The soluble form of Tas2R receptors is considered to act as decoy proteins, blocking cellular functions mediated by membrane receptors.

The aim of the study was to comparatively analyze the association of soluble Tas2R38 and Tas2R31 with the clinical and functional characteristics of BA.

Materials and Methods. A total of 34 apparently healthy individuals, 76 patients with allergic BA (ABA), and 42 patients with non-allergic BA (NABA) were examined. Serum expression levels of Tas2R38 and Tas2R31 were determined using an enzyme-linked immunosorbent assay.

Results. Serum levels of Tas2R38 and Tas2R31 were found to vary significantly across different types of asthma. These levels were significantly higher in NABA than in ABA for both receptor subtypes.

A significant positive correlation was found between Tas2R levels and asthma severity only for Tas2R31. An assessment of the relationship between functional lung function parameters and Tas2R values ​​revealed a significant negative correlation only for Tas2R31. This relationship applies to parameters such as FEV1, MEF50, MEF75, SEF25-75, Tiffeneau index. Significant positive correlations with signs of sensitization (drug and fungal) were found in patients with asthma, and but only for Tas2R31.

Significant associations were found between Tas2R38 and blood formed elements (as a percentage of the leukogram): monocytes and neutrophils. The direction of the association was direct for monocytes and inverse for neutrophils.

A significant direct association was found between Tas2R38 and IL-10 cytokine levels.

A significant direct association was found between Tas2R38 levels and the content of both ciliated and basal epithelial cells in sputum.

Discussion. It is noteworthy that Tas2R38 levels are primarily associated with the levels of cells involved in the immunological response, while Tas2R31 levels are associated with functional parameters characterizing bronchial resistance.

Based on our developing concept of soluble receptors in relation to Tas2R signaling in BA, soluble Tas2R receptors are assigned the role of decoy proteins, blocking cellular functions mediated by membrane receptors.

Tropomyosin (TM) is a protein with high allergenic activity. This protein is present in both invertebrates and vertebrates. However, mainly TM of invertebrates have allergenic activity: helminths, mollusks, arthropods (crustaceans, mites, insects), and a high (up to 80%) cross-IgE reactivity is observed between them. Many researchers consider TM to be panallergenic. The aim of the study was to evaluate the role and place of TM of invertebrates in the formation of the characteristics of various sensitization patterns in patients with allergic diseases living in the central of Russia (Moscow and the Moscow region). In the blood sera of 1,296 patients with allergic diseases, using the ALEX² allergochip (MacroArrayDX (MADx, Austria), sIgE were simultaneously measured for 5 TM molecules: Ani s 3 (Anisakis simplex),  Pen m 1 (Penaeus monodon),  Der p 10 (Dermatophagoides pteronyssinus), Blo t 10 (Blomia tropicalis),  Per a 7 (Periplaneta americana). The frequency of sIgE toTMwas  rangedfrom2.4%to3.7%.At the same time, the level of sIgE tovariousTM more oftencorresponded to 1-2classes of sensitization.AhighpositivePearsoncorrelation was found between the concentration of sIgE toTMandotherallergens,primarilycrustaceansandinsects(r=0.94-0.99,p<0.0005).Of the 59patients with sIgE for at leastoneof the 5TMmolecules weredetected,antibodiestoall of 5molecules were registeredin28(47.5%)patients.sIgE to1TMmolecule was detected in 19patients(32.2%);to2– in 8patients(13.6%);andto3and4molecules in 3(5.1%)and1(1.7%)patients, respectively.Using the principal component analysis, thesensitizationprofiles of 59patientsweregroupedinto4clusters.  59.3%ofpatientsofcluster1 are characterized by polysensitization due tothedominance of sIgE toPR-10(treepollenandcross-reactingfoodallergens).22.0%ofcluster2patients are characterized by the dominance of sIgE tohousedustmites. A feature of cluster3(11.8% of patients)is the predominance of sIgE toseafoodandinsectallergens. The sensitizationprofile of cluster4patients is unclearduetotheirsmall number.

The aim of this study was to evaluate the effect of siRNAs targeting the Nup98 gene on the dynamics of TLR-9, TNF-α, IL-4, and IL-13 cytokine gene expression during siRNA-mediated inhibition of herpes simplex virus type 1 (HSV-1) replication in an in vitro model.

Materials and Methods: The study was conducted using Vero cell culture (I.I. Mechnikov Research Institute of Vaccine and Sera). Nup98.1 and Nup98.2 siRNAs targeting the Nup98 gene (Synthol, Russia) were used. Transfection was performed using the Geneject40 reagent (Molecta, Russia), and cytotoxicity was assessed using the MTT assay. TLR-9, IL-4, IL-13, and TNF-α gene expression was determined using real-time RT-PCR, followed by calculation of the fold change (2^(-ΔΔCt)) relative to non-specific siL2 siRNA. Statistical analysis was performed using the non-parametric Wilcoxon test.

Results: Nup98.1 and Nup98.2 siRNAs did not significantly reduce cell survival (siRNA cytotoxicity did not exceed 30% at any observation time point relative to the siL2 control). Transfection with Nup98.1 siRNA was associated with a significant 3.5-fold decrease in TNF-α expression after 24 hours and a significantly significant 4.8-fold increase in IL-13 expression after 72 hours of transfection relative to the siL2 control. No significant changes in IL-4 and TLR-9 expression were observed with either siRNA. These results indicate that knockdown of the Nup98 gene, while directly suppressing HSV-1 replication, also produces an immunomodulatory effect, including limiting the early proinflammatory response (a trend toward decreased TNF-α expression) and activating reparative programs at later stages (a significant increase in IL-13 expression).

Conclusions: Knockdown of the Nup98 gene using siRNA in HSV-1 infection exerts a complex effect in an in vitro model, combining direct inhibition of pathogen replication with modulation of the innate immune response. This effect may be mediated by activation of the cGAS-STING signaling pathway, a trend toward a decrease in the proinflammatory potential (TNF-α), and a significant induction of the anti-inflammatory cytokine IL-13, without affecting the expression of IL-4 and TLR-9. The obtained results, demonstrating immunomodulation, appear relevant for clinical practice and open up prospects for the development of combination therapeutic strategies aimed simultaneously at viral targets and optimization of the host immune response.

Background. Ischemic heart disease remains one of the leading causes of morbidity, disability, and mortality worldwide. Current evidence indicates that chronic immune inflammation, endothelial dysfunction, and impaired angiogenic regulation play an important role in the development and progression of atherosclerotic coronary artery disease. Assessment of relationships between immunoinflammatory biomarkers, growth factors, and structural and functional cardiovascular changes may improve understanding of disease progression and provide additional criteria for evaluating its severity.

Aim. To evaluate immunoinflammatory markers and growth factors in patients with ischemic heart disease and determine their associations with clinical and instrumental cardiovascular parameters.

Materials and methods. The study included 234 middle-aged patients (mean age 52.4 ± 1.27 years) with arterial hypertension and ischemic heart disease and 60 apparently healthy controls. Ischemic heart disease and arterial hypertension were verified according to World Health Organization criteria and the International Classification of Diseases, 10th Revision. Arterial hypertension was classified according to the 2017 ACC/AHA Hypertension Guidelines, while stable effort angina was classified according to the functional classes of the Canadian Cardiovascular Society. All participants underwent clinical and instrumental assessment, including echocardiography, coronary angiography, and duplex ultrasonography of the carotid arteries. Serum concentrations of immunoinflammatory markers and growth factors were measured. Statistical analysis included descriptive statistics and correlation analysis.

Results. Patients with ischemic heart disease demonstrated a significant increase in immunoinflammatory marker levels with increasing clinical severity. The most pronounced changes were observed in IL-17A, IL-6, IL-1β, TNF-α, and complement component C3, as well as in VEGF-A, IGF-1, and TGF-β1. Statistically significant correlations were identified between these biomarkers and coronary artery diameter, carotid intima-media thickness, and echocardiographic parameters. These findings indicate an association between increased immunoinflammatory activity, vascular remodeling, and structural and functional myocardial changes.

Conclusion. The results confirm the important role of immune inflammation, endothelial dysfunction, and growth factor dysregulation in the pathogenesis of ischemic heart disease. Combined assessment of the investigated biomarkers may be promising for additional evaluation of disease severity and cardiovascular remodeling.

Recurrent pregnancy loss is a multifactorial disorder; in about 50 % of cases, its cause is unknown. This study aimed to assess the link between eNOS gene polymorphisms and recurrent pregnancy loss, as well as to explore their correlation with IL‑1β and TNFα gene expression levels. The analysis covered material from 163 patients with reproductive losses (scrapings from vaginal and cervical mucosa, venous blood). Markers were identified via real‑time PCR; statistical analysis used the Mann‑Whitney U test and Fisher’s exact test. Key findings showed differences in proinflammatory cytokine expression depending on the type of pregnancy loss. In recurrent miscarriage patients, IL‑1β and TNFα gene expression was significantly higher in cervical mucosal cells compared to the sporadic miscarriage and control groups. In sporadic miscarriage, there was a trend toward elevated IL‑1β expression in peripheral white blood cells and TNFα expression in cervical mucosal cells. Notably, IL‑1β expression in vaginal mucosal cells occurred only in the sporadic miscarriage group, suggesting a specific local immune response in this condition. Prognostic relevance was found for eNOS gene polymorphic markers (G894T, C774T, T786C). The GTCTTC haplotype was identified as a risk factor for sporadic miscarriage, whereas the GTCTTT haplotype and the T/T genotype of G894T and C774T polymorphisms showed protective effects. An association between IL‑1β expression and eNOS polymorphisms was confirmed. The TT genotype (T786C) correlated with low IL‑1β expression, while the CC genotype (T786C) was linked to higher expression in peripheral white blood cells. For cervical mucosal cells, IL‑1β expression depended on the T786C genotype: it was absent in TT carriers but present in TC carriers. These results could help predict miscarriage risk.

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.

Toll-like receptors (TLRs) are an important component of the innate immune response. They recognize pathogen-associated molecular patterns and damage-associated molecular signals from cells and tissues, thereby activating the immune response and triggering local inflammation. Ulcerative colitis (UC) is a chronic recurrent inflammation primarily localized in the large intestine. TLR 1, 2, 6 on the surface of colonocytes recognize a wide range of molecules (both independently and as part of heterodimers), and their signaling pathways induce the synthesis of pro-inflammatory cytokines. The genes encoding these receptors are located on chromosome 4 and belong to the TLR1-2-6-10 subfamily. They able to form haplotypes that may confer a selective advantage by enhancing resistance to infections. Single nucleotide polymorphisms (SNPs) in these genes can alter protein structure and receptor function, potentially influencing susceptibility to various diseases. The aim of the study is to analyze the bilocus and trilocus haplotypes formed by SNPs in the TLR 1, 2, 6 genes and to investigate their association with ulcerative colitis. The study included individuals from the Russian population: 143 patients diagnosed with UC and 184 healthy controls. Genotyping was performed: SNPs 2258G>A TLR2 and 745C>T TLR6 were determined by PCR; SNP 1805T>G TLR1 was analyzed using the RFLP method. The linkage disequilibrium parameters and haplotype frequencies were calculated using Arlequin ver3.5. Statistical significance was assessed using standard immunogenetic criteria with p ≤ 0.05 considered significant.  The genetic polymorphisms TLR2 rs5743708 and TLR6 rs5743810 were not associated with UC predisposition. The ancestral 1805*T  allele TLR1 and the T/T genotype exhibited a protective effect. The bilocus haplotype 1805*T~2258*G was defined as a protective factor against UC and 1805*G~745*C as a predisposition factor. The bilocus haplotypes TLR2~TLR6, as well as the trilocus haplotypes TLR2~TLR1~TLR6 showed no significant association with UC susceptibility. Our results are partially  align  with global data: individual polymorphisms of TLR 1, 2 and 6 in the Russian population are not associated with the disease. However, their alleles can form bilocus haplotypes with either protective or predisposing effects on UC development.

Trophoblast cells participate in the placenta formation. In rare cases, they can undergo neoplastic transformation, leading to the development of choriocarcinoma (CC). One approach to antitumor therapy is targeting the transcriptional machinery of tumor cells, specifically the cyclin-dependent kinases CDK8/19, which are associated with RNA polymerase II. Inhibition of CDK8/19 is of general interest as means of regulating cell activity. Research of the potential use of small-molecule CDK8/19 inhibitors in CC and their applicability for regulating trophoblast cell activity is of current interest. The aim of the study was to evaluate the effect of a CDK8/19 inhibitor on the secretory activity of JEG-3 cells. JEG-3 cells, inducers (TNFα, IL-1β, IL-10, PMA), and a CDK8/19 inhibitor (ICDK) were used. The viability of JEG-3 cells and their secretion of βhCG in the presence of ICDK, as well as the secretion of the cytokines TGFβ1, RANTES, and VEGF, were assessed. Results. It was established that ICDK did not induce cell death in JEG-3 cells and did not alter βhCG secretion. Both proinflammatory factors (TNFα, IL-1β, PMA) and the anti-inflammatory cytokine IL-10 stimulated TGFβ1 secretion by JEG-3 cells. ICDK increased TGFβ1 secretion by JEG-3 cells. No effects of ICDK on the secretion profile were observed after subsequent addition of inducers. RANTES and VEGF secretion by JEG-3 cells was not altered by ICDK or inducers. Conclusions. CDK8/19 inhibition might not be a treatment choice for CC due to its lack of effect on βhCG secretion and the absence of a toxic effect on trophoblast cells. Increased TGFβ1 secretion in the presence of ICDK may be important for modulating trophoblast cell function in reproductive pathologies.

 

Background. Louis–Bar syndrome (ataxia-telangiectasia, AT) is a rare autosomal recessive multisystem disorder caused by mutations in the ATM gene and characterized as a severe combined primary immunodeficiency. In the environmentally adverse Aral Sea region, the diagnosis of AT is considerably delayed because of its neurological presentation and the lack of molecular genetic screening programs.

Objective. To investigate the clinical and immunological characteristics of children with Louis–Bar syndrome living in the Aral Sea region and to evaluate the efficacy of intravenous immunoglobulin (IVIG) replacement therapy.

Materials and Methods. Nine children (5 girls and 4 boys) aged 6–19 years (mean age, 14.5±3.5 years) with genetically confirmed Louis–Bar syndrome were enrolled in the study. Immunophenotyping (CD3⁺, CD4⁺, CD8⁺, CD16⁺CD56⁺, CD19⁺) was performed using an Accuri C6 flow cytometer (Becton Dickinson, USA). Humoral immunity was assessed by enzyme-linked immunosorbent assay (ELISA) with determination of IgG, IgG1–4, IgA, IgM, IgE, circulating immune complexes (CIC), and alpha-fetoprotein (AFP). Phagocytic function was evaluated using the dihydrorhodamine 123 (DHR123) assay. Molecular genetic analysis of ATM mutations was performed using the Invitae platform. Patients received IVIG replacement therapy at a dose of 0.4–0.8 g/kg/month for 3 months. Immunological assessment was performed before treatment and after 3 months of therapy. Statistical analysis was conducted using IBM SPSS Statistics version 26. Data distribution was assessed using the Shapiro–Wilk test. Paired comparisons before and after treatment were performed using the Wilcoxon signed-rank test. Differences were considered statistically significant at p<0.05.

Results. Consanguineous marriages were identified in 55.6% of families, while 44.4% of patients had a positive family history. All patients had previously been diagnosed with progressive cerebellar ataxia. Before IVIG therapy, patients demonstrated marked lymphopenia (19.0±0.43% vs. 43.0±0.61% in healthy controls), significantly reduced CD4⁺ T-cell counts (15.4±1.12%), decreased CD4/CD8 ratio (1.11±0.11), reduced NK-cell levels (8.6±1.21%) and B-lymphocyte counts (5.6±0.21%), deficiencies of IgA, IgG2, IgM, and IgE, and markedly elevated AFP levels (235.5±15.7 ng/mL). After 3 months of IVIG therapy, significant increases were observed in CD4⁺ cells (24.4±1.53%, p<0.01), CD3⁺ cells (32.5±1.21%), NK cells (17.2±0.46%), B lymphocytes (7.67±0.45%), and phagocytic activity (82.5±1.28%). Serum IgG levels normalized (9.55±2.14 g/L), whereas AFP levels decreased 3.6-fold (65.4±5.7 ng/mL, p<0.001). One patient died from acute pneumonia complicated by grade III respiratory failure.

Conclusions. Louis–Bar syndrome in the Aral Sea region is characterized by delayed diagnosis (mean age at diagnosis, 14.5 years), primarily because of its neurological presentation. IVIG replacement therapy provides clinically significant improvement in both cellular and humoral immune parameters but does not achieve complete immunological recovery, particularly regarding the B-cell compartment and IgG2 subclass deficiency. These findings support the need for lifelong clinical and immunological follow-up, regular intravenous immunoglobulin (IVIG) replacement therapy, prevention of infectious complications, and timely immunorehabilitation of patients.

One of the leading hypotheses explaining the increase in the incidence of IgE-dependent pathologies in the population of developed countries is the hypothesis about the leading role of air pollutants, including polycyclic aromatic hydrocarbons (PAHs). PAHs such as benzo(a)pyrene (BaP) are known to activate molecular mechanisms associated with ER stress in damaged cells, including the endonuclease IRE1. The aim of this work was to analyze the effect of modulators of this enzyme on the humoral response when a respiratory allergen enters the body together with BaP. The study used BALB/c mice, immunized intranasally with the allergen ovalbumin (OVA) for 10 weeks in the presence of BaP. Small-molecule pharmacological inhibitors of IRE1 at doses of 3 mg/kg were administered to experimental groups. We used 4µ8C and APY-29 as IRE1 inhibitors. Antibody production was analyzed using ELISA in serum samples, recording their titer. Administration of BaP significantly increased the production of allergen-specific IgE (p>0.001), IgG1 (p<0.01), IgA (p<0.01), and IgG2b (p<0.05), while simultaneously suppressing the production of IgG2a (p<0.01). At the doses used, when administered intranasally together with the allergen, the pharmacological modulator 4µ8C significantly (p<0.05) and noticeably (approximately 5 times) reduced the production of OVA-specific IgE, but the suppression of IgG1 production was even more reliable and noticeable (p<0.01, 8 times in absolute terms). In both cases, however, blocking the production of allergen-specific antibodies was incomplete (in the corresponding groups, a significant difference with the negative control group remained). 4µ8C had no significant effect on the production of allergen-specific IgG2a. The pharmacological modulator APY-29 had no significant effect on the production of specific IgE, while significantly (by more than an order of magnitude in absolute terms, p<0.001) suppressing the production of allergen-specific IgG1 antibodies. At the same time, in the presence of APY-29, significantly higher production of IgG2a was observed in the experimental groups (an order of magnitude higher in absolute values, p<0.01). Thus, IRE1 modulators, especially 4µ8C, may be promising for use in the prevention of early stages of allergic pathologies, when it is most important to suppress the formation of an anaphylactogenic IgE-dependent immune response.

The sensitizing, allergenic, and irritating properties of fine organic dust underline the relevance of studying the body's immune reactions to exposure. The aim is to investigate the dynamic effects of organic dust on the mitochondrial activity of thymus and spleen cells, and hematological parameters in rats. Materials and methods. The study was conducted on male Wistar rats exposed to organic dust with a particle size of 1-10 μm with average daily concentration of 15±4 mg/m³ from day 1 to day 60. The animals were then kept in a dust-free environment for an additional 30 days. The hematological parameters were studied dynamically using the Abacus 5 Vet automatic hematological analyzer, while the mitochondrial activity of the thymus and spleen (stained with rhodamine 6G and measured using the Evos M7000 imaging system in RFP mode) and the mass coefficients of these organs were assessed. The lung tissues were subjected to histological analysis using hematoxylin and eosin staining. Statistical analysis included the Mann-Whitney U test. Results. By the 60^th day, the rats were diagnosed with inflammatory pulmonary fibrosis; subsequent 30-day exposure to a dust-free bedding did not improve the histoarchitectonics of the tissue, which showed areas of diffuse and focal leukocytic infiltration. Against the background of developing leukocytosis (from 12.30×10⁹/L on the 0^th day of the experiment to 16.64×10⁹/L, p=0.016 on the 90^th day) and changes in the leukocyte formula (an increase in the lymphocyte index according to B.F. Shagan from 1.70 to 2.19-2.68), an imbalance in the energy metabolism of thymus and spleen mitochondria was established: a decrease of 15.18% (p=0.016) in thymocytes and 5.69% (p>0.05) in splenocytes by the 30^th day, followed by a recovery to the initial values in the thymus and a 13.50% (p>0.05) increase in the spleen by the end of the experiment. Conclusion. The inflammatory process resulting from prolonged exposure to organic dust involves alternating phases of reduced and increased energy exchange in the thymus and spleen. A 30-day recovery period for animals in environments free of dust results in the normalization of energy exchange in the thymus, while heightened activity in the spleen persists.

The aim of this study was to evaluate an integrated inflammatory, neuroendocrine and tumor-associated biomarker profile in patients with metastatic lung adenocarcinoma compared with patients with early-stage disease. A comparative analysis was performed in two clinical groups: 41 patients with stage IV poorly differentiated non-small cell lung cancer adenocarcinoma, multiple metastatic lesions and detectable circulating tumor cells and circulating tumor DNA; and 41 patients with stage I disease without detectable circulating tumor material in peripheral blood. The inflammatory panel included tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, C-reactive protein, serum amyloid A, ferritin, erythrocyte sedimentation rate and leukocytes. The neuroendocrine panel included melatonin, dopamine, serotonin, adrenalin, noradrenalin, cortisol and histamine. The tumor-associated panel included CYFRA 21-1, carcinoembryonic antigen, circulating tumor cells and circulating tumor DNA. The metastatic group demonstrated a coordinated increase in inflammatory markers, most prominently tumor necrosis factor alpha and interleukin-6, indicating activation of systemic inflammatory signaling. At the same time, a marked decrease in melatonin and dopamine was observed together with moderate increases in cortisol, histamine, serotonin and catecholamines. The strongest tumor-associated changes were detected for circulating tumor cells and circulating tumor DNA, supporting active tumor shedding and a high metastatic burden. These findings support the concept that progression of lung adenocarcinoma is accompanied not only by expansion of tumor mass, but also by remodeling of the systemic host response. The combined assessment of cytokines, neuroendocrine mediators and liquid-biopsy markers may represent an integrated tumor-host panel for risk stratification, follow-up planning and prospective immunological research. This work should be interpreted as a preliminary short communication. Further validation in a larger cohort is required, including individual quantitative values, standardized blood sampling times, confidence intervals and formal statistical testing adjusted for clinically relevant covariates.

Neutrophil extracellular traps (NETs) are fibrillar structures composed of decondensed chromatin and bactericidal proteins that play an important role in the pathogenesis of diabetes complications. Of particular interest are aggregated forms of NETs (aggNETs) – macroscopic conglomerates capable of limiting inflammation through cytokine degradation while simultaneously posing a risk of vascular occlusion. Aim of the study: to conduct a comparative analysis of the intensity of formation of aggregated and non-aggregated extracellular traps (ETs) by cells of various peripheral blood leukocyte fractions in patients with diabetic foot lesions.

This cross-sectional study included 73 patients (53 with DFS, 20 with NOA) and 20 healthy controls. Analysis of NET production was performed separately in mononuclear and granulocyte fractions using fluorescence microscopy. NET formation was assessed under spontaneous conditions and upon stimulation with thrombin and a bacterial stimulus (commercial probiotic).

The study revealed a significant increase in serum CitH3 concentration in NOA patients (Me=7.12 ng/mL) compared to controls (Me=1.42 ng/mL; p=0.0003). In the mononuclear fraction of NOA patients, the highest intensity of spontaneous non-aggregated (Me=8.05% vs. 0.40% in controls; p=0.0079) and aggNET formation (Me=4.70% vs. 0.00%; p=0.0072) was recorded. Thrombin stimulation also demonstrated hyperreactivity of the mononuclear fraction in NOA: the proportion of non-aggregated NETs (Me=20.10%) significantly exceeded control (p=0.0003) and DFS group (p=0.0067) values. Additionally, the NOA group showed a statistically significant increase in the number of thrombin-induced aggNETs (p=0.0155). Upon microbial stimulation, a significant increase in aggregate levels was observed in NOA patients in the mononuclear fraction (p=0.0051) and in DFS patients in the granulocyte fraction (p=0.0055).

Thus, NOA patients are characterized by an increased spontaneous ability of mononuclear fraction cells to form both aggregated and non-aggregated NETs compared to the control group and the DFS patient group. An increased ability to form NETs is observed in patients with diabetic foot lesions under conditions of ongoing in vivo NETosis, as evidenced by elevated blood citH3 levels. Low-density neutrophils (15-30%) detected in the mononuclear fraction may be the main source of the NETs formed, which requires further study of their role in the pathogenesis of NOA.