Vol 25, No 4 (2022)

Many drug delivery systems are currently under study, e.g., nanosized cavitands cucurbiturils, which, due to the presence of a cavity, can incorporate drug molecules. Since the immune system is quite sensitive to influence of nanomaterials and other cell-damaging factors, it is necessary to study immunosafety of the new delivery systems, i.e., immunotoxicity and immunomodulatory properties. The aim of this study was to investigate the effect of nanosized cucurbituril cavitands on the cytokine-producing ability of peripheral blood mononuclear cells in apparently healthy donors.

Blood mononuclear cells (106/mL) were cultured in the presence of cucurbiturils at the following concentrations: 0.3 mM cucurbit[6]uril, 0.3 mM cucurbit[7]uril, and 0.01 mM cucurbit[8]uril for 72 h, under additional stimulation with aCD3 antibodies (1 µg/mL), or without it. The level of cytokines in the supernatants was determined using enzyme immunoassay.

It was shown that cucurbit[6]uril increased the level of spontaneous IL-4 production by 1.5 times (p < 0.01) compared with the control. In the case of stimulated cytokine production, we found that cucurbit[6]uril reduced the level of IL-6, and also shows a tendency (p = 0.09) towards an increase in the IL-4 level. When cells were cultured with cucurbit[7]uril, we gave revealed a trend for increased production of pro-inflammatory TNF. It was also found that cucurbit[7]uril is able to suppress the production of IL-10 in aCD3-stimulated cell culture by 1.5 times. Cucurbit[8]uril was shown to inhibit production of cytokines in non-stimulated cell cultures. A significant decrease in the level of IFNγ and IL-10 was revealed as compared with the production of these cytokines in control cultures. When assessing the effect of cucurbit[8]uril on the IFNγ production upon stimulation with aCD3 antibodies, no significant differences were found, but there is also a trend for a decreased concentration of this cytokine agains control levels.

Cucurbiturils can influence both spontaneous and stimulated production of cytokines by the blood mononuclear cells. The effect on cytokine-producing ability of the cells depends on the tested homologue compound.

Association of Helicobacter pylori infection with gastrointestinal tract disorders is one of the most common problems in the modern medicine. There are conflicting data in the literature on the role of H. pylori infection in development of allergic diseases and its effect on the course of gastrointestinal disorders in allergic conditions. There is currently no conclusive evidence about the role of H. pylori in etiology and pathogenesis of allergic states. Hence, the studies of gastrointestinal disorders in allergic conditions in the presence of H. pylori infection are of sufficient relevance. Our aim was to study the features of sensitization spectrum and clinical course of gastrointestinal manifestations in allergic disorders in the children infected with H. pylori.

We have carried out a retrospective analysis of medical histories of the children with gastrointestinal manifestations of allergies (n = 29) aged from 1 to 18 years (middle age, 11±0.7 years), living in Eastern Siberia. The presence of H. pylori infection was determined with enzyme immunoassay technique, by measuring concentrations of total antibodies to the CagA H. pylori antigen. Depending on the carriage of H. pylori infection, 2 groups were discerned: HP-infected (n = 8), and HP-non-infected patients (n = 21). The spectrum of sensitization was determined by evaluating skin-prick tests for the non-infectious allergens. Gastrointestinal tract evaluation was based on the results of anamnesis, complaints, objective examination and data of esophagogastroduodenoscopy.

It was found that, in most cases, gastrointestinal manifestations of allergy were combined with dermatorespiratory syndrome (41.3% of total group). The incidence of H. pylori infection in the patients with gastrointestinal manifestations of allergies was 27.5% of the group. Among the gastrointestinal manifestations of allergies, inflammatory diseases of the esophagus, stomach, and intestines, e.g., gastroesophageal reflux, gastritis, and duodenitis were most common. In the group of HP-infected children the incompetence of cardia was more often, being statistically significant. In the group of HP-noninfected children, esophagitis, bulbitis, erosive lesions of the stomach and duodenum were more common, however, the difference did not reach statistical significance. The spectrum of sensitization in the patients with gastrointestinal manifestations of allergies showed some features depending on the presence of HP infection. E.g., sensitization to birch and meadow grass mixture was found to be significantly more often in the group of HP-infected children, Among the HP-noninfected children, sensitization to house dust mite, cat wool, and dog wool was more often detected. Hence, when examining children with gastrointestinal manifestations of allergies it is necessary to exclude the presence of H. pylori infection, which can modify the course of a genuine allergic pathology.

Currently, rheumatoid arthritis (RA) is considered among the most common autoimmune diseases worldwide, being associated with progressing disability, systemic organ and tissue lesions, as well as social and economic losses for the state. Studies of innate lymphoid cells (ILS) seems to be actual and significant when studying development of autoimmune inflammation in RA, in particular, the issues of the cell plasticity. ILC represent tissue resident lymphoid cells that display functional diversity, like as T cells. Moreover, ILC regulate orientation of immune response by means of cytokine production. Small amounts of ILCs are present in the bloodstream, presumably for migration to target organs and tissues. Accordingly, the study of ILC in RA will promote understanding of the RA pathogenesis. It is also possible in the future to develop new therapeutic strategies based on the impact on the immunological balance, as well as reducing the inflammatory process in RA. The aim of this study was to determine the subpopulation composition and phenotypic features of ILCs in RA.

We have isolated and studied peripheral blood mononuclear cells (PBMC) from 7 patients with RA and 6 healthy donors. The isolated blood MNCs were stained with monoclonal antibodies conjugated to fluorochromes: lineage-specific (CD3/14/16/19/20/56) and anti-FceR1 alpha-FITC, anti-CD294-APC/Cy7, anti-CD127-PerCP/Cy5.5, anti-CD336-PE, anti-CD117-APC. ILCs were defined as Lin-CD127+. The numbers of CD294+ILCs (ILC2) were estimated in the general population, CD117-CD294-ILCs were defined as ILC1, and CD117+CD294-ILCs, as ILC3. The cell phenotype was analyzed with a FACS Canto II flow cytometer (BD Biosciences, USA).

We determined relative numbers of different ILC subpopulations (ILC1, ILC2, and ILC3) among the total blood MNCs. It was shown, that the number of ILC2 cells in RA patients was statistically significantly reduced compared to healthy donors, whereas no significant differences in percentage of ILC1 and ILC3 were revealed between donors and patients. We also evaluated the amount of c-Kit+ILC2; there were no significant differences in the proportion of these cells between donors and patients.

ILCs represent a population of cells that contribute to the RA pathogenesis. The role of ILC2 in RA is, presumably, protective. The ILC imbalance may contribute to the development of RA. For a better understanding of the RA pathogenesis, further studies of the subpopulation profile, phenotypic and functional characteristics of ILC are required in this disorder.

Atopic dermatitis (AD) is a multifactorial genetically determined inflammatory skin disease characterized by itching, chronic course, age-related features of localization and lesion morphology. Atopic dermatitis is caused by complex interactions between genetic, immunological, and environmental factors. The barrier function of the skin is impaired in atopic dermatitis. Antimicrobial peptides, e.g., LL-37, b-defensins are involved in maintaining the skin barrier function (especially, intercellular contacts). An imbalance of antimicrobial peptides may cause different disorders, including allergic pathologies. The aim of this study is to investigate gene expression profile of the HBD1 and LL37 encoding antimicrobial peptides in the samples of skin and blood mononuclear cells obtained from the children with moderate and severe atopic dermatitis before and after treatment. By means of real-time polymerase chain reaction, the levels of HBD1 and LL37 gene expression were evaluated in the samples. Statistical analysis showed significantly increased (p ≤ 0.017) expression levels of both HBD1 (H-test = 24.76; 2, n = 72; p = 0.00001), and LL37 genes (H-test = 15.69; 2, n = 72; p = 0.00039) in blood cells of AD patients compared to the control group, as well as decreased (p ≤ 0.05) levels of HBD1 expression in the affected skin compared to the control group. Our data on the cathelicidin gene in the skin do not differ from the literature data, since its expression is reduced in AD. In our series, an increase of the gene expression was revealed in PBMCs. The HBD1 peptide is expressed in both monocytes and macrophages, representing a link between innate and adaptive immunity. In our study, the expression of the HBD1 gene was increased only in blood, thus suggesting activation of innate immunity components at the systemic level in response to inflammation. Of importance, understanding the role of immunological markers in AD will help to develop novel prognostic approaches in management of the patients with atopic disorders. Therefore, one should understand pathogenetic mechanisms of allergic diseases.

The article presents the results of population immunity assessment in residents of the Kaliningrad region to current antigenic variants of influenza viruses over the period of 2018 to 2021. To assess spectrum of influenza types circulating in Kaliningrad region, the real-time PCR method was used using AmpliSense reagent kits. The biological material for the study was obtained from oropharyngeal swabs from the persons who applied to polyclinics with inflammatory diseases of upper respiratory tract, or underwent treatment at the out- or inpatient basis in a healthcare facilities of Kaliningrad region. Humoral immunity was assessed by testing blood sera obtained from healthy residents of Kaliningrad region during periodic prophylactic examinations at the city and regional polyclinics. The study of residents covered all age groups. For the period of 2018-2021, more than 14,000 studies have been carried out. Determination of specific serum antibody titers was carried out by staging the hemagglutination suppression reaction using local influenza antigens (LLC «PPDP», St. Petersburg). Antibody titers of 1/40 and higher were considered sufficient to reduce the risk of disease by > 50%. During the study period, 2165 cases of influenza were confirmed in the region by laboratory tests. Over the study period, the A(H1N1) pdm serotype proved to be the major strain causing influenza, its proportion reached 57.5%. However, along with A(H1N1) pdm, a significant contribution was also made the A(H3N2) strain to the epidemic process, being the etiological cause of influenza infection in 2019 (42.2%), type B influenza strains being actual in 2020 (42.5%). Over the period of 2018-2021, 420 samples of blood sera from vaccinated and non-vaccinated individuals were tested for specific antibodies. The sera were taken 1-2 months after vaccination and between epidemic rises of influenza (April-May). In vaccinated individuals, the antibody titer was protective in 58.3-64.5%. In this group of persons, the titer sufficient to produce immunity was maintained over the spring/summer period. Among those persons who refused vaccination, a protective antibody titer in the pre-epidemic period was noted in 41.2% of the examined, and during the off-season it was detected in 37.4% of the volunteers. Thus, the A(H1N1) pdm strain was the main etiological factor of influenza in Kaliningrad Region in 2018-2021. The protective level of antibodies in vaccinated population over the period preceding the epidemic peak, was observed 30% more often than in unvaccinated individuals. High incidence of influenza B strains noted in 2020 appears to require a change of specific vaccine preparation.

The SARS-CoV-2 virus can enter the cells using S1 viral spike (S) protein, not only by binding to ACE2, but also through other cellular receptors. These candidate receptors include CD46, which, like CD45, belongs to pan-leukocyte receptors and is expressed on all types of lymphocytes. In turn, SARS-CoV-2 infection is accompanied by damage to almost all compartments of the immune system, mainly T lymphocytes. The purpose of the study was to evaluate the expression levels of CD45⁺ and CD46⁺ in various subpopulations of lymphocytes in patients who had undergone SARS-CoV-2 infection.

72 patients who had undergone SARS-CoV-2 infection were examined. Using flow cytometry technique, we determined CD45⁺ and CD46⁺ (panleukocyte marker for lymphocyte gating), CD45⁺ and CD46⁺, CD3⁺ (T lymphocytes), CD45⁺ and CD46⁺, CD3⁺, CD4⁺ (helper inducers), CD45⁺ and CD46⁺, CD3⁺, CD8⁺ (cytotoxic T-lymphocytes), CD45⁺ and CD46⁺, CD3⁺, CD56⁺ (TNK cells) CD45⁺ and CD46⁺, CD3^-, CD56⁺ (natural killers), CD45⁺ and CD46⁺, CD3^-, CD19⁺ (B lymphocytes), CD45⁺ and CD46⁺, CD3⁺, CD4⁺, CD25⁺ (activated helpers, early activation of lymphocytes), CD45⁺ and CD46⁺, CD3⁺, HLA-DR (activated T lymphocytes – late activation of lymphocytes). Our studies have shown that a decrease in CD46⁺ expression in T lymphocytes (CD3⁺) is accompanied by similar decrease of its expression in cytotoxic T lymphocytes (CD3⁺, CD8⁺), TNK (CD3⁺, CD56⁺), as well as in helpers T carrying markers of early activation (CD3⁺, CD4⁺, CD25⁺). At the same time, the most pronounced decrease was observed both among total T lymphocytes and cytotoxic T cells. In these patients, the expression level of CD46⁺ in B lymphocytes was slightly increased. Recent data suggest that there is no involvement of CD46 receptor on B lymphocytes. Our data suggest that the SARS-CoV-2 virus may affect the CD46 receptor. Such exposure may lead to promotion of the long-COVID (post-COVID) symptoms in such patients, thus requiring new approaches to correction of these disorders.

Chronic inflammatory diseases of the pelvic organs (CIDPO) in women represent one of the urgent and insufficiently studied problems in gynecology across the world. These disorders are followed by adverse medical and socio-economic consequences, i.e., chronic local inflammatory process, chronic pelvic pain syndrome, ectopic pregnancy, infertility. Due to increasing chronicity and recurrence rates of genital infections and inflammatory diseases, there is a need for further studying the effector and regulatory mechanisms of immune system. Of special relevance are the studies of the receptor transformation in neutrophilic granulocytes (NG), the basic population of antimicrobial defense, with further substantiation of targeted immunomodulatory therapy. Purpose of the present study was to assess transformation of neutrophilic granulocytes from CD11b⁺CD64^-CD32⁺CD16⁺ to that CD11b⁺CD64⁺CD32⁺CD16⁺ phenotype in immunocompromised women with CIDPO exacerbation, as well as to evaluate the possibility of in vitro reprogramming the neutrophile phenotype under the action of recombinant interferon (recIFNα2b). Peripheral blood neutrophils were tested in the comparison group of 10 conditionally healthy women 20 to 40 years old, and in 17 women (20-40 years old) with the CIDPO exacerbation (group 1). The in vitro effect of recIFNa2b on the blood neutrophils was evaluated for 17 women with CIDPO (group 2). Flow cytometric technique (FCT, CYTOMICS FC500, Beckman Coulter, USA) was used to determine the number of NGs and cell receptor expression levels of neutrophilic CD11b⁺CD64^-CD32⁺CD16⁺NG and CD11b⁺CD64⁺CD32⁺CD16⁺ subpopulations. In peripheral blood of women with CIDPO exacerbation, an increased expression density of surface membrane molecules was revealed by means of FCT: in the subpopulation CD11b⁺CD64^-CD32⁺CD16⁺NG, CD16 proved to be 91.7% higher; in CD11b⁺CD64⁺CD32⁺CD16⁺NG subpopulation, CD16 was increased by 116%, and CD32 being higher by 81% against the comparison group. In the in vitro system, during the incubation of PB with recIFNα2b (group 2), we have revealed an increased number of CD11b⁺CD64^-CD32⁺CD16⁺ subpopulation relative to the comparison group and group 1, and significantly increased expression density of CD16 (by 212%); CD11b (by 56%), and CD32 (by 83%) than in comparison group, as well as higher density of CD16 expression by 163%; CD11b (by 223%) compared to group 1. The changes in expression density of membrane molecules was also detected by FCT for the activated subpopulation CD11b⁺CD64⁺CD32⁺CD16⁺NG, i.e., an increase in CD16 by 232% against control group, and decreased expression density of CD64 by 150% against the background, along with increased density of CD16 expression (by 54%), and CD11b (by 103%), relative to group 1, thus suggesting a reprogramming of negatively transformed NC phenotype. These findings may be considered a positive immunomodulatory effect providing a basis for further research in order to develop new integrated approaches to treatment of CIDPO of various etiologies.

Common variable immunodeficiency (CVID) is one of the most frequent forms of primary immunodeficiencies with predominant antibody deficiency. Unlike most other primary immunodeficiencies, this variant often manifests in adults thus creating certain difficulties in its detection. Manifestations of common variable immune deficiency are very diverse: infectious syndrome (respiratory tract infections, septic arthritis), diarrheal clinical pattern of both infectious and non-infectious genesis, autoimmune syndrome (autoimmune cytopenias, systemic rheumatic diseases), lymphoproliferative syndrome (benign lymphoid proliferation, lymphomas), interstitial lung disease and sarcoidosis-like granulomatous changes are quite common. Due to the lack of a distinct clinical pattern, the common variable immunodeficiency is often diagnosed too late. Such patients are observed for a long time by various specialists, and the absence of pathogenetic therapy (intravenous immunoglobulins) leads to steady progression of the disease and, often, to lethal outcome. The article presents a clinical observation illustrating the difficulties in making this diagnosis. A woman hospitalized with pneumonia presented with a mass in colonic submucosa. After excluding tuberculosis and lymphoma, a diagnosis of colon lipoma was made on the basis of histological examination. A few years later, the patient’s submandibular lymph nodes were periodically enlarged. Upon repeated histological examination, the diagnosis of granulomatous necrotizing lymphadenitis was established, the patient was referred to a rheumatologist to rule out systemic vasculitis. This diagnosis was not confirmed, but further examination revealed a sharp decrease in the gamma fraction of serum proteins. Therefore, an immunologist’s counseling was recommended to rule out immunodeficiency. The following blood serum analysis revealed an extremely low IgG and IgM content, with absence of detectable immunoglobulin A. On the basis of these findings, the diagnosis of common variable immune deficiency was made for the first time. Replacement therapy with high-dose intravenous immunoglobulins with control of pre-transfusion Ig levels was recommended, with further transition to a supporting treatment schedule. Hence, one may state that general practitioners are still poorly aware of primary immunodeficiencies, especially if non-infectious manifestations dominating in the clinical pattern. Routine analysis of total protein content and protein fractions can provide information that allows to suspect deficiency of antibodies and, therefore, to assess contents of distinct serum immunoglobulins in order to confirm CVID diagnosis.

Traumatic brain injury (TBI) is an important problem of the healthcare system. A lPeading role in pathogenesis belongs to the action of shock wave upon skull and brain integuments, extending from the impacted site, as well as displacement and rotation of the cerebral hemispheres relative to the fixed brain stem. As a result, a cascade of metabolic, biochemical and inflammatory changes is initiated, leading to secondary damage. TBI, depending on its mechanism, severity and type, causes various primary structural and functional brain lesions at molecular, cellular, tissue and organ levels with dysregulation of all systems in the body, dependent on its degree and extent. In most cases, the brain injury increases the risk of developing epilepsy and neurodegenerative diseases such as Alzheimer’s disease, arkinson’s disease and chronic traumatic encephalopathy (CTE), with mental health disorders. TBI is a long-term symptomatic process in patients with functional and structural damage. In response to a traumatic event, the damage-associated molecular patterns (DAMPs) encountered upon tissue damage are expressed, which cause activation of the resident brain tissue cells, and secretion of multiple chemokine and cytokine by distinct cell populations. Neutrophils migrate to focal lesions, which remove damaged cells and debris. Migration of T and B cells is observed 3-7 days after the trauma. Hence, following primary injury, due to a cascade of immune reactions, a more extensive lesion, the so-called secondary trauma, is developed. The aim of our study was to evaluate the role of immune response in pathogenesis of mild traumatic brain injury.

An increased number of Bm2 cells, IgD^dimCD27^low “naive” B cells and B cells with the IgD^lowCD27^hi (“plasmablasts”) phenotype was found in patients with mild brain contusion, compared to comparison group. Moreover, the number of “naive” mature B cells with the CD27^lowCD38^dim phenotype was significantly decreased compared with the controls.

Influenza is one of the most urgent global health problems today. The influenza virus has immunosuppressive properties, which can lead to the development of secondary immunodeficiencies, interfering with the functioning of the interferon system activation, thus leading to impaired production of pro-inflammatory cytokines. IL-1β is the most important player in development of antiviral immunity. This cytokine plays an important role in boosting the expression of the MCP-1 and MCP-3 genes and maturation of macrophages and dendritic cells. Induction of IL-1β production occurs due to interaction of the ligand with Toll-like receptors. Currently, there is a lot of drugs aimed at the prevention and treatment of influenza infection. However, their use in some cases is difficult due to high mutational variability of the influenza virus, thus making it resistant to these drugs. Therefore, the issue of developing and creating effective methods to combat such infections is of particular importance. A promising approach to the treatment and prevention of viral respiratory infections may be connected with RNA interference. This process consists of degradation of foreign mRNA by small interfering RNA (siRNA) molecules. The aim of the present study was to evaluate expression of the IL-1β gene upon transfection of miRNA complexes directed to the cellular FLT4, Nup98, Nup205 genes. Evaluation of changed viral reproduction was carried out using titration by CPE virus-containing fluid. Expression level of the IL-1β gene was determined by means of real-time RT-PCR. Assessment of the changes in viral reproduction allowed us to reveal that the use of all the miRNA complexes directed to the cellular genes lead to a significant decrease in viral reproduction on the 1^st day after infection. Usage of Nup205 + FLT4 and FLT4 + Nup205 + Nup98 complexes proved to cause a decrease in viral reproduction on the second day as well (p < 0.05), as compared with nonspecific and viral controls. When analyzing expression profile of the IL-1β gene, an increase in its expression was observed on the 1^st day for all miRNA complexes and on the 2^nd and 3^rd days for the Nup98 + FLT4 and Nup205 + Nup98 complexes. In the course of the study, it was found that suppression of the cellular genes FLT4, Nup98 and Nup205 activities, which are necessary for viral reproduction, led to a significant decrease in viral activity and an increase in IL-1β expression.

COVID-19 is a multisystem disease, but the extent of its consequences is currently poorly understood, especially in the persons with metabolic disorders. The aim of the present study was to evaluate the special changes in the cytokines of IL-6 family (IL-6 and sIL-6, LIF and sLIFr), adiponectin and leptin within 360 days after SARS-CoV-2 infection in the patients with metabolic syndrome (MetS), to discern features of immunopathogenesis depending on previous vaccination against COVID-19.

We have classified the patients in two groups: (1) patients with MetS who underwent COVID-19 6-12 months after full-course vaccination with a vector vaccine (n = 32); (2) patients with MetS who underwent COVID-19 without story of vaccination (n = 29). Control group included conditionally healthy individuals without MetS: (3) vaccinated, and (4) non-vaccinated, who also had COVID-19. The levels of IL-6 and sIL-6, LIF and sLIFr, leptin and adiponectin, NO, ADMA, SDMA were determined by ELISA technique.

In patients with MetS, changes in cytokine regulation towards proinflammatory reactions were revealed (an increase in blood IL-6 and leptin levels), which was most pronounced in MetS within first 30 days post-COVID, but with a number of changes which remained for 12 months (e.g., increased leptin concentration in blood). Vaccination against COVID-19 reduced the severity of pro-inflammatory changes in the sIL- 6r/ IL-6 and leptin/adiponectin systems towards protective adiponectin. However, the persistent increase in leptin was not canceled. When interpreting these results, no negative differences were revealed in the group of once vaccinated individuals with MetS, concerning the mentioned cytokine regulations of MetS over 1 year after COVID-19. The univariate, and then multifactorial correlation analysis between serum contents of sIL- 6r/ IL- 6, LIF/ sLIFr, adiponectin and leptin and the levels of vasoactive substances (NO, ADMA and SDMA), glycated hemoglobin, LDL has shown that the increased ratio of sIL-6r/IL-6 is an independent factor for the NO reduction of (r = 0.74, p < 0.01); an increase in sLIFr positively correlates with increase in glycated hemoglobin (r = 0.69, p < 0.01), and an association with increase of ADMA (r = 0.82, p < 0.001), leptin (in this model) are shown to be an independent factor of LDL increase (r = 0.69, p < 0.05).

Influence of «pre-COVID» modifiable factors, in particular, vaccination, is relevant in terms of reducing the likelihood of progression of pre-existing chronic diseases (hypertension, atherosclerosis, diabetes mellitus) in the persons with MetS after COVID-19 and has prospects for implementation into clinical practice.

The authors present a clinical case of rehabilitation after the development of Guillain–Barré syndrome, an acute autoimmune inflammatory polyradiculoneuropathy, in a patient who underwent a SARS CoV-2 infection. The patient previously manifested with severe comorbidities (arterial hypertension, hypercholesterolemia, type 2 diabetes mellitus, stenosing atherosclerosis of brachiocephalic arteries). A diagnostic panel of single nucleotide gene polymorphisms associated with risk factors of cardiovascular diseases, metabolic disorders, immunopathology, pharmacogenetics was applied using PCR-RT “Genetic Passport” test system, and the results were interpreted in order to predict potential complications, adverse drug reactions and the choice of biomarkers for preventive measures. We have compared clinical manifestations, comorbid background and the identified genotype features, as follows: minor homo- and heterozygous variants of ACE, AGT, CYP1A2, NOS3, PPARD, EDN, PALLD, SNX19 genes associated with predisposition to cardiovascular diseases, increasing the risk of dysregulation of blood pressure, development of endothelial dysfunction. The following gene variants were revealed: FXII, ITGA2, ITGB3, MTHFR, MTRR, MTR, PAI-1 that increase the risk of venous and arterial thrombosis, along with gene variants of ADRB3, FTO, INSIG2, KCNG11, LEP, PPARD, TCF7L2, ApoC3, PON1 associated with carbohydrate and lipid metabolism disorders; polymorphisms in the genes determining the immune response, i.e., IL4, IL6, IL8, IL10, CDH1, BDNF1, CRP, CCR5 (with del32 allele considered a risk factor of severe SARS-CoV-2), homozygous polymorphism of a gene of FCGR2 associated with risk of antigen-antibody-complement-mediated cytotoxicity, circulation arrest, deposition of immune complexes in endothelium of microvessels, decreased antithrombotic effects and increased procoagulant activity. Pharmacogenetic study revealed a variant of the CYP4F2 gene, a CYP2C19 gene polymorphism associated with delayed metabolism of a number of pharmaceuticals which requires higher drug dosage, or choosing a drug with a different mechanism of action; gene variants of CYP1A2, GSTP1, GSTT1 reducing efficiency of the cellular detoxification system; NAT2*5 and NAT2*6 variants determining a decrease in appropriate enzyme activities when administering a standard dose of drugs with slowdown of their detoxification, accumulation of toxic metabolites causing clinical adverse effects (hepatotoxicity, dyspepsia, lupus-like syndrome, polyneuritis). Based on the genotype that determines pathogenesis of the multifactorial pathology (including immune-mediated complications of COVID-19), a personalized approach is recommended to the patient, in terms of treatment and prevention of complications. On the basis of testing the biochemical, immunological and blood coagulation biomarkers, an adequate choice of pharmaceuticals is recommended for the patient.

With the accumulation of data on the evolving SARS-CoV-2 infection pandemic, it became clear that the risk factors for severe course of COVID-19 among the patients with primary immunodeficiency include disorders associated with dysregulation of the immune response. In this regard, it is of interest to identify possible predictors of the pronounced inflammatory reaction upon infection with coronavirus in the patients with general variable immune insufficiency. For this purpose, the dynamics of immune system parameters was studied in a patient with CVID who underwent a severe clinical variant of COVID-19, as an example of clinical case.

We present patient K., 49 years old, with CVID diagnosis verified at the age of 35 years who received regular replacement therapy with IVIG. He suffered from COVID-19 in severe form, received anti-cytokine therapy and an additional course of IVIG during the treatment. He was discharged in satisfactory condition. The quantitative and functional parameters of the T and B lineages of immune system were evaluated by flow cytofluorimetry during routine examinations before the infection and three months after the discharge from the hospital after COVID-19. It has been shown that, before the disease, there were changes in the parameters of B cells characteristic of CVID manifesting as a decrease in switched-memory B cells and plasmoblasts. Alterations in the T cell subsets were also revealed, as redistribution of the subpopulation composition towards T effectors with an increased cytolytic potential of these cells and a weakening of T cell suppression, due to decreased Treg in peripheral blood. After undergoing COVID-19, the patient developed specific IgM and IgG antibodies. The development of immune response was accompanied by an increase in the number of un-switched and switched memory B cells. At the same time, we have registered an increase in memory T cells ready for the proliferative response of T helper cells and Treg cells. The initial pro-inflammatory pattern of the T cell lineage system in our patient with CVID is explained by the implementation of the compensatory capabilities of the immune system, thus leading to activation of the cytolytic effects of cellular compartment in adaptive immune response, along with attenuation of the humoral component. Moreover, it is likely that these changes contributed to the clinical course of COVID-19 in this clinical case. Development of a specific humoral response to SARS-CoV-2 in a patient with CVID after a COVID-19 infection is accompanied by an increased proportion of memory B cells, coordinated dynamics of T cell suppression and activation parameters.

Incidence of chronic diseases is increased in the 21^st century due to prolonged life expectancy. Cardiovascular disease is the most common disorder worldwide, complicated with high morbidity and mortality. Upon increased prevalence of this disease, cardiac surgery has become an essential strategy for patients that do not respond to medications and other therapeutic procedures. Some potential complications in cardiac surgery affect kidneys, lung, brain over the postoperative period. Acute kidney injury (AKI) is considered a serious complication of cardiac surgery characterized by rapid loss of kidney function leading to acute increase in the serum creatinine concentration. AKI occurs in up to 30% of patients after cardiac surgery and is observed in 2% of the cases with isolated coronary artery bypass grafting (CABG). There are literature data concerning the patients with coronary artery disease after CABG in the presence of evolving atherosclerosis. Development of inflammation and dysadaptation of innate immunity was established in this work. An imbalance in the cytokine system contributes to the progression of endothelial dysfunction and may promote development of renal injury after CABG. Hypercytokinemia in AKI patients suggests involvement of innate immunity factors in the development of acute inflammatory response. The purpose of this article was to assess the innate immune response in the patients subjected to CABG with different duration of extracorporeal circulation. In the present study, 100 patients underwent CABG, all of whom were in the on-pump group. General clinical, functional, biochemical, instrumental, immunological and statistical methods were used in the work. After analyzing the data on the content of pro- and anti-inflammatory cytokines in blood serum of the patients with stage 1 and 2 AKI (KDIGO), depending on the duration of cardiopulmonary bypass surgery, we found that their dynamics corresponded to the standard pattern of changes after CABG groups and hyperproduction of pro- and anti-inflammatory cytokines in the groups with higher duration of cardiopulmonary bypass. The pathogenetic role of pro- and anti-inflammatory mediators remains unclear. We support the view that the clinical prognosis after cardiopulmonary bypass depends on the balance of pro- and anti-inflammatory cytokines.

In the modern world, inborn errors of immunity (IEIs), or primary immunodeficiencies (PIDs), are among of the main causes of childhood disability and mortality, determining the demographic state of mankind not only at present, but also in the future. In the Sverdlovsk Region over the past 5 years, there were about 30% of children who died from severe combined primary immunodeficiency. This retrospective study is devoted to the study of the nosological profile of mortality in the children with immune-dependent disorders in the Sverdlovsk Region, as well as to assess information significance of extrachromosomal circular DNA molecules (TREC and KREC) analysis. Some anamnestic data on the course of prenatal period in the current and previous pregnancies were considered the signs of suggested diagnosis of primary immunodeficiencies, i.e., threats of pregnancy loss at the early terms, documented cases of early childhood death, persistent viral and bacterial infections in the mother, complicated course of pregnancy in the mother, as well as some clinical manifestations, including fungal-bacterial sepsis, generalized viral infection, repair disorders, reduced physiological tolerance accompanied by autoimmune organ damage and uncontrolled systemic inflammation. The study demonstrated a wide range of nosological entities of innate errors of immunity in the structure of early childhood mortality, including both classical forms of primary immunodeficiencies and the disorders not directly related to innate errors of immunity, but those showing phenotypically pronounced immunodeficiency and their immediate role in statistical deviations. Among the main criteria that may presume possible presence of an immune-dependent pathology in the early neonatal period we considered the molecular markers of naive T and B cells (TREC and KREC, respectively) revealed in 70% of the cases studied, with, at least, one of these indexes found to be reduced. It is important to understand that primary immunodeficiencies are not as rare as previously thought. Therefore, it is necessary to carry out timely and high-quality diagnostics, in order to avoid unavoidable deaths.

The problem of acute osteomyelitis in children is of special importance among the inflammatory diseases of musculoskeletal system, due to infectious conditions arising in the body and spreading to the bone tissue caused by impaired immune regulation, first of all, concerning neutrophilic granulocytes. Of interest is studying the subsets of neutrophilic granulocytes arising when the cells are involved into the inflammatory process in acute pediatric osteomyelitis, and determining the opportinity to influence the level of receptor expression aiming for correction of their functions. The purpose of our study was to evaluate the effect of hexapeptide arginyl-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine on the altered phenotype of neutrophilic granulocytes in children with acute osteomyelitis using an in vitro experimental model. We examined the peripheral blood samples from children with acute hematogenous or post-traumatic osteomyelitis at the age of 10 to 17 years (n = 12) upon their admission to the hospital, and from healthy children (n = 7). Blood samples from children with acute osteomyelitis were incubated with hexapeptide (10^-6 g/L) for 60 min, at 37 °C. The content of neutrophilic granulocyte subsets (CD16⁺CD62L⁺CD11b⁺CD63^- and CD16⁺CD62L⁺CD11b⁺CD63⁺), expression density of appropriate membrane receptors were assessed by flow cytometric technique (FC 500 “Beckman Coulter”, USA). Phagocytic function was studied by assessing the degree of completed phagocytosis of S. aureus. It was found that, in acute osteomyelitis, a 8.5-fold increased proportion of activated CD16⁺CD62L⁺CD11b⁺CD63⁺NG subset with the CD16^brightCD62L^brightCD11b^brightCD63^dimNG phenotype was revealed, along with a decrease in the CD16⁺CD62L⁺CD11b⁺CD63^-NG subset and changes in the CD16^dimCD62L^brightCD11b^midCD63^- NG phenotype as compared with reference indexes of healthy children. At the same time, an increased number of actively phagocytic cells was noted, however, with decreased indexes characterizing capture and digestion of the bacterial antigen. In the in vitro experiments, the tested hexapeptide was shown to modulate the phenotypes of both studied subsets (CD16^brightCD62L^midCD11b^midCD63^- and CD16^midCD62L^midCD11b^midCD63^dimNG), thus promoting restoration of the receptor expression levels to the reference group values, as well as phagocytic activity, in terms of uptake and digestive capacity of microbial cells. Thus, the dominance of a diagnostically significant activated CD16⁺CD62L⁺CD11b⁺CD63⁺ neutrophil subset with the CD16^brightCD62L^brightCD11b^brightCD63^dimNG phenotype was found in acute osteomyelitis in children. The results of in vitro studies have shown that the hexapeptide caused phenotypic modulation of the CD16⁺CD62L⁺CD11b⁺CD63^- neutrophils, and CD16⁺CD62L⁺CD11b⁺CD63⁺NG subsets, along with recovery of their phagocytic activity. In the future, our results may provide a basis for the development of new effective therapeutic regimens.