Despite significant advances in pathogenetic treatments for patients with diabetes mellitus type 1 (DM1) and reduction of mortality in this cohort of patients, as compared with general population, the difference in life expectancy in DM1 patients at the age of 20 years is about 10-12 years. Microvascular complications that increase the risk of cardiovascular disease (CVD) and overall mortality represent one of the most important problems in management of patients with DM1. The excessive risks persist even with proper control of all CVD risk factors, thus determining the need for in-depth research, in order to clarify and identify all factors of development and progression of microvascular complications in patients with DM1, as well as to develop methods for their modification and correction. According to current literature, the main pathogenetic links in the development of microvascular complications in DM1 concern, e.g., direct glucosemediated endothelial damage, oxidative stress, as well as microvascular fibrotic processes. In this review article, we consider additional possible route of these changes, i.e., chronic exposure to increased burden of bacterial lipopolysaccharide (LPS) derived from Gram-negative flora retained in systemic blood flow. LPS, by promoting generation of reactive oxygen species via NADPH-oxidase, thus leading to a significantly decreased bioavailability of endothelial NO and development of endothelial dysfunction (ED). Activation of toll-like receptor type 4 (TLR4) is accompanied by activation of p38MAPK, and subsequent translocation of NF-κB to the nucleus, increasing transcription of the interleukin-6 (IL-6) gene and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). LPS is able to inhibit the anti-inflammatory effect of TGF-β, increasing the number of polarized M1 macrophages and leading to persistence of inflammation, activate TGFBR1 receptors, promotes PAI-1 gene expression, thus increasing the risk of atherogenesis and thrombosis in the vascular bed. The data presented in this literature review suggest a possible “LPS-gut-microvascular network” axis, which is an important pathogenic component of microvascular complications in patients with DM1. Chronic excessive intake of LPS into the systemic bloodstream can lead to the development of persistent low-grade inflammation accompanied by changes in architectonics of extracellular matrix, potentiate the development of endothelial dysfunction and vascular inflammation. The studies of LPS effects upon clinical course of DM1 are promising and require further in-depth research.

This article provides a comprehensive overview of research focusing on the role of antibodies, cytokines, complement proteins, major histocompatibility complex (MHC) molecules, and Toll-like receptors (TLRs) in the immune response and their potential as targets for immunotherapy. The review specifically examines the influence of various carriers on the immune activity of proteins, with a particular emphasis on the role of carriers in developing therapeutic approaches for diseases including cancer, autoimmune disorders, and infections. The findings highlight the importance of understanding the molecular mechanisms underlying the immune response and the role of different components of the immune system.
Antibodies, as key components of adaptive immunity, play a crucial role in pathogen neutralization and can be utilized as targets for immunotherapy. Cytokines and complement proteins serve multiple functions, including immune cell activation, antiviral activity, and regulation of inflammatory processes. MHC molecules facilitate antigen presentation and activation of adaptive immunity. TLRs recognize pathogen-associated molecular patterns and initiate the immune response. Current research has also demonstrated the potential of lipid-based carriers, proteins, carbohydrates, and nucleic acids for enhancing the immune activity of proteins.
The review discusses the use of carriers to improve the immune activity of proteins, which can be valuable for developing new vaccines and therapeutic agents. In recent years, there has been increasing interest in proteinbased therapeutic approaches, including monoclonal antibodies, cytokines, and others. The efficacy of these methods is influenced by the choice of carrier molecule. Conjugation of proteins with other molecules such as nanoparticles or liposomes can enhance stability, specificity, and efficacy. The presence of carriers on the surface of tumor cells can stimulate anti-tumor immune responses. However, challenges remain in the development of carrier-based therapies including potential carrier-induced immunogenicity, which may trigger undesired immune responses and limit therapeutic efficacy. Additionally, the complex selection of appropriate protein carriers for specific therapeutic applications requires further investigation into the underlying mechanisms of carrier function and immune activation.
As based on the analysis of scientific literature, this review establishes that the use of carriers and ligands represents a promising approach for enhancing protein immune activity and developing new vaccination and immunotherapy strategies.

A major issue in treatment of solid malignancies is associated with multiplicity and rapid adaptation of immunosuppressive effects exerted by immune cells reprogrammed by the tumor. Tumor-associated macrophages (TAM), neutrophils, and tumor-infiltrating lymphocytes lose their ability to protect healthy tissues and to destroy malignant cells by activating a number of tools causing blockage of immune surveillance and reduction of therapeutic effects. Immune cells attracted by chemokines and reprogrammed by the tumor supply the malignant cells with missing nutrients (e.g., by producing arginase), support the survival of de novo recruited cells at low pH (acidosis) around malignant tissues, produce increased amounts of angiogenic factors thus contributing to increased blood supply to the tumor. Productive inflammation, being among the main types of immune response, destroys tumor pathogens and moves into chronic inflammation with progression of the tumor, thus causing immune suppression. Restoration of inflammatory immune reactions after tumor resection, chemotherapy, and radiotherapy is necessary to achieve remission without relapse or, at least, increases the time period until next episode of the disease progression.
Transplantation of NK cells has a number of advantages over T lymphocytes in order of restored productive inflammation. However, it also requires additional therapeutic impacts, since various mechanisms of tumor immune escape block anti-tumor immunity. To achieve a pronounced therapeutic effect, the optimal ratio is important between the activity and number of NK cells, supporting therapeutic agents, with regard of aggressiveness and spread of malignant tumor. Among the developing areas of NK cells support, one may consider the NK cell “enhancers” (NKCE), engineered proteins that make cell therapy more selective and targeted. NKCE may activate the targeted migration of NK cells, along with blockage of inhibitory ligands. Currently, the blockage of inhibitory signals is studied in order to control metastatic tumors via KIR, NKG2A, TIGIT, TIM-3, EGFR, PD1 receptors, PDL1 and NKG2D ligand, as reported in a number of clinical and preclinical trials. The increased specificity of therapy is also achieved by usage of new-generation antibodies – nanoantibodies, aimed for targeted blocking of tumor-derived exosomes (TDE), as well as protein domains that enhance targeted migration of NK cells and therapeutic nanoparticles.

IL-40, also known as C17orf99, is an intriguing cytokine that has recently been discovered as a novel protein secreted by B cells. It is expressed in specific mammals and is derived from the bone marrow and fetal liver. While its primary role is in maintaining B cell homeostasis and promoting B cell maturation and development, IL-40 also plays a crucial role in humoral immunity, particularly in the production of antibodies, with a specific emphasis on IgA production. As well as there are relationship between IL-40 and neutrophil extracellular traps externalization (NETosis) markers. In addition to its involvement in normal B cell functions, IL-40 has been found to have significant implications in the pathogenesis of several diseases. Research has linked IL-40 to rheumatoid arthritis, hepatocellular carcinoma, non-Hodgkin B cell lymphoma, Sjogren’s syndrome, pSS-associated NHL, autoimmune thyroid disease, Type 2 diabetes mellitus, ankylosing spondylitis, chronic obstructive pulmonary disease, and systemic lupus erythematosus. This suggests that IL-40 could potentially serve as a diagnostic or treatment biomarker for these conditions. However, despite these exciting findings, there is still much to be learned about IL-40. Further research is necessary to uncover additional properties and functions of this cytokine. Ongoing studies aim to elucidate the mechanisms by which IL-40 contributes to B cell biology and humoral immunity, as well as its role in disease pathogenesis. These investigations will help determine the potential therapeutic applications of IL-40 and its utility as a diagnostic marker. In this minireview, we aim to discuss the recent findings surrounding IL-40. 

Aseptic necrosis of the femoral head is a staged process in which osteodestruction is replaced by the bone repair. The outcome of this disease may be characterized by severe discongruence of the hip joint area, disability of the patient. Recently, the research interest is drawn to molecular and cellular mechanisms of bone homeostasis disorders and ways of its correction. A number of studies have demonstrated the role of nonspecific inflammation in pathogenesis of aseptic necrosis. However, a more detailed study of dynamic changes in the activity of osteogenesis signaling pathways is required. The aim of this study was to assess the role of molecular patterns of inflammation and osteogenesis during aseptic necrosis of femoral head in experimental model. Surgical induction of aseptic necrosis of the femoral head was performed in 16 rats, which were removed biweekly from experiment (by 4 animals), for 8 weeks. The expression of genes encoding proteins involved in osteogenesis regulation was studied by qPCR with reverse transcription. Concentration of VCAM1, MMP9 proteins was assessed by immunoblotting. The results of our study demonstrated heterogenous dynamics of changes in molecular and cellular disorders associated with bone homeostasis regulation in pathogenesis of aseptic necrosis. For the first two weeks after surgical procedure, the expression of HIF1α and TNFα genes, as well as the concentration of MMP9 and VCAM1 proteins, were determined as predictor factors. After 1 month, VCAM1 protein concentration and TNFα gene expression acted as protector factors, whereas IL6 gene and MMP9 protein were considered predictive factors. After 6 weeks, the development of aseptic necrosis was promoted by expression of the IL4 gene, and after 8 weeks, by IL6 gene. Thus, an important role in regulation of osteoresorption belongs to nonspecific inflammation, which can be triggered by acute tissue hypoxia. A significant effect of the inflammation process persists up to 8 weeks after induction of avascular necrosis of femoral head. Pathogenesis of bone destruction is associated not only with an increased activity of osteoclastogenesis, but also with a decreased intensity of osteoblastogenesis. In general, the molecular and cellular pattern of bone homeostasis disorders varies depending on the stage of aseptic necrosis.

Imbalance of Th1/Th2 lymphocytes and cytokines is responsible for increasing rate of pathology, such as allergy, autoimmune processes and cancer. Pyrimidines have a wide spectrum of pharmacological activity, for example antiallergic properties.
The aim of this study is to investigate effects of 5-hydroxypyrimidine derivatives on systemic anaphylaxis, concentrations of immunoglobulin E (IgE) and cytokines in comparison with Aerius in experiments on ovalbumin-induced systemic anaphylaxis model.
Effects of 7-day course of intraperitoneal (i/p) administration of SNK-411, SNK-578 at the doses of 25 mg/kg and 50 mg/kg, Aerius (i/p, 1.3 mg/kg) were studied in 140 male Balb/c ovalbumin-sensitized mice. 120 mice were immunized by two injections (two-week interval) of ovalbumin (100 mg per mouse) mixed with aluminum hydroxide (5 mg per mouse). 20 mice were used as intact control. Administration of SNK-411, SNK-578, or Aerius began after second immunization and lasted for 7 days. Within one hour after last injection of the compounds, 70 mice received injection of ovalbumin (100 mg dissolved in 0.1 mL saline) in retroorbital sinus. 70 mice from control and experimental groups were euthanized by decapitation. IgE, Interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-10, IL-11, IL-17A, IL-17F, Interferon gamma (IFNγ), IL-13 concentrations were measured in blood sera.
Administration of SNK-411, SNK-578 at the dose of 50 mg/kg decreased systemic anaphylaxis, lowered IgE concentration by 1.5-1.6 times compared to ovalbumin control group whereas Aerius did not reduce concentration of IgE. Administration of SNK-411, SNK-578 at 25 mg/kg, and 50 mg/kg, and Aerius decreased concentration of Th-2 cytokines (IL-4, IL-5, IL-13) compared to ovalbumin-treated control group. SNK-411, SNK-578 at the doses of 25 mg/kg and 50 mg/kg increased level of IL-2. SNK-578 at 50 mg/kg increased concentration of IFNγ up to intact control level and decreased concentration of IL-6.
7-day administration of 5-hydroxypyrimidine derivatives at the dose of 50 mg/kg decreased severity of systemic anaphylaxis. SNK-411, SNK-578, Aerius lowered levels of proallergic cytokines in serum of sensitized mice. In contrast to Aerius, the 5-hydroxypyrimidine derivatives decreased serum IgE concentrations.

Vincristine polyneuropathy is the leading neurotoxic effect when treating pediatric acute lymphoblastic leukemia (ALL). Recent studies have demonstrated involvement of immune system in pathogenesis of peripheral nervous system damage. Over recent years, there have been reports examining the relationship between interleukin-13 (IL-13) and development of toxic effects of chemotherapeutic drugs. Our objective was to assess clinical value of IL-13 level in children with vincristine polyneuropathy.
The study included 27 children with ALL aged from 3 to 17 years, who received chemotherapy according to the conventional protocol. Plasma IL-13 levels were determined, and the values in two subgroups have been compared taking into account development of vincristine polyneuropathy. IL-13 content was assessed by multiparametric immunofluorescent analysis with magnetic microspheres (xMAP technology, Luminex 200, USA) and using ProcartaPlex Human Cytokine/Chemokine test system (Invitrogen, USA).
Vincristine polyneuropathy in the study group was registered in the majority of children (n = 15) manifesting mainly at the induction stage of chemotherapy and presenting as predominance of sensory disorders. In a comparative analysis of IL-13 plasma levels in patients with vincristine polyneuropathy, we observed a statistically significant increase of its concentration, in contrast to patients without signs of peripheral nervous system damage (p = 0.042). The diagnostic sensitivity of this index was 75%, specificity – 100%, the integral index characterizing the accuracy of the test was 0.89. IL-13 changes were found to correlate with higher relative risk level, indicating its significant relationship to the development of vincristine polyneuropathy.
The results of the study on the IL-13 content in blood plasma in children with vincristine polyneuropathy allowed us to consider it a predictive biological marker of peripheral nervous system damage.

Atopic bronchial asthma is the most common and severe allergic disease among a wide range of similar diseases. The main pathogenesis of this disease is characterized by a disturbance of T lymphocyte homeostasis, which significantly worsens the general state of health. In atopic bronchial asthma, there is impaired process of T cell apoptosis. This entails dysregulation and maintenance of peripheral lymphocyte homeostasis. Normally, T cells must undergo apoptosis, and its products should be utilized by neighboring cells, or professional phagocytes: monocytes, macrophages, or dendritic cells. This process is altered in atopic bronchial asthma. The immune system disorders, such as autoimmunity, often result from dysregulation of lymphocyte apoptosis. This is especially true in cases of insufficient or missed clearance of apoptotic bodies.
Recently, the research and medical communities pay much attention to efferocytosis, a form of phagocytosi which proceeds by removal of apoptotic cells by phagocytes by means of LC3-associated phagocytosis (LAP). This process initiates uptake of the particles due to interactions between the phagocyte plasma membrane receptors and apoptotic cell. Further on, a single-membrane phagosome is formed in the cell with the participation of certain autophagy proteins (Beclin-1, VPS34, UVRAG, ATG5, ATG12, ATG7, ATG4, ATG4, LC3). The phagosome is enriched with LC3 protein molecules and fused with lysosomes, in which the captured “cargo” is then lysed. As a part of our work, a detailed analysis of some key protein contents at the LAP pathway was carried out for peripheral blood monocytes of patients with severe bronchial asthma. It was found that the expression of Rubicon protein is increased, thus allowing to conclude that the LAP pathway is activated in monocytes of healthy donors, thus allowing phagocytosis of dying T cells. At the same time, the components characteristic of both autophagy and LC3-associated phagocytosis are activated in the monocytes of patients with severe atopic asthma. However, one should note that decreased expression of the Rubicon protein, a putative marker of LC3-associated phagocytosis, has been clearly confirmed.

Infectious endocarditis is characterized by dysfunction of heart valves and contribute significantly to the cardiovascular morbidity and mortality worldwide, especially in low- and middle-income countries. Immune response is playing the important role in the pathophysiology of this disease. This work was aimed to study the local cytokine profile in native heart valves obtained from the patients with infectious endocarditis. Cytokine profiling were performed in biopsies of native heart valves explanted from 4 patients with infective endocarditis (experimental group) and 10 patients with rheumatic heart disease (comparison group) by dot blotting using the Proteome Profiler™ Human Cytokine Array Kit (ARY005B). The results of dot blotting were validated by the gene expression profiling using quantitative polymerase chain reaction. MIF, PAI-1, ICAM-1 and CXCL12 were found in the native heart valves explanted from both infective endocarditis and rheumatic heart disease patients. Upon a semi-quantitative assessment, the heart valves explanted from the infective endocarditis patients were characterized by 4-fold increased secretion of PAI-1 and twofold decreased secretion of ICAM-1 and CXCL12 compared to the heart valves ffected by rheumatic heart disease. MIF was expressed on similar levels in the both studied groups. IL-1ra, IL-6, IL-8, IL-16, CCL4, CCL5 and CXCL1 were detected only in heart valves affected by infectious endocarditis. At the gene expression level, MIF, IL6, IL8 genes were upregulated and PAI1, IL1RA, CXCL1 genes were downregulated in heart valves explanted from infectious endocarditis patients compared to the subjects affected by rheumatic heart disease. Native heart valves in cases of infectious endocarditis are characterized by nonspecific local inflammatory response associated with pathogenic bacteremia, along with active neovascularization. The data obtained can help to better understand fundamental pathogenetic mechanisms of infectious endocarditis.

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, TGF-α, 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, TGF-α, 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 TGF-α, 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. 

Atopic dermatitis (AD) is a chronic recurrent inflammatory disease accompanied by severe itching. One of the leading mechanisms underlying the development of AD is an imbalance of the Th1/Th2 cells immune response, which leads to an increased production of inflammatory mediators, including IL-1 family. The IL-1 family includes the recently discovered IL-33 and IL-37, and their role in the pathogenesis of AD has been actively studied. IL-33 functions as an alarmin that can induce IL-31 production, thereby leading to skin barrier impairment, pruritus and scratching. Having both immunomodulatory and immunosuppressive properties, IL-37 suppresses leukocyte infiltration of the affected skin and reduces the activity of proinflammatory cytokines. The aim of our study was to search for associations between gene polymorphisms of IL33, IL37 genes, and risk of AD. A total of 98 patients with moderate and severe AD were included in the study. The control group included 72 healthy volunteers. Polymorphic markers were determined in peripheral blood. After extraction of total RNA, polymorphic markers rs7019575 in the IL33 gene, rs3811046 and rs3811047 in the IL37 gene were analyzed using RT-PCR. There was no statistically significant difference in allele frequency and genotype distribution of rs7019575 (IL33) and rs3811047 (IL37). Studying the rs3811046 polymorphic marker in the IL37 gene showed that the risk of AD was almost 2 times lower for the G allele carriers and more than 2-fold higher for TT homozygous carriers. The haplotype analysis revealed that the GTAA and TTGG haplotypes of IL37 were associated with AD, thus increasing the risk of AD development by 2 and 10 times, respectively. In conclusion, SNP markers identified in this study can be used to predict the risk of AD development in the subjects with a positive family history of atopic diseases.

The aim of the present study was to perform a comparative quantitative analysis of natural neurotropic autoantibodies (Nabs) in blood serum of patients with COVID-19 associated ischemic strokes (IS) in dynamics of disease.
A total of 150 consecutive patients with acute primary IS were included, being divided in two groups: 100 patients with IS on the background of COVID-19 pneumonia (main group No. 1) and 50 patients with IS without COVID-19 symptoms and positive viral test (comparison group No. 2). The stroke severity and consciousness were measured by NIHSS and Glasgow coma scale. In blood serum of patients (n = 110), we have studied the levels of IgG Nabs to NF-200, GFAP, S100β, MBP, receptors to dopamine, serotonin, choline, glutamate, GABA by means of ELISA technique. The blood samples for analyses were taken at the 5^th, 14^th and 28^th days of disease.
In group 1 (n = 80), the Nabs levels have been increased as follows: antibodies to NF-200 (132.9±4.1 CU), by 1.09 and 1.8 times; for GFAP (118.9±3.9 CU), by 1.4 and 2 times; S100β antibodies (129.5±10.2 CU), by 1.05 and 1.6 times; MBP antibodies (97.3±4.5 CU) were 1.14 and 1.6 times higher; antibodies to dopamine receptors (77.9±4.4 CU) in 1.2 and 1.6 times; to serotonin receptors (81.96±3.25 CU) in 1.2 and 1.4 times; choline receptor antibodies (61.42±3.6 CU) were increased 1.4- and 1.8-fold; to glutamate (85.28±4.25 CU) by 1.19 and 1.4 times; to GABA (82.4±5.2 CU) the increase was 1.5- and 1.8-fold, respectively, when compared with group 2 and controls. The time-dependent monitoring of Nabs level in patients with COVID-19 associated ischemic stroke showed the highest increase in Nabs to the S-100, NF-200 and MBP proteins at the day +28 following the brain stroke.
In patients with COVID-19 associated IS, more enhanced production of serum autoantibodies to neuroproteins and neurotransmitter receptors was detected, which accompanied a worse course of IS and can be considered as a predictor of unfavorable outcome of disease. 

Nongenomic effects of antibodies specific to membrane steroid receptors are well known. Autoantibodies against estrogen receptor (ER) were revealed in blood serum of breast cancer patients (BCP). Their serum levels correlated with Ki-67, a protein tumor proliferation marker,. Purified antibodies stimulated in vitro proliferation of cultured MCF-7 tumor cells. Antiidiotypic antibodies against monoclonal antibodies, specific to estradiol, showed similar agonist activity. However, the function of auto-antibodies against progesterone receptor (PR) remained unknown. The purpose of this study was to search for an association between serum antiidiotypic antibodies specific to estradiol and progesterone (IgG₂-E2 and IgG₂-Pg), and expression of Ki-67 tumor protein in BCP. The IgG₂-E2 and IgG₂-Pg were studied in 204 healthy women and 663 BCP with ER⁺/PR⁺ tumors using ELISA technique with adsorbed monoclonal antibodies against E2 and Pg. Ki-67, ER and PR were detected by immunohistochemical methods. High levels of IgG₂-E2 in stage I BCP were detected more frequently than in healthy women (63.9% vs 40.2%, р < 0.001), being more common in cases with Ki-67 > 14, than with tumors with Ki-67 ≤ 14 (63.9% vs 56.9%, р = 0.03). Similar association of IgG₂- Pg with Ki-67 was not revealed. The individually low levels of both IgG₂-E2 and IgG₂-Pg in stage I BCP with Ki-67 ≤ 14 tumors were found in 55.2%, compared to 22.4% in cases with Ki-67 > 30. The cooperatively high IgG₂-E2 and IgG₂-Pg levels were detected in 35.7% of stage I BCP with Ki-67 ≤ 14 tumors and in 28.6% with Ki-67 > 30 cases (p = 0.03). On the contrary, high IgG₂-E2 levels in BCP II-IV stages with tumor Ki-67 > 30 were less comon, than with Ki-67 ≤ 14 (49.1% vs 64.2%, р = 0.03). Similar association was found with IgG₂-Pg (47.2% vs 62.2%, р = 0.03). The cooperatively high individual IgG₂- E2 and IgG₂-Pg levels were detected in BCP at II-IV stages with Ki-67 ≤ 14 and Ki-67 > 30 (respectively, 38.0% and 37.0). These indices comprised 21.5% and 53.9% when the levels of studied antibodies were low (p = 0.003). In conclusion, high individual levels of both IgG₂-E2 and IgG₂-Pg were associated with high proliferative activity of ER⁺/PR⁺ breast cancer at initial tumor growth (stage I), and with low proliferation rates at subsequent tumor growth (stages II-IV).

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, autoimmune disease, the development of which is associated with impaired mechanisms of cell number control, proliferation balance, and apoptosis. The aim of our study was to perform a comprehensive analysis of cellular and humoral effects exerted by “apoptotic” T lymphocyte culture upon “proliferating” cells, taking into account the parameters of “primary” and “secondary” apoptosis induction, activation and proliferation markers, viable cell contents, role of cortisol, caspase and cytokines during cultivation under the “cell neighborhood” conditions in healthy subjects and patients with RA. The results of the analysis, with respect to previous data, revealed both similar and different functions of the T cell systems generated under “cell-neighborhood” conditions in healthy individuals and RA patients. Both groups under study were characterized by secondary induction of apoptosis, which refers to non-autonomous effects, along with appearance of activated T lymphocytes at significant amounts, increase of IL-6 and IL-4 levels, as well as low levels of IFNγ and caspase 8, decrease potential of receptor and mitochondrial apoptosis. No differences in apoptosis level were found between donor and patient groups. At the same time, the initially high level of TNFα in healthy subjects decreased during the induction of apoptosis, along with moderate increase of IL-6. The levels of intracellular p53 and Bcl-2 molecules did not change, and many positive correlations remained between the studied factors in all variants of mixed and “apoptotic” cultures, thus suggesting maintenance of functional T cell balance under the unfavorable conditions in donors. The RA patients were characterized by increased number of live cells in “apoptotic” cultures, a significant increase in the number of Ki-67+ T lymphocytes, being indicative for proliferative processes under conditions of apoptosis, like as absence of TNFα response to apoptosis induction. Lack of relations between the studied molecules in “apoptotic” cultures and local cortisol synthesis, as well as presence of correlations between cortisol and the studied molecules in apoptotic cultures, presumed some changes of intercellular interactions and disturbance of homeostasis among T lymphocytes under the conditions of “cellular neighborhood” were also observed in RA patients.

Comprehensive analysis of adaptive immune response to SARS-CoV-2 is critical for epidemiological monitoring, as well as for tracking immune response stages and vaccination strategies. Understanding the differences between immunity formed after COVID-19 infection and vaccine-induced immunity is a specific task within this problem. Moreover, the obvious task is to assess the effect of repeated antigenic stimulation on immunological defense against SARS-CoV-2. The aim of present study was a comparative analysis of humoral immunity (anti-SARS-CoV-2 IgA and IgG) developing after natural infection with SARS-CoV-2 and/or after vaccination with anti-COVID vaccine “Sputnik V”. The study involved 36 volunteers. 21 of them had COVID-19 and were vaccinated 8-10 months later (group 1). In 15 primarily vaccinated persons, previous SARS-CoV-2 infection was excluded by means of regular PCR screening and serological testing (group 2). Results: Intensity of humoral immune response to the primary natural SARS-CoV-2 infection and similar indexes of antiviral adaptive immunity after vaccination with “Sputnik V” vaccine were similar in both groups. However, both maximal values of anti-SARS-CoV-2 IgA and IgG and the rates of post-vaccination humoral immune response differed significantly between the persons who have previously had COVID-19 and those who have not previously been infected with SARS-CoV-2. We’ve got statistically significant differences between two groups of participants using Student’s t test comparing the average maximum IgA levels after vaccination (p < 0.05). For IgG levels, these differences are less pronounced. In the first group, the average maximal values of specific IgA and IgG levels after natural infection with SARS-CoV-2 and after subsequent vaccination differed by more than 2 times. The time intervals for reaching maximal antibody levels after vaccination proved to be significantly shorter in the subjects who had a story of COVID-19, than in persons who did not report a clinical COVID-19 infection. Concerning the terms of arising IgG antibody response after vaccination versus cases of COVID-19 in the first group, we obtained a statistically significant difference by the Student’s t-test (p < 0.05). Hence, the persons with a previous natural COVID-19 infection develop a faster, stronger and more durable response to the “Sputnik V” vaccine than the subjects who had no such infection in their history

Natural killer cells (NK cells) are a population of innate immune lymphocytes capable of cytolysis of infected or transformed cells without prior sensitization. Natural killers are detected in various organs and tissues and may differ in phenotypic and functional characteristics depending on localization. For example, NK cells are the dominant population (up to 70%) of decidual lymphocytes in early pregnancy. NK cells are able to contact with trophoblast cells, exert cytotoxicity towards them, as well as regulate their invasion, contributing to spiral arteries remodeling and establishment of physiological blood flow between mother and fetus. The contribution of impaired NK cell functional activity to immune mechanisms of the reproductive disorders is widely discussed. Various drugs are used to treat infertility, including intravenous immunoglobulins (IVIG) and recombinant granulocyte colony stimulating factor (G-CSF). Increased rates of embryo implantation and higher frequency of successful gestation have been shown after treatment with these drugs. The effect of these drugs on NK cells phenotype and functional activity is assumed, thus requiring further studies on the effects of IVIG and G-CSF on the receptor profile of NK cells.
The aim of this work was to evaluate expression of cytotoxic receptors on the NK-92 cells in presence of IVIG and recombinant G-CSF preparations.
NK-92 cells were used as effectors, and trophoblast-derived JEG-3 line served as target population. The cells were co-cultured in presence of drugs, as well as without them. Expression of CD45, CD56, CD215, KIR2DL3, KIR2DS4, NKG2D, NKp44, NKp30 receptors by NK-92 cells was evaluated by flow cytometry.
The number of NK-92 cells expressing NKG2D, NKp30, KIR2DL3 receptors and the expression intensity of NKG2D and NKp30 receptors were reduced in presence of IVIG preparations. The numbers of KIR2DL3⁺ and NKp44⁺ NK cells were reduced when supplied with G-CSF and trophoblast cells.
The obtained results may be associated with both direct and indirect effects of the studied drugs on the NK cell phenotype.

We evaluated some functional indices of neutrophils in 100 adult patients with a verified diagnosis of primary antibody production deficiency (44 patients with common variable immunodeficiency – CVID, and 56 patients with selective IgA deficiency – SigAD). The diagnosis was made according to the criteria of the Pan-American Group for Immunodeficiency and European Society for Immunodeficiency. The criteria for diagnosis were based on clinical data, medical history and results of laboratory tests. All patients with CVID received regular immunoglobulin replacement therapy, and the SIgAD patients received symptomatic treatment on demand. The examination was performed beyond the infectious episodes, inflammatory events or exacerbation of chronic disorders upon admission for planned hospitalisation, before any therapeutic and diagnostic procedures. In addition to standard clinical and laboratory examination appointed for the mentioned diseases, we assessed fnctional status of neutrophils: superoxide-anion radical production, NETosis, phagocytosis and apoptosis. Taking into account clinical manifestations, the patients with CVID were divided into 6 clinical subgroups: without CVID-related complications (13.6%); with infectious complications, i.e., bronchiectatic disease (15.9%), autoimmune syndromes (22.7%), polyclonal lymphoid infiltration (13.6%), enteropathic syndrome (34.1%), and malignant neoplasms (9.1%). Four phenotypes were identified in the patients with SIgAD: absence of SIgAD-related complications (28.6%); autoimmune syndrome (16.1%), non-malignant lymphoproliferation (3.6%) and enteropathy (28.6%). Higher incidence of non-infectious complications (autoimmune syndrome, non-malignant lymphoproliferation, enteropathies) was found in СVID compared to SIgAD patients (χ² = 10.27; p = 0.001). Patients from the both groups showed changes in neutrophil reactivity compared to control values expressing higher basal generation of superoxide radicals (p < 0.001), NETosis activity (p = 0.005) and apoptosis (p < 0.001) with decreased phagocytic function (p < 0.001) and lower reserve for reactive oxygen species formation (p < 0.001). The maximal degree of changes in phagocytosis and superoxide-producing activity was observed in СVID; altered NETosis was revealed in SIgAD. The development of non-infectious complications was accompanied by a significant increase in stimulated NETosis indexes, thus suggesting a promising index in order to assess stability of clinical course and to predict development of complications in congenital defects of antibody production.

γδT cells are unique lymphocytes that take an intermediate position between the cells of innate and adaptive immunity. Even at the stage of differentiation in the thymus, they acquire the status of effectors with cytotoxic activity and become powerful cytokine producers. The antigen-recognizing receptor of γδT cells formed by γ and δ chains and is assigned an important role in activation of these cells in tissues: it recognizes infected and tumor cells by the presence of intracellular stress molecules. γδT cells are found in the blood and mucous membranes. Today, researchers’ attention is focused on two subpopulations of γδT cells: γδ1 and γδ2. The first is abundantly represented in the mucous membranes, the second forms the bulk (90%) of circulating γδT cells. The aim of this study was to assess the level of circulating γδT cells in patients of older age groups with proven pathologies affecting mucous surfaces at various segments of the digestive tract. We have recruited older patients from the Russian Gerontological Research and Clinical Center aged 60 to 90 years. The main group (n = 28) included patients with lesions of the gastric mucosa and duodenum with erosive ulcerative foci. The age-matched comparison group (n = 33) consisted of patients without gastrointestinal manifestations and did not have indications for gastroduodenoscopy. A separate group (n = 35) included patients with varying degrees of colon dysbiosis. The number of γδT cells in the blood was determined by two-color flow cytofluorometry using monoclonal antibodies. Presence of erosive and ulcerative foci in the mucous membranes of the stomach and duodenum was associated with increased numbers of circulating γδT cells population. An impaired function of intestinal barrier is considered a detrimental consequence of colon dysbiosis. Among patients with severe dysbiosis (3rd degree), the proportion of patients with a high content of γδT cells was significantly higher than among patients with the 1st (milder) degree of dysbiosis. Hence, the circulating population of γδT cells in the patients of the older age group responds by increased numbers to the damage (severity of damage) of the mucous membrane observed at different segments of digestive tract. The nonspecific nature of this response is obvious. Nevertheless, the expansion of this population in the circulating blood may be a sign of particular pathological process thus requiring further advanced diagnosis.