This review presents data from the literature that provide insight into the role of the lipopolysaccharide (LPS) of the Gram-negative bacteria in pathogenesis of acute respiratory distress syndrome (ARDS) caused by the novel SARS-CoV-2 coronavirus infection. ARDS is a syndrome of severe respiratory failure, an acutely occurring diffuse inflammatory lesion of lung tissue that develops as a nonspecific reaction to various direct (aspiration, inhalation of toxic gases), and systemic (sepsis, polytrauma) damaging factors and leading to development of acute respiratory failure (ARF), due to impaired structure of the lung parenchyma, disturbances in vascular permeability, decreased area of ventilated lung tissue. ARDS from coronavirus infection appears to have worse outcomes than ARDS from other causes. Mortality from typical ARDS at the intensive care units and hospitals is 35.3% and 40.0%, respectively, while the lethality rates for COVID-19-associated ARDS, ranged from 26% to 61.5%. Among patients who underwent artificial ventilation of the lungs, the mortality rates can range from 65.7% to 94%. Risk factors for poor outcomes include, e.g., older age, presence of concomitant diseases such as hypertension, cardiovascular disease and diabetes mellitus; decreased number of lymphocytes, kidney injury, and increased D-dimer levels. Death with ARDS in COVID-19 occurs as a result of respiratory failure (53%), respiratory failure combined with heart failure (33%), myocardial damage and circulatory failure (7%), or death from an unknown cause. A large number of studies show that bacterial LPS is directly or indirectly involved in all pathogenetic links of ARDS caused by the SARS-CoV-2 virus, i.e., worsening the course of inflammatory lung diseases due to decreased level of angiotensin-converting enzyme 2 (ACE2); increasing generation of reactive oxygen species (ROS) via NADPH oxidase and subsequent inactivation of endothelial nitric oxide synthase (eNOS) and decreasing bioavailability of endothelial NO, thus leading to endothelial dysfunction; interacting with proteins of surfactants. SP-A and SP-D, promoting early destruction of the cellular monolayers and lowering surface tension, interact with soluble CD14 receptor, which also has a pro-inflammatory effect on epithelial and endothelial cells, leading to p38MAPK activation via TLR4 receptors, causing degradation of IêBá protein and subsequent translocation of p65 NF-êB into the nucleus, thus inducing transcription of IL-6 and adhesion molecules (ICAM-1, VCAM-1 and E-selectin), and, as shown by Petruk et al. (2020), causing direct binding to the viral S protein in combination with LPS, thus enhancing activation of nuclear factor-kappa B (NF-êB) in monocytic THP-1 cells and cytokine responses in mononuclear blood cells. These pathophysiological mechanisms require further in-depth study in order to understand the nature of changes that occur in the patients with new SARS-CoV-2 infection.

Dengue fever known from literary sources since the Qin dynasty (265-420) is caused in humans when bitten by Aedes mosquitoes infected with the dengue virus (DENV) and manifests as a flu-like disease. A feverish state can be accompanied by dyspeptic disorders (nausea, vomiting, diarrhea) and a rash. Approximately 1-2% of infections are clinically presented as the most severe form – it is dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) leading to 500 thousand annual hospitalizations with a mortality rate of about 5% in endemic areas.

Four genetically removed DENV serotypes (1, 2, 3, and 4) are classified as different types of viruses within the same antigen complex and have almost identical epidemiological features. In 2013 a new serotype DENV-5 was isolated.

Until the 1980s in most geographical regions of the world where dengue fever was registered only one or two viral serotypes were detected as an etiological agent of the disease. Over time there is an increase in the cocirculation of four types of viruses which can serve as a key indicator of their global spread. As the “traces” of the four DENV species overlap more and more the threat of severe disease increases due to the phenomenon of antibody-dependent of infection when re-infected with a heterologous viral serotype.

Development of specific dengue fever prevention has been underway since 1944 (since the discovery of viral agents of this disease) but the first and so far only licensed in 2015 tetravalent vaccine-Dengvaxia developed by the French pharmaceutical company Sanofi Pasteur has been effective in varying degrees of protection against infection with each of the viral serotypes and in addition dangerous for previously seronegative people. Research aimed at obtaining a safe and effective vaccine is continuing. Neutralizing monoclonal antibodies are a necessary tool for studying the antigenic structure of viral immunogens as base of prevention preparates against dengue fever.

Intermediate uveitis is among most severe forms of endogenous uveitis which is more common in young people, being characterized by minimal clinical manifestations at early stages of the disorder. A significant and, sometimes, irreversible decrease in visual acuity is associated with development of long-term complications of chronic cintermediate uveitis (CIU), i.e., complicating cataracts (in up to 57% of the cases), cystic maular edema developing at a frequency of up to 31%), as well as ophthalmic hypertension and glaucoma (up to 16% of the patients). The incidence rate of CIU is 1.5 per 100,000 per year. The eye, despite its high immune privilege, is susceptible to infectious and inflammatory diseases. Clinical and histopathological data suggest autoimmune origin of CIU associated with possible response to some endogenous antigen of unknown origin. The main effectors of inflammation in peripheral chorioretinal structures are CD4⁺T lymphocytes, which are found in paravasal infiltrates and vitreoretinal exudates in CIU. An important role in CIU pathogenesis is attributed to IL-6 and IL-8, TNFá, vascular endothelial growth factor (VEGF), and micro-RNAs, which show increased expression in most CIU patients. Impaired state of intestinal bacterial microbiome is a potential trigger of intraocular inflammation. Genetic predisposition for CIU was also revealed, due to polymorphisms of human leukocyte antigens and some other genes. It is necessary to expand and deepen our knowledge on the disease pathogenesis, in order to develop effective pharmacological treatment of CIU. The article is review of literature discussing the modern scientific ideas concerning etiology and mechanisms of the CIU development.

The MIC genes are located on chromosome 6 in the class I major histocompatibility complex (MHC) region and encode a membrane-bound stress-inducible protein that acts as a ligand to stimulate the NKG2D activating receptor expressed on the surface of the most natural killer cells (NK). Currently, 7 MIC loci are known, of which only MICA and MICB encode proteins and show a significant allelic polymorphism. The MIC gene polymorphism and their location in the HLA region suggests presence of some ethnic and populational differences for the gene frequencies, linkage disequilibrium of distinct loci, and distribution of HLA-MIC haplotypes, thus making it possible to get information on genetic relationship of human populations. The aim of our study was to assess immunogenetic profile of Russian population in Chelyabinsk Region based on the non-classical HLA loci, i.e., MICA and MICB, in the context of worldwide population data. Methods of the study included immunogenetic typing of 100 donors identifying themselves as Russians, taken from the Registry of Stem Cell Donors at the Chelyabinsk Regional Blood Transfusion Station. The 2 loci (MICA and MICB) were typed at basic resolution, using PCR technique with sequence-specific primers (SSP-PCR). Gene frequencies (GF) were calculated using programs for immunogenetic research (Arlequin 3.5).

Among Russian population from Chelyabinsk Region, the following characteristics of the MICA gene distributions were found: MICA *008, *002, *010, *009, frequency of > 7%; average frequencies, for MICA *004, *007, *018, *017; whereas MICA *027, *011, *006, *009:02, *049, *012, *016 was registered at a frequency of < 3.5%. MICB gene profile was as follows: MICB *005:02, *004, *002, *008 at a frequency of > 6%; at a frequency of 4% MICB *003, *005:03; MICB *005:01, * 005:04, * 009N, MICB *013, *014 at a frequency of

0.5%. As based on calculated genetic distances (according to Ney) for the MICA locus, the dendrogram and scatter plot were designed by means of multidimensional scaling (MDS) method, presenting location of 30 world populations, including data on Russians in Chelyabinsk Region. The smallest genetic distances between the population of Russians from Chelyabinsk Region and other world populations were found between the population of Slovenia, as well as the USA population of European origin. As based on scatterplot obtained by the MDS approach for MICA gene frequencies, using the data of cluster analysis, we have found that the population of Russians from Chelyabinsk Region belongs to a cluster of typical European populations.

The obtained patterns could be used for practical purposes to create a registry of stem cell donors in Russia. In addition, the data may be used as a control group for further research in the area of HLA-disease association, and could be also demanded by the specialists in population ethnogenesis.

The aim of our study was to specify the features of the HLA system in patients registered on the waiting list for kidney transplantation in the Republic of Bashkortostan. HLA-A, HLA-B, and HLA-DR phenotypes were assayed by polymerase chain reaction using PROTRANS and OLERUP SSP kits. The frequency of antigen occurence was determined as the percentage of individuals with the given antigen to the total number of examined individuals. To determine the patterns of distinct antigens within various HLA combinations, we determined maximal percentage of the antigen frequency in combination with other HLA. The largest number of patients on the waiting list suffered from chronic glomerulonephritis, followed by diabetes mellitus, chronic interstitial nephritis, chronic pyelonephritis and polycystic kidney disease. The occurrence frequency of various HLA and their combinations was established both among all the patients suffering from stage 5 chronic kidney disease, and among patients with regard to each nosological category, and the patterns of various HLA combinations were established. The data obtained have been compared with the study results of patients from the waiting lists for organ transplantation in other regions. HLA-A02 (similar to Brazil, Great Britain), HLA-DR07, HLA-DR04 (like as in Nepal, European population of Kazakhstan, Southern China), HLA-A24 (as in Nepal, Southern China), and combinations of HLA-A02-A03, HLA-A02-DR04, HLA-A02-DR01, HLA-A02-B07, HLA-A03-DR01, HLA-B35-DR01 were most common in the patients with chronic kidney disease which can be considered as risk factor for severe nephropathy. HLA-B15, HLA-B40, HLA-vA30, HLA-A32, HLA-B56, HLA-B60, HLA-DR10 were found at minimal frequency; as well as the following combinations: HLA-A01-A24-B08-DR17, HLA-A01-A68-DR07, HLAA24-B07-B13, HLA-A01-B08-B13, HLA-A02-B35-B38-DR01, HLA-A02-B50-B61-DR07, HLA-A01-B55-DR04, HLA-A02-B55-DR03, HLA-A24-B55-DR13, HLA-A01-A02-B08-DR03, HLA-A02-DR01-DR13. The following antigens were absent among our patients: HLA-A28 (similar to Kuwait); HLA-A11, HLA-A23, HLA-A28, HLA-A33, HLA-B46, HLA-B62;-DR03, HLA-DR14 (as in Kazakhstan); HLAA19, HLA-A43, HLA-B16, HLA-B21, HLA-B22, HLA-B83 and HLA-DR05 (as in Great Britain); HLAB14 (as in Brazil). The results obtained were either similar, or different from the literature data, both in terms of the most common HLA and their combinations with regard of special nephropathy types. The revealed differences can be explained by presence of population-specifical HLA features in the patients from different ethnic groups and living in different geographical areas. The found stable associative links between the disorders and HLA may contribute to better understanding of pathogenesis of the disorders, their early preclinical detection, evaluating risk for development of pathological conditions, thus allowing timely justification of preventive measures.

Laboratory tests are significant for the detection of immunopathological disorders in kidney transplantation. As a rule, the choice of tests is carried out individually and is based on the clinical characteristics and the presumptive diagnosis. Most often, in patients after kidney transplantation, atypical and not always standard changes in immunological parameters are observed, which is associated with a combination of many factors leading to different immune responses. All this served as the basis for typing immunological parameters in renal allograft recipients using one of the methods of system analysis – cluster analysis. Kidney transplantation was performed in 104 recipients. Immunological examination was performed on the 360^th day after the surgery. The following groups of recipients were identified: KTR1 – with primary graft function on the 7^th day and satisfactory graft function within a year, KTR2 – with renal graft dysfunction on the 7^th day and within a year. By means of cluster analysis, immunotypes of regulatory complexes were detected and characterized in various courses of the post-transplant period. To assess the immune response in allogeneic kidney transplantation, a set of immune cells with a phenotype should be determined: CD3⁺CD4⁺CD25^+highCD127^+low, CD3⁺CD4^-CD8^-, CD3⁺CD4⁺CD69⁺, CD3⁺CD16⁺CD56⁺, CD19⁺CD5⁺, LIN^-HLA-DR⁺CD11c^-CD123⁺, CD3⁺CD8⁺CD69⁺, CD3⁺CD4⁺CD8⁺, CD3⁺CD8⁺CD38⁺, CD19⁺CD86⁺, CD19⁺IgD⁺CD27^-, CD3^-CD16⁺CD56⁺, CD3⁺CD38⁺, CD14^+lowCD86⁺, LIN^-HLA-DR⁺CD11c⁺CD123^-. According to our data, the immunological cellular composition of the central point of clustering of the tolerogenic immunological complex is represented by regulatory CD3⁺CD4⁺CD25^+highCD127^+low and double-negative CD3⁺CD4^-CD8^-T lymphocytes. The composition of the central point of clustering of the hyperergic immunological complex is represented by the cooperation of CD3⁺CD8⁺CD69⁺ and CD3⁺CD4⁺CD8⁺ cells. The structure of the tolerogenic immune response in patients after kidney transplantation is based on intercellular interactions, which has a hierarchical system, the basis of which is represented by the cooperation of regulatory cells CD3⁺CD4⁺CD25^+highCD127^+low, CD3⁺CD4^-CD8^-, CD3⁺CD4⁺CD69⁺, CD3⁺CD16⁺CD56⁺, CD19⁺CD5⁺, LIN^-HLA-DR⁺CD11c^-CD123⁺. The hyperergic variant of the immune response in renal allograft transplantation is based on excessive activation of the following links of the immune response: CD3⁺CD8⁺CD38⁺, CD19⁺CD86⁺, CD3⁺CD38⁺, LIN^-HLADR⁺CD11c⁺CD123^-, CD19⁺IgD⁺CD27^-, CD3^-CD16⁺CD56⁺, CD3⁺CD8⁺CD69⁺ and CD14^+lowCD86⁺. The detected immunotypes will make it possible to implement a personalized approach to the diagnosis and treatment of patients with various types of immune response in kidney transplantation.

Choroidal melanoma is a malignant tumor characterized by early metastasis and poor vital prognosis. Prognostic indexes for the tumor development are of importance, depending on various factors and making it possible to optimize therapeutic measures. Usage of present models for prediction of the uveal melanoma course enables optimal management of the patients with a malignant tumor upon primary admission, and to perform maximally efficient counseling. So far, however, a complex of clinical, morphometric and immunological indexes predictive for unfavorable course of initial choroidal melanoma following the eye-saving treatment remains not fully determined. Our purpose was to create a prognostic model for initial choroidal melanoma after eye-saving treatment, basing on clinical, morphometric and immunological parameters.

We have performed examination and treatment of 31 patients with small choroidal melanoma (53.7 to 12.2 years old). To perform the analysis, we used clinical data (age, decreased vision, tumor localization, degree of pigmentation, presence of hemorrhages, orange pigmentation), morphometric indexes (intra- and subretinal exudate and disorganization of pigment of the retinal epithelium) and immunological parameters (serum levels of pro-inflammatory, pro-angiogenic, proliferative, metastasis-causing cytokines). Selection of variables for this model was based on assessment of significant differences between the groups with chorio-retinal scar (n = 14) and residual tumor and/or continued tumor growth (n = 17).

Multivariate analysis with conditional exclusion of variables revealed prognostic significance with four markers: morphometric, i.e., disorganization of the pigment in retinal pigment epithelium – Z₁ (r_s = 0.455); immunological, increased blood serum concentration of hepatocyte growth factor (HGF) – Z₂ (r_s = 0.377); level of pro-inflammatory chemokine RANTES – Z₃ (r_s = 0.362), content of transforming growth factor (TGF-2â) – Z₄ (r_s = 0.431). A formula was calculated where P (z) is the value of the logistic function; Z, linear combination of symptoms; b_o , intercept (free term), b_{i – regression coefficients for parameters Zi.}

P (z) = 1 : 1 + e – b₀– b₁z₁– b₂z₂– b₃z₃– b₄z₄

The logistic function increases monotonically and takes the values from 0 to 1 for any b and Z values [P∈ (0;1)]. If P (Z) is under the cutoff value, chorioretinal scar prognosis is predicted, at the higher values, a residual tumor or continued growth is expected. In ROC analysis, the area under the curve with this model was 0.891±0.11, thus providing good predictive quality.

Usage of the predictive model is a possible solution for planning and correcting treatment strategy in the patients with small choroidal melanoma, in order to minimize complications and errors, and to ensure control of treatment.

Obstructive jaundice caused by cholangiocarcinoma takes a special place among malignant disorders and surgical pathology in Russia. Involvement of nonspecific immunity and the role of neutrophils in carcinogenesis are ambiguously evaluated. The aim of this study was to study functional activity of peripheral blood neutrophilic granulocytes and their phenotype in obstructive jaundice caused by cholangiocarcinoma. The study included 56 patients with obstructive jaundice associated with cholangiocarcinoma at the T_{2- 3}N_{0- 1}M₀ stage (clinical stages II-III), and 90 apparently healthy volunteers of similar age group. Neutrophilic granulocytes were isolated from peripheral blood by means of double-density Ficoll-Urografin gradient.

Venous blood was collected in patients into vacutainers with heparin upon admission to the hospital, before the surgery was performed. Spontaneous cytokine production (IL-8, IFNá) was determined by enzyme-linked immunosorbent assay using Vector-Best diagnostic kits. To assess phagocytic activity of neutrophilic granulocytes, the phagocytic index (according to Hamburger), number of phagocytes (according to Wright) and the index of completed phagocytosis (according to Rudik, 2006) were calculated. Immunophenotyping of neutrophilic granulocytes was carried out using an FC500 flow cytometer (Beckman Coulter, USA) with monoclonal antibodies to CD11b⁺, CD16⁺, CD95⁺. The results were statistically analyzed using the Statistica v.12.0 software (StatSoft Inc., USA). To assess intergroup differences, the nonparametric Kruskal-Wallis tests (for three or more comparison groups) and Mann-Whitney tests (for pairwise comparison) were used. Comparison of groups for a qualitative binary trait was carried out using the two-sided Fisher’s exact test. Data are presented as Median (25 quartile-75 quartile).

The study of the functional activity of peripheral blood neutrophiles in obstructive jaundice patients caused by cholangiocarcinoma revealed an increase in their relative and absolute number, increased phagocytic index and decreased phagocytic number of neutrophilic granulocytes, increased expression of CD11b⁺, CD16⁺, CD95⁺ immunological markers. The changes in neutrophil secretory activity were characterized by a decrease in cytokine production (IL-2, IFNá). An increase in functional activity of neutrophilic granulocytes, along with a decrease in their cytokine production suggests that, in obstructive jaundice observed in cholangiocarcinoma at clinical stage T_2-3N_0-1M₀, an equilibrium stage is revealed between the cells of immune system and malignant tumor.

Rhinitis is a socially significant and widespread disease. Often, various forms of rhinitis are combined, and thus cause severe clinical manifestations, insufficient effectiveness of drug treatment, as well as difficulties in differential diagnosis. It is known that a significant number of patients have a combination of allergic rhinitis (AR) with chronic rhinosinusitis of bacterial etiology. This condition is based on a chronic multifactorial inflammatory process of the nasal mucosa, which determines the steady progression of the disease. Of interest is the study of a number of allergo-immunological parameters in nasal secretions in order to assess local inflammation and changes in mucosal immunity in allergic rhinitis in combination with chronic rhinosinusitis of bacterial etiology (AR with HRSBE). Mucosal immunity and biological mediators determine local inflammation and pathophysiological response to etiological factors in the immunopathogenesis of AR with CRSBE. The work carried out the determination of the level of cytokines: IL-4, IL-10, TGF-â1, IFNã spontaneous and induced; immunoglobulins: IgA, IgM, IgG, sIgA in nasal secretions; leukotrienes: LT C4/ D4/E4 and LTB4 in plasma and total IgE in serum in patients with AR with moderate-severity HRSBE without exacerbation. It has been shown that the leading role in the formation of the inflammatory process in AR with CRSBE belongs to cytokines: IL-4, IL-10, TGF-â; immunoglobulins: IgM, sIgA; leukotrienes: LT C4/D4/E4 and LTB4 and total IgE. Induced cytokine production largely reflects the reserve capabilities of immunocompetent cells in response to the action of a pathogenic factor. The results obtained are associated with the persistent course of allergic and infectious inflammation and the progression of the disease. Thus, cytokines: IL-4, IL-10, TGF-â1; immunoglobulins: IgM, sIgA, IgE total and LT C4/D4/E4 and LTB4 make a significant contribution to pathogenetic mechanisms, determining the clinical course of AR with CRSBE, and can serve as biological markers of the activity of the pathological process. Undoubtedly, the immune mechanisms in the combined pathological inflammatory reaction from the mucosa in AR with HRSBE are complex and multifaceted. A personalized approach to the treatment of patients with AR with CRSBE is determined by the severity and intensity of the inflammatory reaction, as well as mucosal mucosal immunity disorders. The study of the role and significance of the production of leading cytokines, immunoglobulins in nasal secretions, as well as leukotrienes and total IgE in the blood will help the doctor in determining the tactics and duration of pharmacotherapy.

Chronic obstructive pulmonary disease (COPD) is considered a heterogeneous disorder exhibiting different phenotypes. Chronic systemic inflammation is an important link in the COPD pathogenesis. The studies of immune response in the context of clinical and functional phenotypes seems relevant. Objective of our work was to study the features of immune response in clinical and functional phenotypes of COPD.

Eighty-three COPD patients of different severity grade and 22 apparently healthy volunteers were examined. After determining the COPD phenotype by clinical and functional signs, the patients were divided in two groups, i.e., 38 subjects with bronchitis, and 45 patients with emphysematous phenotype. Clinical, functional and laboratory research was carried out in standard mode. Static lung volumes and respiratory capacities were investigated, i.e., functional residual capacity, residual lung volume, total lung capacity, bronchial resistance on inspiration and expiration to assess phenotype of the disease. Subpopulations of Th1 and Th17 lymphocytes were determined by the level of blood serum cytokines, tumor necrosis factor (TNFá), interleukins (IL) IL-4, IL-10, IL-17A, IFNã).

Different features of immune response were revealed in bronchitic and emphysematous phenotypes of the COPD patients. Activation of inflammatory process with differentiation of naive T lymphocytes along the Th1-dependent pathway was found in 68% of cases with bronchitis and 16% of patients with emphysematous phenotypes. As compared with control group, the patients showed a statistically significant increase in the level of TNFá, IFNã, along with decrease in IL-4. Development of immune response by the Th17 type was found in 32% of cases with bronchitis, and 84% of cases with emphysematous phenotypes. Its emergence was associated with increased IL-17A and IL-10 levels, and a decrease in IFNã/IL-17A compared to the control. Differentiation of T helper cells towards Th1 pathway of immune response has been shown to predominate in bronchitic phenotype and at early stages of the disease. The Th17 type of immune response prevailed with increasing severity of the disorder. In emphysematous phenotype of COPD, the Th17-pathway of immune response develops at early stages of the disease. Some relationships are revealed between the systemic inflammation indexes and functional parameters of external respiration. An inverse relationship between TNFá and the OOL/OEL ratio in Th1 type of immune response has been shown. A direct correlation was found between the level of IL-17A and the parameters of external respiration function (FEV1, FEV1/FVC), as well as between IFNã/IL-17A and functional residual capacity in Th17 type of immune response.

The type of immune response is associated with severity of the disease, as well with clinical and functional phenotype of COPD. Progression of the disease, broncho-obstructive disorders and hyperinflation are associated with increased levels of cytokines that provide cell polarization along the Th17 pathway. Determination of COPD phenotype and the type of immune response already at an early stage of the disease will enable prediction of its course and justify the choice of phenotype-oriented therapy.

Clinical prognosis in malignant tumors` is among the most challenging problems of contemporary medicine. It is thought to depend on both biologic properties of tumor cells and patients` immune status. The features of tumor cells and immune reactions are closely interrelated and mutually conditioned. Therefore, possible application of their characteristics as prognostic markers is of great fundamental and clinical importance. The aim of our study is to find out the most significant immune factors for prognosis of colorectal cancer (CRC) based on estimation of local and system immune factors, and some characteristics of tumor cells in the patients at various stages of the disease and different clinical course. Cellular factors of immunity and cytokines were studied in blood and tumor tissue of 299 patients with colorectal cancer (stages I-IV). Malignant cells expressing stem cell markers CSC), MHC and PDL-1 molecules were also counted in the tumor tissue. Blood samples were drawn prior to operation, and tissue samples were taken during surgery being the 1^st line of treatment. Flow cytometry techniques (FCM), immunohistochemistry (IHC), and ELISA approach were employed. We have compared data on the patients at different CRC stages (with or without local and distant metastases), as well as cases with different course of the disease (evolving distant metastases and fatal outcome during period of observation). Our results demonstrated increased amounts of NK-cells and IL-6 concentration, along with decreased percentage of blood CD4⁺ cells in the patients with local metastases, as well as higher CSC numbers in malignant tissue. The initially generalized CRC cases with distant metastases were characterized by high levels of blood IL-6, monocytes and granulocytes responding to fMLF, while in tumor tissue elevated amounts of NKT, CSC and decreased expression of MHC and PDL-1 were observed on tumor cells, like as lower PD-1/ PDL-1 expression on tumor-infiltrating lymhocytes. Unfavorable CRC dynamics, i.e., metastasizing during the observation period was preceded by increased levels of IL-10 in blood, NK cells with poor cytotoxicity, monocytes and granulocytes responding to fMLF. In tumor tissue, overexpression of CSC markers and hypo-expression of MHC on tumor cells were noted. Fatal outcome was preceded by elevation of blood IL-6levels, tissue levels of NKТ and CSC percentages, along with decreased NK cells subset (CD16^dimCD56^bright) in blood, and decline of MHC-expressing cells in the tumor. Thus, high blood levels of IL-6 and IL-10, fMLF-responding monocytes and granulocytes, as well as elevated amounts of NKT and CSC, hypo-expression of MHC in tumor tissue could be considered prognostic markers of unfavorable course in CRC patients. Decrease of PD-1/PDL-1 expression on tumor cells and lymphocytes from its microenvironment in advanced CRC is of special attention, because checkpoint inhibitors are prescribed in such cases.

Understanding the pathogenetic mechanism of development and identifying trigger markers of the disease will significantly increase the efficiency of pre-nosological diagnosis and medical follow-up of patients. In this case, one should take into account the role of mutations in cytokine genes, which affect their biochemical activity and production level. The objective of the study was to investigate the role of mediators of acute and chronic inflammation (IL-17A, IL-1â, TNFá and IL-4), the ratio of natural killer cell subpopulations (CD56^hiCD16^-/CD56^loCD16⁺) in pathogenesis of coronary atherosclerosis resulting into coronary heart disease.

To analyze the results, an integrated approach was used, including molecular genetic methods such as polymerase chain reaction, typing of single-nucleotide substitutions in cytokine genes, isolation and cultivation of peripheral blood mononuclear cells, assessment of spontaneous and in vitro-induced production of immune system mediators, enzyme-linked immunosorbent assay, cytotoxic test, flow cytometry with monoclonal antibodies (Beckman Coulter, USA) to CD16, CD56 NK markers.

The study included 130 residents of the North Caucasus, including the patients (n = 62) treated at the Cardiology Department of the Adyghe Republican Clinical Hospital (ARCB) with a verified diagnosis of ischemic heart disease (IHD), and a control group (n = 68), represented by unrelated healthy donors.

Overexpression of cytokines in IHD patients was associated with distinct single nucleotide substitutions in certain genes. Studying a group of residents from the Republic of Adygeya, the authors experimentally established that harboring the 511C allele of the IL-1â gene (p < 0.0004; OR = 4.67), A197A of the IL-17A gene genotype (p < 0.04; OR = 3.88), G308 SNP of TNFá gene (p < 0.01; OR = 3.41), and 589T variant of IL-4 gene (p < 0.04; OR = 2.45) are associated with hyperproduction of the first-wave inflammatory mediators that increase the risk of developing ischemic heart disease. In atherosclerosis and associated cardiovascular diseases, we have noted a significant decrease in spontaneous and induced activity of natural killer cells involved in the utilization of “foamy cells”. The NK activity of peripheral blood mononuclear cell in patients with coronary heart disease is significantly reduced. In the IHD patients, an imbalance of phenotypically and functionally different CD56^hiCD16^-/CD56^loCD16⁺ NK subpopulations with a predominance of CD56^hiCD16^- phenotype were revealed. Conclusions: Immuno-inflammatory mechanisms of evolving coronary atherosclerosis are associated with single-nucleotide substitutions, i.e., polymorphisms in the promoter regions of the IL-17A (G197A), IL-1 â (T511C), and TNFá (G308A), the known mediators of acute and chronic inflammation.

Genetically determined overexpression of IL-17A, IL-1â, and TNFá, confirmed in experiments on evaluation of spontaneous and stimulated cytokine production in patients with CHD, together with reduced NK activity of РВМС, due to predominance of CD56^hiCD16^-, a subpopulation with high cytokine production, manifested by an increased pro-inflammatory component that triggers and provides long-term support to pathophysiological processes of atherosclerosis.

Chronic rhinosinusitis with nasal polyps (CRSP) is a heterogenous disease. We have earlier detected differences in severity of clinical manifestations, cellular infiltration degree shown in nasal polyps, of eosinophil-to-neutrophil ratio, efficacy of intranasal glucocorticosteroid baseline therapy, and various inflammatory patterns for several cytokines on the mRNA expression level in different phenotypes with isolated CRSP cases, CRSP associated with respiratory allergy (RA), or non-allergic bronchial asthma.

The purpose of this work was to study the cytokines of TGF-â family in the tissues of nasal polyps in patients with different CRSP phenotypes. The research involved 292 patients suffering from CRSP divided into 3 phenotypic groups. Group I consisted of patients with isolated CRSP free of associated BA and/or sensitization to atopic allergens. Group II included patients with CRSP combined with respiratory allergy and was further divided into two subgroups. I.e., Group 2a comprised patients with CRSP, allergic BA (aBA), and allergic rhinitis (AR), while the patients with CRSP, AR, and non-allergic BA were placed to the group 2b. The patients suffering from CRSP complicated with non-allergic BA were allocated to the group III. The patients with hypertrophic rhinitis served as control. The levels of TGF-â1, TGF-â2, and TGF-â3 proteins (pg/mg) were measured by means of multiplex immunoassay approach in supernates of tissue homogenates from nasal polyps removed by surgery, and in posterior parts of inferior nasal conchae. The total protein level was determined in tissue supernatant, with cytokine contents recalculated for the mg/ml protein concentration for standardization of measurements.

In the control group, trace concentrations of all three growth factors were detected. Significant difference in protein contents was found for the studied cytokines, depending on CRSP phenotype. The levels of TGF-â1 and TGF-â2 were statistically lower in isolated CRSP than in other groups of comorbid CRSP patients. TGF-â1 and TGF-â2 concentrations were significantly lower in CRSP + allergic BA group IIa than in CRSP + nonallergic BA and CRSP + RA groups. The amount of TGF-â3 cytokine was maximal in CRSP + non-allergic BA group III compared to the patients with isolated CRSP of group I and CRSP + non-allergic BA group 2a.

Conclusions.

1. The high level of all three TGF-â isoforms in patients with CRSP compared to the control group suggested a high potential of mucous membranes of paranasal sinuses for active tissue remodeling followed by nasal polype formation.
2. Different mechanisms were presumed for development of local pathological process in different clinical phenotypes of CRSP, depending on the comorbid pathology, especially, BA or respiratory disorders.
3. Minimal TGF-â1 and TGF-â2 levels were detected in isolated CRSP.
4. The highest concentrations of TGF-â1, TGF-â2, and TGF-â3 were discovered in the patients with CRSP accompanied by non-allergic BA as compared to the groups with isolated CRSP and CRSP+allergic BA.

5. Determination of TGF-â1, TGF-â2, and TGF-â3 levels can serve as an additional criterion for differentiating between the mechanisms of mucous membrane damage in local pathological process in tissues of comorbid patients with different CRSP phenotypes.

Cytokines play an integral role in pathogenesis of age-related macular degeneration (AMD). Of particular interest are the late stages of this disease, which causes progressive visual impairment. Therapy-induced effects of post-treatment cytokine concentrations also need to be studied, both at long and short observation terms. These studies are of vital importance if the atrophy occurs during antiangiogenic therapy. Our purpose was to study an array of 45 cytokines, in blood serum (BS) and lacrimal liquid (LL) of the patients with wet and atrophic AMD.

The study included 70 people (85 eyes) with stage 3-4 AMD according to AREDS. Depending on the form of AMD, 3 groups were discerned: I group (n = 24) included the patients with “geographic atrophy”; II group (n = 22), consisted of the patients with macular atrophy treated with antiangiogenic therapy of wet AMD; III group (n = 24), comprised the patients with a wet AMD who did not previously receive the treatment. Control group consisted of healthy volunteers (n = 25). All the groups were comparable for age and gender. The patients underwent a comprehensive ophthalmological examination to make a diagnosis. A multiplex study of the local (in the BS) and systemic (in the LL) cytokine status was carried out on a MAGPIX device (platform хMAP, Luminex Corporation, USA) in the Luminexx PONENT 3.1 software, using Procarta Plex kits (eBioscience, Austria). We determined 45 cytokines causing various biological effects, i.e., IL-1á, IL-1â, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-18, IL-21, IL-22, IL-23, IL-27, IL-31, IFNá, IFNã, IL-8/CXCL8, IP-10/CXCL10, SDF-1á/CXCL12, MCP-1/CCL2, MIP-1á/CCL3, MIP-1â/ CCL4, RANTES/CCL5, Eotaxin/CCL11, TNFá, TNFâ, GM-CSF, VEGF-A, VEGF-D, FGF-2, EGF, PDGF-BB, HGF, SCF, GRO-á, NGF-â, BDNF, LIF, PIGF-1.

Screening of a wide range of cytokines showing various biological effects was carried out in BS and LL of patients with atrophic and wet forms of AMD. It has been shown that the late stages of the disease are associated with local and systemic changes of pro / anti-inflammatory mediators (IL-1â, IL-1ra, IL-18, LIF), chemoattractant cytokines (IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, MIP-1á/CCL3, MIP-1â/ CCL4, RANTES/CCL5, Eotaxin/CCL11), hematopoietic regulators (IL-7), and growth factors with known angiogenic activity (EGF, HGF, PDGF-BB, VEGF-A). Altered concentrations of numerous chemokines, e.g., IP-10/CXCL10, SDF-1á/CXCL12, MIP-1á/CCL3, MIP-1â/CCL4, RANTES/CCL5 and Eotaxin/CCL11 (p < 0.05) in BS of the patients with atrophic and wet AMD may be of interest for the search of biomarkers associated with various clinical phenotypes of the disease and may be also helpful for development of new therapeutic strategies.

Priming and activation mediated by cytokines cause transient reactions of actin polymerization in neutrophils (Nph), expansion and softening of cells, changes in receptor status, phagocytic ability, and generation of extracellular traps (NET), thus ultimately determining pro- or antitumor phenotype of Nph. To assess the effects of pro-inflammatory cytokines on membrane rigidity and morphofunctional state of neutrophils in benign tumors and ovarian cancer, the levels of circulating cytokines (IL-2, IL-18, MCP-1, TIMP-1), expression of adhesion markers (CD11b), degranulation (CD63), as well as FcãRIIIb receptors promoting phagocytosis (CD16). Ability of neutrophils to phagocytosis and the formation of NET was determined. Statistical evaluation of the data obtained was carried out using Statistica 13.0, Jamovi 1.6.5.0 software. An increase in membrane rigidity was found in benign and malignant ovarian tumors. In benign ovarian tumors, phagocytic activity and expression of CD11b were enhanced. In ovarian cancer, the number of CD11b⁺Nph and CD63⁺Nph were increased. Meaanwhile, at initial cancer stage, the ability to form NET predominates, and phagocytic activity increases with advancing ovarian cancer. Serum MCP-1 levels are elevated in benign tumors and at all stages of ovarian cancer. IL-2 is elevated at early stage and in advanced ovarian cancer. The level of IL-18 and TIMP-1 in the serum of patients with benign ovarian tumor did not differ significantly from the norm. Using multiple regression approach, the dependence of neutrophil membrane rigidity on the levels of circulating IL-2, TIMP-1, MCP-1, IL-18 was revealed in benign ovarian tumors, and a direct correlation was found between the neutrophil membrane rigidity and CD11b expression. Only IL-2 was associated with neutrophil membrane rigidity in ovarian cancer. At the same time, the rigidity of the neutrophil membrane directly correlated with CD16, CD63, expression like as with phagocytic index and inversely correlates with the number of traps. A combination of IL-2, MCP-1 and membrane rigidity of circulating neutrophils (based on multivariate analysis) could be used for differential diagnosis of ovarian cancer. Thus, in a benign ovarian tumor, circulating proinflammatory cytokines are associated with increased rigidity of neutrophil membrane and increase in their adhesion capacity. In ovarian cancer, only IL-2 is associated with altered rigidity of circulating neutrophils. Increase of the latter index is accompanied by elevated phagocytic activity and decreased ability to form NET.

Chronic urticaria is a polyetiological disease proceeding by various immunological and non-immunological (pseudo-allergic) mechanisms. Food intolerance is a distinct type of pseudo-allergies, manifesting, e.g., with histamine intolerance syndrome, caused by imbalance between the histamine accumulation and the ability to degrade it. The purpose of this article was to summarize results of recent studies, to discuss the difficulties of diagnosing this pathology, which primarily depends on the degree of impaired histamine degradation under the influence of diamine oxidase. Diamine oxidase is the main enzyme required for histamine destruction in the intestines, being synthesized by apical enterocytes. The review draws attention to the reasons leading to increased level of histamine not only with consumed food, given its different concentration in the same food products, depending, for example, on their processing and storage, but also with suppressing activity of the enzymes required for metabolism of histamine by various food additives, by the influence of microbiota. The results of studies in which the levels of histamine and/or diamine oxidase activity were determined, which depend on adherence to the diet confirming the association of diamine oxidase with the symptoms of histamine intolerance. According to most studies, the compliance with diet led to increased level of diamine oxidase. However, in some studies, no changes in the activity of this enzyme were found. There are several studies that have evaluated the levels of diamine oxidase in patients with true allergies. Moreover, some authors, in addition to adherence to the diet, evaluated the effectiveness of drugs containing diamine oxidase in patients with low levels of this enzyme in blood serum. The workers also confirm high proportion of histamine intolerance syndrome among various food reactions, suggesting a need for differential diagnosis with other non-immune reactions, including disorders of gastrointestinal tract and psychosomatic reactions. Thus, all the authors confirm the need for laboratory diagnosis of histamine intolerance syndrome, since this will not only increase the efficiency of dietary adherence, but also substantiate the usage of drugs containing diamine oxidase, which will improve quality of life in these cohorts. However, these patients are still treated with low-histamine diets. The literature data confirm the opportunity of using this histamine degradation enzyme as a biological marker of histamine intolerance syndrome, and recommend its assays for inclusion into the diagnostic algorithm for chronic urticaria.

Pneumofibrosis is a pathological outcome of pulmonary tissue inflammation. It can complicate any lung and bronchial disorder. The mitochondrial membrane potential reflects functional state of immunocompetent blood cells that influence progression of a chronic inflammatory process. The aim of this work was to study the features of mitochondrial membrane potential (MMP) of immunocompetent blood cells in children with chronic nonspecific lung diseases (CNPD), accompanied by pneumofibrosis. We have examined 79 children with CNPD manifesting with symptoms of focal pneumofibrosis. The group of patients included children with congenital lung malformations (43%), consequences of bronchopulmonary dysplasia (41%), chronic bronchitis (10%), post-pneumonic pulmonary fibrosis (6%). The average age of children was 6.5±1.2 years, including 43 boys (54%) and 36 girls (46%). The comparison group included 46 children with COPD without signs of pulmonary fibrosis, the control group consisted of 30 apparently healthy children. The contents of cells with reduced MMP among lymphocytes, monocytes, and granulocytes in peripheral blood was determined with JC-1 dye, using the BD FACSCalibur instrument and Cell Quest Pro software (Becton Dickinson, USA). The proportion of lymphocytes with reduced MMP in patients with COPD was similar in the children of the main and comparison group, exceeding the indexes of the control group by 1.7 times (p < 0.001). Decreased MMP of granulocytes in children with pneumofibrosis was detected 1.9 times more often than in children with fibrosis-free CNPD cases (p < 0.05), and 3.4 times more common than in children from the control group (p < 0.001). Monocytes with reduced MMM in children with pulmonary fibrosis were detected 2 times more often than in children with COPD without fibrosis (p < 0.05), and 7.3 times more frequent than in the control group (p < 0.001). The changes were more expressed in children during exacerbation of the disease. The revealed features suggest a decreased level of metabolic activity of blood cells, thus, probably, presenting an immunopathogenetic basis for development of pneumofibrosis.

Features of expression of differentiation markers of peripheral blood lymphocytes were studied by flow cytofluorimetry in combination with clinical manifestations in 30 adult patients (12 men and 18 women, mean age 37.5±12.3 years) with the established diagnosis of сommon variable immunodeficiency (CVID). The examination of patients was carried out in the period of obvious absence of infectious and inflammatory diseases. It was found that the dominant immunophenotype in adult patients with СVID is an increase in the blood content of T cytotoxic lymphocytes (CD3⁺CD8⁺) with high expression of activation markers HLA- DR⁺ and CD38⁺ and a decrease in isotype-switched B lymphocytes IgD^-27⁺ (in almost 100% of the examined individuals). The maximum degree of increase in the number of T killers was observed in patients with a low level of B lymphocytes (CD19⁺ less than 6%, p = 0.005) and a minimum concentration of IgG in the blood serum (less than 2 g/l, p = 0.02). The content of isotype-switched B cells correlated with the level of IgG, as well as the total concentration of serum immunoglobulins A, M and G (p = 0.02; p = 0.003). In adult СVID patients with the combined clinical phenotype “infectious syndrome + autoimmune disease”, the content of isotype-switched B lymphocytes, IgG and the total concentration of Ig in the blood is significantly lower (p = 0.04; p = 0.03 and p = 0.02), and activated T killers with HLA-DR⁺ and CD38⁺ expression are higher (p_% = 0.01; r_abs = 0.02 and p_% = 0.004; r_abs = 0.001, respectively) compared to patients with isolated infectious – inflammatory syndrome. We also found that among patients with the lowest number of isotype-switched IgD^- 27⁺ B cells (less than 5%) and serum IgG concentration (less than 2 g/l), the incidence of lymphoproliferative syndrome is higher (p = 0.04 and p = 0.01, respectively). Thus, the low content of isotype-switched memory B lymphocytes in peripheral blood is most characteristic of patients with a more severe clinical phenotype of СVID.

At the present time, vast majority of human population lacks immunity against orthopoxvirus infections caused by variola (smallpox), monkeypox, cowpox, or buffalopox viruses. More and more mass outbreaks of orthopoxvirus infections are yearly registered among humans on different continents. To prevent transition of these outbreaks to widespread epidemics, we should develop appropriate immunoprophylaxis strategies. Currently, massive usage of the classic live vaccine based on vaccinia virus is not acceptable, due to its high reactogenicity. Therefore, it is necessary to develop the variants of vaccinia virus with reduced virulence and increased immunogenicity/protectivity. The aim of this work was to study protective effects against a lethal orthopoxvirus infection occuring after low-dose immunization of mice with vaccinia virus variants, i.e., carrying mutant A34R gene causing increased production of extracellular virions, or a A35R gene deletion encoding protein product inhibiting antigen presentation by the major histocompatibility complex class II. The LIVP viral strain used in Russia as a smallpox vaccine, and its recombinant variants (LIVP-A34R*, LIVP-dA35R and LIVP-A34R*-dA35R) were compared with intranasal or intradermal immunization of BALB/c mice at the doses of 10⁵ or 10³ PFU. 28 days following administration of viral preparations (experimental groups) or saline (control groups), the mice underwent intravital blood sampling from retroorbital venous sinus. The levels of virion-specific antibodies were determined in individual serum samples by enzyme immunoassay. On the day 30 of experiment, the mice were infected with cowpox virus at a dose of 32 LD₅₀, which caused total death of control mice on days 6-10. In the groups immunized with the studied viruses at a dose of 10⁵ PFU, all the animals survived, regardless of strain, or immunization method. Upon intradermal immunization (10³ PFU) of mice immunized with the original LIVP virus, 83% of the animals survived, whereas all mutant strains of the vaccinia virus provided 100% protection of the mice from subsequent cowpox virus infection. Intranasal immunization of mice at a dose of 10³ PFU with LIVP strain protected only 33% of animals from lethal infection with cowpox virus, while the mutant strains LIVP-A34R* and LIVP-A34R*-dA35R provided 67% protection, and the LIVP-dA35R strain has resqued 75% of the mice. The studied mutant vaccinia viruses can be considered not only new candidate vaccines against smallpox and other human orthopoxvirus infections, but also as vector platforms for creating live multivalent vaccines against other infectious diseases.