MICA and MICB molecules, MHC class I chain-related proteins, are expressed on the membranes of damaged, transformed or infected cells. These glycoproteins bind to the NKG2D receptor of NK cells, resulting in their activation and cytotoxic response against MICA- and/or MICB-expressing cells. Expression of NKG2D receptor ligands allows the elimination of tumor and damaged cells. Soluble forms of MICA/B proteins are produced as a result of protein cleavage. Binding of soluble ligands to NKG2D receptors causes their internalization and degradation, leading to a decrease in NK cell activity. Malignant growth of gastrointestinal tissues, pancreas, liver, kidney, lung, skin, and blood cancers is accompanied by increased concentration of soluble MICA/B in blood plasma of the patients. High concentrations of these proteins are associated with lower overall and recurrence-free survival in the patients. Soluble MICA/B contribute to immunosuppressive tumor microenvironment, and increase in their plasma contents is considered an index of tumor escape from the immune surveillance. The role of MICA/B protein changes during carcinogenesis is also under studies. At the early stage of tumor formation, these proteins contribute to activation of NK cells and elimination of transformed cells, whereas, at the later stage of this process, the increased production of its soluble forms leads to a decrease in anti-tumor activity of NK cells. Standard cancer treatment, such as chemotherapy, is accompanied by increased density of these molecules on the tumor cells. In addition, preclinical studies show that inhibition of MICA/B shedding with antibodies or their derivatives may also promote the anti-tumor activity of NK cells. This review summarizes basic information on the biology of MICA/B molecules, their expression by normal and transformed cells, elucidates the role of these molecules in anti-tumor immune surveillance, and provides information on the potential use of MICA/B in diagnosis and therapy of malignant diseases.

The problem of smoking, as well as incidence of tuberculosis, has existed for a long time. The latest WHO data indicate that 1.3 million people die from tuberculosis, and another 7 millions die from smoking every year. Tobacco smoke contains many harmful chemicals, including carbon monoxide, nicotine, nitrogen oxides, and cadmium. A number of studies indicate a high prevalence of smoking among patients with tuberculosis. In most cases, infection with Mycobacterium tuberculosis does not lead to active disease, due to the development of a balanced, homeostatic immune response. The key protective components are inflammatory responses aimed at inhibition of the pathogen growth, its sequestration and final elimination. At the same time, excessive or inadequate immune response may lead to granuloma destruction, tissue damage and, as a result, prolonged duration of treatment due to decreased respiratory function of the lungs. Along with pro-inflammatory mediators, anti-inflammatory mediators are synthesized in the host organism, which can positively or negatively affect the course of disease, depending on the place and time of their production. The balance between pro-and anti-inflammatory mediators in terms of time and expression level plays a crucial role in determining the outcome of infection. In our review, we consider the impact of tobacco smoke on various components of the human immune system, as well as upon the course and outcome of tuberculosis and other lung diseases. In addition, we would like to draw the reader’s attention to the need of adjusting pathogenetic therapy of bronchopulmonary diseases, taking into account the patient’s smoking habits. Tobacco smoking is one of the main causes of the severe course of many infectious and non-infectious diseases of the bronchopulmonary system. The decay products of cigarette smoke disrupt the functioning of the ciliated epithelium of respiratory tract, the production of the mucous component in the bronchi, and reduce the effectiveness of the surfactant system. These negative events interfere with protective mechanisms of the human respiratory system. It is worth of note that tobacco smoke also exerts a systemic effect on the immune system. Data are accumulating on the association between the terms of exposure to tobacco smoke, and a range of adverse tunerculosis manifestations, such as extent of infection, severity of course, reactivation, treatment outcome, and mortality. At the same time, epidemiological studies are able to reveal the associations, but they do not allow us to determine exact causal relationships.

Microvesicles are membrane-derived formations ranging in size from 100 to 1000 nm, being produced by a variety of resting and activated cells. They can transfer their cargo to target cells, regulate physiological processes, and participate in the development of clinical disorders. Among the microvesicles of different origin, natural killers are of special interest. They represent a subpopulation of lymphocytes that eliminate aberrant cells, including virally infected and malignant cells, and participate in regulation of angiogenesis. By producing various stimuli and inhibitors of the latter process, natural killers are able to change functional activity of endothelial cells by means of microvesicle-mediated contacts. There are only scarce literature data on ability of the extracellular vesicles to influence endothelial functions, depending on the intrinsic balance of pro- and anti-angiogenic factors. Therefore, the aim of our study was to evaluate the effect of protein fractions derived from microvesicle lysate of the NK-92 natural killer cell line upon phenotype and functional characteristics of EA.hy926 endothelial cell line under in vitro experimental conditions. Using chromatographic micro-preparatory separation, twelve protein fractions (inducers) were obtained from the lysate. It was found that proliferation and migration of EA.hy926 cells after their cultivation with 10 of 12 protein fractions, were changed in different directions. These effects were dose-dependent, or remained unchanged, at distinct concentrations of active components in the fractions. The inducing factors from these fractions exerted predominantly stimulating effects on proliferation of the target cells, thus suggesting presence of proteins which are able of regulating endothelial functions. However, the size of residual area free of migrating endothelial cells treated by the inducers did not always correlate with the migration intensity and did not inversely correlate with the number of migrating cells. Moreover, it was found that the obtained protein fractions had no effect upon expression of CD54 (ICAM-1), CD34, CD31 (PECAM-1) and CD119 (IFNγR1) receptors by EA.hy926 cells. The data obtained confirm an involvement of microvesicles in communications between natural killer cells and endothelial cells, and presume different participation modes of microvesicle-derived effector proteins in the angiogenesis machinery.

Adoptive immunotherapy using NK cells has become a promising therapeutic area. NK cells are a component of the innate immune system, act as key regulators, and have potent antitumor cytolytic activity. In order to be able to evaluate the therapeutic effect of adoptive NK cell immunotherapy at preclinical stages, there is a need for reliable protocols for in vitro production of NK cells. There are a large number of publications on methods for activating and generating human NK cells, including using feeder-cells and various cytokines. The article describes the experience of cultivation of NK cells from cancer patients or donors with feedercells and without feeder-cells (control group). The K562 cell line was used as a feeder after irradiation of two types: after gene modification of K562 (gmK562) with membrane-bound mbIL15, mbIL21 and without it. NK cells donors and cancer patients were mixed with K562 in a ratio of 1:1, 1:2 and 1:5 on 0, 7 and 14 days respectively. Daily morphological assessment showed that, NK cells donors and cancer patients began to proliferate and increase in size, while the viability of feeder cells began to decrease after 3 days of cultivation, and they were less than 20% on 21 days. NK cells of donors and cancer patients went into apoptosis, their viability level decreased to 70% in the control group (without feeder-cells) after 3 days of cultivation. A comparative evaluation of two different methods of obtaining human NK cells was carried out. It was shown when NK cells were isolated by magnetic selection, the proportion of CD3-CD56+CD16+ cells were more than 90%, and after the removal of adherent cells, it was at least 60%. When cultivating NK cells cancer patients (after magnetic separation) together with gmK562 on the 21st day, it was possible to increase the number of NK cells up to 85 times. When cultivating NK cells donors (after adhesion) together with non-genetically modified K562 cells on 21 days, it was possible to increase the number of NK cells up to 8 times. It was shown that in the supernatants collected during the cultivation of NK cells with feeder cells (both irradiated with K562 and genetically modified with K562), the concentrations of TNFα and IFNγ increased many times relative to the control group. The optimal conditions for culturing NK cells were experimentally selected to obtain a large number of NK cells.

Pregnancy-specific beta-1-glycoprotein (PSG) is a protein with pleiotropic biological effects, particularly immunoregulatory and immunosuppressive potential. The use of recombinant PSG may exert therapeutic effects in experimental animals with induced autoimmune diseases. Recently, a search for the biological effects of short linear motifs (SLiMs) has become a new strategy for designing the pharmacological compounds. Tetrapeptide regions have been identified in the primary structure of several PSGs: YQCE, YECE and YACS, these SLiMs exhibit immunomodulatory activity. The aim of our study was to evaluate the prospectives for usage of PSG peptide fragments as pharmacological agents to modulate transplant immunity. We used an original model of host-versus-graft response in male Wistar rats transplanted with bone marrow, without prior conditioning treatment of recipients. We used a cocktail of the PSG peptide fragments administered to Wistar rats in the course of allogeneic bone marrow transplantation (BM) in dynamic manner, evaluating the cytokine profile as an integral index of immune response. Cytokine levels were determined by multiplex method using Bio-Plex ProTM Rat 23-Plex kit. Statistical processing of the data was performed by means of two-way analysis of variance and Tukey’s post hoc test for multiple comparisons. We have found that the levels of pro-inflammatory cytokines (IFNγ, IL-1α, IL-1β, IL-18), as well as the contents of G-CSF, GM-CSF and IL-7 were increased in the animals injected with BM only. In the group of animals injected with BM + PSG peptides, an increase in IFNγ, IL-6, TNFα was observed, which decreased by the end of the experiment. Increased levels of antiinflammatory cytokines IL-4 and IL-13 were detected in blood serum of the animals on day +14. Moreover, administration of PSG peptides also led to increase in IL-2, M-CSF, MCP-1, and RANTES levels on day 14 from the beginning of the experiment, and to a gradual decrease in their levels till the end of the experiment. Meanwhile, control group showed a marked tendency for increase of these and other cytokines. Thus, it was shown that the use of PSG peptides upon development of immune response to BM allograft may promote a return to normal levels for the most cytokines studied, thus presuming the immunopharmacological potential of these peptides. The obtained data can be used to develop a pharmacological preparation of the studied peptides to correct the imbalance of immune system.

Non-inflammatory exudative lesions of Reinke’ pos space present the most common cause of phonation disorders in representatives of vocal professions. The leading role in pathogenesis of this disorder is given to the nearly complete absence of lymphatic drainage of Reinke space and local deposition of tissue fluid. The mechanisms of its progression are of particular importance when determining the condition of mucosaassociated laryngeal tissue. The aim of our work was to evaluate the parameters of immunohistochemical lymphocyte typing in exudative lesions from the Reinke’s space. Materials and methods: The main group consisted of 40 patients, at the mean age of 43.2±2.1 years, exhibiting tumor-like exudative lesions of Reinke’s space. The biopsy material was taken from the vocal folds, including polyps, vocal nodules and Reinke’s edema. Myxoid and angiomatous types of the polyps were separately assessed. Videofibrolaryngoscopy was performed using an Olympus TYPE 150 bronchofibroscope (Germany). Morphological studies were carried out using a DMRXA microscope (Leika, Germany) by means of the ImageScopeM computer program (Germany). The uniformly treated sections were stained with Hematoxylin & Eosin (Biovitrum, Russia). Immunohistochemical quantitative assessment of the main T cell populations (CD3⁺, CD4⁺, CD8⁺), B cells (CD20⁺), histiocytes (CD68⁺), and the cells expressing bcl-2 and p53 cell regulators was carried out automatically using the BenchMarkXT immunohistotainer (Ventana, USA). The results were expressed as U/mm². Results and Discussion. Some special features of cellular immunophenotype were revealed in exudative lesions of Reinke’s space. Reinke’s edema was characterized by high content of CD3⁺ lymphocytes, CD4⁺, CD8⁺, CD20⁺, p53 positive cells of the basal epithelium, as well as low numbers of CD68⁺, bcl-2 positive lymphocytes and cells of the basal epithelium. Myxoid type of polyps was characterized by low content of CD3⁺, CD4⁺, CD8⁺, CD20⁺ lymphocytes, bcl-2 positive lymphocytes and basal epithelium cells, CD68+ monocyte-macrophage cells, and high amounts of p53 positive basal epithelial cells. In the angioma-type polyps, we have registered low contents of CD3⁺, CD4⁺, CD8⁺, CD20⁺ lymphocytes, high numbers of monocyte-macrophage CD68⁺ cells, MMP-9⁺, bcl-2 positive lymphocytes, and low content of p53 positive cells of basal epithelium. The samples from the vocal nodules were characterized by low content of CD3⁺, CD4⁺, CD8⁺, CD20⁺ and p53 positive basal epithelial cells; high numbers of CD68⁺ cells (monocyte-macrophage series), MMP-9+ and bcl-2 positive lymphocytes.

Аsthma is among the commonest chronic bronchopulmonary diseases in childhood, being a  serious medical, social and economic problem. Asthma represents a multifactorial chronic inflammatory disease characterized by activation of T-mediated factors, including adhesion molecules in bronchial mucosa, as well as minimal persistent inflammation which is characterized by a long-term inflammatory process (despite complete absence of clinical manifestations) in the patients with allergic disorders accompanied by increased expression of ICAM-1 (type 1 intercellular adhesion molecule) and CD62L (L-selectin) in the bloodstream.

Lymphocyte and eosinophil counts in allergic inflammation show direct dependence on ICAM-1 contents, an intercellular adhesion molecule that provides transmigration of eosinophils and leukocytes through the endothelial barrier. Increased amount of ICAM-1 directly depends on excessive production of various reactive oxygen species in bronchial asthma. In turn, ICAM-1 induces changes in the cellular cytoskeleton which play a significant role in pathogenesis of asthma. It has been noted that ICAM-1 and CD62L molecules are those factors that exert changes at the microrheological level, including respiratory pathology of allergic nature. Increased amounts of vascular adhesion molecules in respiratory tract It has been proven are proven to be an important component of pathogenesis in bronchial asthma.

Maximal expression of vascular cell adhesion molecule 1 (VCAM-1) and ICAM-1 in the persons prone to allergic diseases may occur after undetermined time period, and it immediately causes pronounced degranulation of eosinophils in respiratory tract and capillary bed. Viral infection is also an important trigger for the asthma  exacerbation. Epithelial expression of intercellular adhesion molecule ICAM-1, a cellular receptor for the most rhinoviruses, is increased after the rhinovirus infection itself. Both eosinophils and neutrophils contribute to the development of severe asthma, or exacerbation of asthma. ICAM-1 is a cellular receptor for rhinoviruses. Adhesion of eosinophils to ICAM-1 promotes functional activation of eosinophils. Therefore, adhesion of eosinophils to epithelial cells via ICAM-1 may activate this population during exacerbation in bronchial asthma.

Changes in the immunohemorheology system in children with bronchial asthma represent the starting point of disorders at either hemostatic pathways, with a trend for increased adhesiveness and hypercoagulability, thus activating entire cascade of immunometabolic disorders and initiate clinical development of asthma. Exacerbation of asthma is characterized by the distinct expression pattern of the ICAM-1 adhesion factor, depending on the agent which promotes the airway obstruction. In the patients with asthma, depending on severity of exacerbation, there are pronounced changes in the levels of adhesion molecules. A pronounced increase in ICAM-1 at the time of bronchial obstruction is caused by the both causal allergen and infectious agent. However, more pronounced increase occurs during pollination, as well as slight elevation is observed in the course of obstruction caused by an infectious agent.

Sialadenosis is a dystrophic disease of the salivary glands parenchyma, which leads to secretory disorders and hypertrophy of salivary glands. Sialadenitis develops in cases of secondary inflammation. Standard methods and medications for the treatment of sialadenosis lead to regression of clinical manifestations and remission. Usage of herbal extracts with prolonged action has a long-term local anti-inflammatory effect with minimal side effects, including those affecting oral mucosa. However, their use in the complex treatment of sialadenosis has been scarcely studied. Objective of our investigation was to estimate cytokine status dynamics in saliva from the parotid glands in the patients with sialadenosis and hypothyroidism during complex treatment which included the prolonged-action herbal remedy. 52 patients with sialadenosis of parotid salivary glands and hypothyroidism were divided into 2 groups: in the I group, 26 patients received basic therapy; in the II group, 26 patients received basic therapy + herbal drugs with prolonged effect as resorbable tablets. Control group consisted of 20 conditionally healthy people without disorders of parotid glands and thyroid gland. Comparative evaluation was performed 1 and 6 months after starting the treatment, with respect to clinical findings, sialometry and cytokine profile. The content of interleukins IL-1β, IL-6, IL-10 and tumor necrosis factor (TNF) was determined in saliva of parotid glands by ELISA technique. The 1st group of patients showed exacerbations within six months of basic treatment, and the sialometry data pointed to maintenance of decreased parotid function. In the 2nd group, when using basic treatment + herbal drugs, no clinical features of sialadenosis were evident within 6 months. The sialometry values were normalized, and the secretory function of the parotid glands was found to be increased. Therefore, it exerted an effect upon moisturization of oral mucosal and improvement quality of life in the patients. Regression of IL- 1β, IL-6 and TNF contents, and IL-10 increase in parotid gland secretions was significantly more pronounced at the terms of 1 and 6 months in cases treated with herbal drugs, compared to Group 1, where a conventional protocol was used. Addition of herbal drugs of prolonged action to the standard protocol of sialadenosis treatment is reasonable and effective.

Chronic rhinosinusitis (CRS) affects 5-12% of the world’s adult population. Chronic rhinosinusitis with nasal polyps (CRSwNP) accounts for 25-30% of all cases of CRS. CRSwNP-associated inflammatory process in nasal mucosa and paranasal sinuses depends on the characteristics of local immunity, including expression of a number of cytokines. The aim of this work was to investigate the parameters of local immunity in various clinical forms of CRSwNP. In this work, the concentrations of pro-inflammatory cytokines, i.e., interleukin-1β (IL-1β) and IL-8, antimicrobial function of neutrophils from the nasal cavity was evaluated, along with histological and immunohistochemical studies of polyposis tissue. The study included 4 groups of patients: a control group of practically healthy individuals, patients with CRSwNP, clinical cases with chronic purulent rhinosinusitis and nasal polyps (CPRSwNP), and patients with CRSwNP complicated by bronchial asthma (CRSwNP + BA), including the cases with asthmatic triad (CRSwNP + intolerance to NSAIDs + BA). The patients were classified on the basis of their clinical characteristics and severity of the course of the disease. Interleukin-1β (IL-1β) and IL-8 concentrations in nasal secretions were determined by enzyme-linked immunosorbent assay (ELISA). To assess functional activity of neutrophils, a lysosomal cationic test was used on the smears from mucous surface of inferior turbinate. Histological examination of the polypous tissue biopsies was performed in slices stained with Carazzi’s hematoxylin and eosin. IL-1β and IL-8 location in the polypous tissue were detected by indirect immunohistochemistry. In all groups of the patients, IL-1β and IL-8 concentrations exceeded those in the control group. The levels of IL-1β in the groups with CPRSwNP, CRSwNP + BA were significantly increased as compared with the CRSwNP group. IL-8 concentrations in the CRSwNP and CPRSwNP groups were significantly higher than in the CRSwNP + BA group. When analyzing antimicrobial function of neutrophils, the decreased average values of cytochemical coefficient were shown in CPRSwNP and CRSwNP + BA groups, compared with the control group and CRSwNP. In all clinical forms of CPMS, complex histopathological changes were observed, including leukocyte infiltration, fibrosis, edema, and collagen depositions. In addition, the integrity of epithelial layer was found to be damaged in polyposis, epithelial metaplasia is detected as well as increased mucus production. These disorders lead to a decrease in muco-ciliary clearance in nasal cavity. The most significant pathomorphological changes occur in CRSwNP + BA, especially in cases of asthmatic triad. According to immunohistochemical data, in various forms of CRSwNP, IL-1β- and IL-8-positive leukocytes, predominantly macrophages, are detected in the polypous tissue both subepithelially and in the connective tissue stroma of the polyps. Changed concentrations of pro-inflammatory cytokines in nasal secretion of the patients, altered antimicrobial activity of mucosal neutrophils, and characteristic pathomorphological disorders in polypous tissue of patients with CRSwNP are associated with severity of inflammatory process and clinical course of the disease. The results obtained are essential to understanding the mechanisms of pathogenesis in various subgroups of CRSwNP, assessing severity of the disease and efficiency of the treatment applied.

Acute peritonitis (AP) is among the most frequent and severe conditions in pediatric abdominal surgery. Due to development of antibiotic resistance and increasing number of atypical infectious and inflammatory diseases (IIDs), a lot of specialists suggest combined treatments for these patients which should include not only surgical and etiotropic approaches, as well as therapy aimed at correction of functional defects of immunity. Neutrophilic granulocytes (NGs) reepresent a unique population of cells of primary anti-infectious immune response. Functional NG defects in pediatric AP play a leading role in development, prevalence, severity of peritoneal inflammation, and response to the therapy. Special role is given to functionally significant NG subsets responsible for triggering and implementation of phagocytosis and microbicidal properties of NG in purulent lesions and inflammatory process in children. There is an urgent need for development of new approaches to targeted immunomodulatory therapy in order to correct the NG dysfunction. The aim of the present study was to arrange the programs of immunomodulatory therapy after surgical treatment of immunocompromised children with various forms of acute peritonitis followed by subsequent evaluation of its clinical and immunological efficacy. The study included 12 immunocompromised children aged 5-12 years with different clinical course of acute peritonitis. The study group 1 included patients with local nonrestricted AP; study group 2 involved children with diffuse AP. The comparison groups consisted of 6 children who received standard therapy, i.e., clinical comparison groups 1 and 2, matched for sex, age and diagnosis. A control group consisted of 18 conditionally healthy children at similar age. Clinical examination included collection of the patient’s history, complaints, objective examination and clinical course assessment of the underlying disease. Immunological study included determination of receptor, phagocytic and microbicidal activity of NCs; assessment of NC subpopulations by their numbers and phenotype using flow cytometry, i.e., the cells co-expressing CD64, CD16, CD32, CD11b, with testing density of these membrane receptors by the MFI approach. Targeted immunomodulatory therapy programs were applied for treatment of children with unrestricted local and diffuse AP, taking into account clinical features of AP, as well as changes in number and phenotype of NC subpopulations, and impairment of their effector function. The standards of postsurgical treatment in the children with various forms of AP included different courses of treatment with Imunofan (Hexapeptide – arginyl-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine; HP) using different schedules and duration. We have shown high clinical and immunological efficiency of these therapeutic programs. Thus, reversal of adequate NG functioning was observed, including positive rearrangements of negatively transformed functional NG subpopulations. In this respect, a positive clinical effect was noted in children with atypical AP with various clinical courses, i.e., absence of postsurgical complications, rapid regression of intoxication signs, normalization of body temperature, reduced volume of antibiotic therapy and shorter hospitalization terms.

Sarcoidosis is a multisystemic granulomatous disorder of unknown cause, characterized by formation of immune granulomas in various organs, mainly in lungs. Currently, two main phenotypes of pulmonary sarcoidosis are described, i.e., Lofgren’s syndrome (LS) is an acute form with favorable outcome, and non-Lofgren’s syndrome (nLS) is a chronic type of disease with a high risk of pulmonary fibrosis. Our study was aimed to investigate the balance of main “polarized” CD4⁺ central and effector memory T cells from treatment-naive patients with pulmonary sarcoidosis (LS (n = 19) and nLS (n = 63)) compared to healthy volunteers (HC, n = 48). This marker might be used as immunological markers for predicting severity of this disorder. Multicolor flow cytometry analysis demonstrated that the patients with nLS showed significantly low levels of relative and absolute numbers of CD3⁺CD4⁺ lymphocytes if compared to patients with LS and control group (38.94% (31.33-44.24) versus 48.96% (43.34-53.54) and 47.63% (43.82-52.73), p < 0.001 in both cases). Moreover, patients with nLS had reduced frequencies and absolute numbers of “naive”, CM and EM Th cells if compared with healthy controls. Furthermore, the patients with LS showed increased relative and absolute numbers of peripheral blood EM Th cells, capable for migration to peripheral inflamed tissues, when compared with nLS. Finally, patients with LS had increased frequencies and absolute numbers of effector TEMRA Th cells as compared to HC and nLS. Next, significant differences Th1 and Th2 cells frequencies were shown between the patients with nLS and HC (9.64% (7.06-13.65) versus 13.80% (11.24-18.03) with p < 0.001, and 11.96% (9.86-14.78) versus 10.67% (9.13-12.98) with p = 0.048, respectively). But there were no significant differences in the relative numbers of CXCR5-CCR6⁺Th17 and CXCR5⁺ follicular T helper cells (Tfh) between the groups. Finally, both groups of patients with pulmonary sarcoidosis contained low proportions of “non-classical” Th17 and DN Th17 cell, but increased levels of DP Th17 cells within total CXCR5-CCR6+ CM Th if compared with HC. Nevertheless, patients with nLS had increased frequency of “classical” Th17 in comparison with healthy controls. A very similar imbalance between different Th17 cell subsets was observed within total CXCR5CCR6+ effector memory Th, that were able to migrate from the bloodstream to the sites of infection, or tissue injury. Taken together, the data suggest that the proportions of Th17 cell subsets in pulmonary sarcoidosis can be evaluated as a diagnostic and/or prognostic marker in clinical practice and these cells could serve as a new therapeutic target.

Purinergic signaling modulates systemic and local inflammatory responses in immune-mediated and autoimmune diseases, including psoriasis. Extracellular ATP is an important factor of purinergic regulation, and its levels are regulated by catalytic effects of CD39 and CD73 ectonucleotidases. The aim of the present study was to estimate the number of regulatory T cells (Tregs), activated T-helper cells (Thact), T-helper type 17 (Th17) expressing CD39 and CD73 ectonucleotidases in children with psoriasis vulgaris, depending on age, disease duration and severity of the pathological process. We have examined a total of 114 children with psoriasis vulgaris (70 girls and 44 boys) and 41 healthy children serving as a comparison group (25 girls and 16 boys). The age of children with psoriasis was 12.5 (10.1-15.8) years, and 12.4 (7.4-16.1) years for the comparison group. The severity of psoriasis was assessed by the PASI and BSA indices. The number of cells with CD39 and CD73 expression on Tregs, Thact and Th17 was estimated by flow cytofluorimetry. The highest number of CD39-expressing cells was found in the Tregs and CD73-expressing cells in Thact, both in children with psoriasis and in the comparison group. The number of CD39⁺Th17 was lower in children with psoriasis, but CD39⁺CD73⁺Thact and CD39⁺CD73⁺Th17 were higher than in comparison group (p < 0.05). There was a decreased number of CD73⁺Tregs, CD39⁺Thact, CD39⁺Th17, CD39⁺CD73⁺Thact and CD39⁺CD73⁺Th17 with age in healthy children (p < 0.05). In patients with psoriasis, the number of CD73⁺Th17 increased with age. A decrease in CD73⁺Th17, and an increase in CD39⁺CD73⁺ Tregs with higher PASI and BSA indices were detected. An increased PASI (> 10) showed patients with both high and low CD39⁺Tregs, with CD39⁺Tregs being reduced in 48% of cases, increased in 35% and normal values in only 17% of cases. Monitoring the numbers of Tregs, Thact and Th17 cells expressing CD39 and CD73 in children with psoriasis may be used to evaluate chronic inflammation, given the role of CD39 and CD73 ectonucleotidases in shaping the immune response in immune-mediated diseases,

In accordance with Clinical Guidelines of the Russian Society of Dermatovenerologists and Cosmetologists, atopic dermatitis is a chronic allergic genetically determined dermatosis of a multifactorial nature. There are, however, some aspects that challenge the allergic nature of dermatosis. For example, according to literature data, not all the patients have increased synthesis of immunoglobulin E, some of them are torpid to antihistamine treatment, and, when examining the skin of some patients with atopic dermatitis, an absolute polymorphism of rashes is revealed, thus being not typical to the reagin-type allergic reactions. According to modern data, autoimmune theory is assumed for the mechanisms of atopic dermatitis. However, objective proofs of this theory have not been presented, thus drawing our attention to the studies of this issue. The aim of this study was to identify autoimmune pathogenetic mechanisms of atopic dermatitis. The study included 40 adolescents and 40 adult patients with limited and extended forms of atopic dermatitis. The patients were evaluated during the period of exacerbation and remission of the disease. Blood and skin exudates samples were taken from all the patients. The control group consisted of 30 practically healthy volunteers in whom skin exudate was obtained by the “skin window” technique as proposed by Klimov V.V. et al. “A method for assessing minimal inflammatory activity of skin in atopic dermatitis in remission”. Concentrations of IgG autoantibodies to collagen types I and III were determined in blood serum and skin exudate samples applying ELISA techniques with ready-made panels AEA571Hu ELISA Kit for Anti-Collagen Type I Antibody (USA), AEA176Hu ELISA Kit for Anti-Collagen Type III Antibody (USA), according to the manufacturer’s protocols. For the first time, the contents of autoantibodies to skin collagen types I and III in the patients with atopic dermatitis we studied in parallel, i.e., at systemic level and in affected skin. If compared to the group of healthy volunteers, the concentration of autoantibodies to collagen types I and III was found to be increased in all the patients with atopic dermatitis, both during exacerbation and in remission of the disease. The maximal values of autoantibodies to collagen types I and III were recorded in blood serum upon development of clinical symptoms of dermatosis, along with low contents of these antibodies detectable in their skin exudates. Permanently high concentrations of autoantibodies to collagen types I and III in blood serum at exacerbation and remission of atopic dermatitis, and their low level in their skin exudate suggest emergence of circulating and precipitating immune complexes, thus allowing us to consider atopic dermatitis as an autoimmune process.

Sporadic congenital heart disease (CHD) may result from immune disorders in the mother – embryo system and/or constitutional disorders in regulatory systems, including those associated with TLR receptors, cytokines and their receptors. The aim of our study was to investigate associations between cytokine and TLR genes and sporadic congenital heart disease in children. In the main group, 188 children with sporadic (without family history) congenital heart defects were examined. Separate groups of CHD were identified: septal CHD – 98 children; valvular heart disease – 17 children; Fallot tetralogy – 15 children; aorta coarctation – 10 children; fetal drains – 32 children; single ventricle affection – 9 children, and anomalous drainage of v. pulmonalis was diagnosed in 7 children. The control group included 103 age- and sex-matched healthy children. We have determined gene polymorphisms of five genes encoding cytokines and their receptors (IL6 rs1800796, IL6 rs2069827, IL6R rs2228145, IL6R rs2229238, IL8 rs4073, IL10 rs1800871, IL10 rs1800896, IL10 rs1800872, TNF rs1800629, TNF rs361525, TNF rs1799964), four genes Toll-like receptors (TLR: TLR1 rs5743611, TLR1 rs5743551, TLR2 rs5743708, TLR2 rs3804099, TLR4 rs4986791, TLR4 rs4986790, TLR6 rs3775073, TLR6 rs5743810). The dbSNP, SNPinfo, SNPnexus databases were used to select and design test systems. Stepwise logistic regression was the main method of statistical analysis. Clinical diagnosis of congenital heart defects is associated with immune regulatory genes. In particular, the missense mutation TLR6 rs5743810, which was a predictor of congenital valvular heart disease, is of particular importance. Development of congenital heart valve defects and aortic coarctation is associated with intergenic interactions of TLR2 rs5743708 with TLR6 rs5743810, and TLR2 rs5743708 with TLR6 rs3775073, respectively. For congenital heart valve defects, such polymorphic regions are as follows: IL6 rs2069827, IL6R rs2229238, and IL8 rs4073, for aortic coarctation – IL6R rs2228145, IL8 rs4073. Development of septal congenital heart defects is associated with general contribution of polymorphic variants of the TLR genes and cytokines to this pathology. A missense mutation of the TLR4 rs4986790 gene and a TNF rs1799964 mutation leading to increased synthesis of the TNFα molecule, may have a combined effect on this process. In general, contribution of TLR and cytokine genes interactions to the CHD development seems to be not significant.

Rapid emergence and evolution of novel SARS-CoV-2 variants has raised concerns about their potential impact on efficiency of currently available vaccines. Among the most significant target mutations in the virus are those of the spike glycoprotein. Remdesivir, which inhibits the polymerase activity of the RNAdependent RNA polymerase RdRp, is the only medicine approved by FDA for treatment of COVID-19 (nsp12). The docking features of the flexible ligand (remdesivir) with the stiff receptors was investigated in the present study (S protein and RdRp interaction). In various studies, the spike glycoprotein and RdRp mutations were found to have a significant influence upon viral behaviour and, as a result, affect human health. The docking position of remdesivir with the S and RdRp proteins was shown to be unaffected by mutations in the missing loops. The remdesivir can only bind the B and C chains of S protein. Some mutations can be transferred between variations, without changing the type of amino acid, such as K417N, L452R, N501Y, D614G, T716I, and S982A.

The relevance of the current epidemic situation of a new coronavirus infection is determined by new strains of the virus and the registration of cases of re-infection in COVID-19 survivors earlier. In this regard, the questions about the expediency and nature of vaccination of those who have been ill attract close attention, moreover it has affected the formation of the concept of “hybrid immunity”. The aim of this study was to analyze changes in the parameters of the immune system, reflecting their regulatory and functional potential, in response to the introduction of the peptide vaccine EpiVacCorona to persons who have suffered from the new coronavirus infection. To study the features of the formation of hybrid immunity, a retrospective analysis of the observation of 43 study participants was carried out. The inclusion criteria were data confirming COVID-19 in mild and moderate forms of the course in the period from six months to a year ago, a low level or absence of antibodies to the nucleocapsid protein SARS-CoV-2, a negative PCR result for the presence of the SARS-CoV-2 virus, the absence of comorbid pathology. The subpopulation composition, regulatory and functional potential of the immune system were determined by flow cytofluorimetry using a set of monoclonal antibodies corresponding to the goals. 21 days after the administration of a single dose of EpiVacCorona, antibodies to the vaccine peptide antigens were registered in all study participants at the highest coefficient of positivity values for the SARS-CoV-2-IgG-Vector test system used. In addition, there was a fourfold increase in the number of specific IgG to the N protein. A specific immune response to recombinant SARS-CoV-2 antigens was accompanied by a decrease in the circulation of the number of monocytes expressing TLR4, T helper cells expressing the interaction coreceptor with antigen-presenting cells, unconnected B memory with an increase in the number of B lymphocytes expressing the CD40 T-B coreceptor interaction molecule. The remaining differences in the functioning of the immune system identified in patients with COVID-19 before the vaccination in comparison with the control data have not changed. The differences consist in a decrease in the proportion of monocytes expressing HLA-DR, an increase in the expression of interaction molecules on T and B lymphocytes, an increase in the number of Treg, B1 cells, activated B lymphocytes with a decrease in the proportion of suppressor Breg and B memory. The totality of the presented data demonstrates that the COVID-19 infection that preceded vaccination in mild and moderate clinical course contributes to the formation of immunological memory, which made it possible to form a secondary immune response even to a single injection of peptide antigens of the virus.

Infections represent a common health problem in people at any age. Usually, a local reaction develops in response to the infection, and intensive treatment is not required. However, sometimes the response to infection is inadequate and may lead to organ dysfunction; such condition is defined as septic state. The pathophysiology of sepsis is multifactorial, and the immune system is directly involved in development of pathological processes accompanying septic conditions. Dysregulatory disorders in sepsis may be observed, in particular, those affecting immune system and, immediately, innate immunity, which presents the first line of immune defense. Currently, neutrophilic granulocytes are considered important players in development and maintenance of inflammatory processes, which is due to their ability to produce various inflammatory mediators. At the same time, at different stages of pathogenesis, immune factors and mechanisms act both as a generating factors and effectors of damage reactions, as well as the main components of the defense responses. Uncontrolled release of endogenous inflammatory mediators induced by microorganisms, and lack of damagelimiting mechanisms mutually synergize when promoting the organ dysfunction. Hence, dysfunction of the immune system may develop and deepen upon any inappropriate strategy of response to distinct infectious pathogen. The aim of our study was to assess the spectrum of microorganisms, levels of neutrophilic extracellular traps (NVL), PAD4, IL-6, IL-8 and their correlations in the patients with sepsis and septic shock, depending on the outcome of the disease. The study included 44 patients with sepsis and septic shock, and 20 apparently healthy donors. Peripheral blood samples were taken from the ulnar vein serially in dynamics, from the moment of diagnosis to clinical outcome. Microbiological and immunological studies have been carried out. The obtained data were processed with “SPSS Statistic 23.0” software. Development of septic conditions was found to be accompanied by a significant changes in the levels of studied immunological parameters (NLV, IL-6, IL-8 and PAD4). Toxicity of lysosomal enzymes and oxygen metabolites present in neutrophilic extracellular traps leads to endothelial damage, appearance of focal intravascular inflammation, which, along with damaging effects of microorganisms and their toxins, leads to development of organ failure and onset. High burden   of these factors is most likely to cause lethal outcomes.