Blood platelets are the central players in thrombosis and blood coagulation. Moreover, they also exhibit immunoregulatory properties and bridge hemostasis and immunity. Morphological and functional characteristics of the platelets ensure continuous surveillance for the vascular system, recognition of different hazards, development of appropriate response and recruitment of immune cells. Indirect platelet-leukocyte interactions are mediated by immunoregulatory molecules that are released, along with coagulation and thrombosis factors in the course of platelet activation and degranulation. Chemokines, cytokines, growth factors, some of which are synthesized de novo, are released from activated platelets and modulate cellular functions, thus modulating both innate and adaptive immune response. Activated platelets enter contacts with immune cells to form heterotypic aggregates, i.e., platelet-leukocyte complexes that reside in blood circulation along with other blood cells. The aggregate formation and stabilization is mediated by interaction between the molecules expressed on the surface of platelets and leukocytes, in particular, P-selectin (CD62P) and PSGL-1 (CD162). Platelet-monocyte and platelet-neutrophil complexes are most abundant, with platelet-monocyte aggregates being most stable. Moreover, the platelet-derived microvesicles also interact with leukocytes to form heterotypic aggregates, thus, probably, modulating the immune cell functions via transfer of non-coding RNA molecules. Formation of platelet-leukocyte complexes results into mutual activation of platelets and leukocytes. Platelets and platelet-derived microvesicles stimulate phagocytic activity, cytokine secretion, and generation of reactive oxygen species in monocytes and neutrophils, inducing formation of neutrophilic extracellular traps and procoagulant phenotype in monocytes. The blood platelets regulate monocyte differentiation, promote adhesion, as well as transmigration of lymphocytes and NK cells. At the sites of inflammation, platelets enhance extravasation and infiltration of leukocytes into the damaged tissue. Impaired interactions of platelets with endothelial layer and immune cells may underlie pathogenic conditions. Increased level of circulating plateletleukocyte complexes is observed in various disorders including cardiovascular diseases, acute ischemic stroke, respiratory disorders, renal pathologies, liver diseases, diabetes, reproductive disorders, bacterial and viral infections. Further studies of platelet-leukocyte interactions are warranted to unveil pathogenic mechanisms and to develop new therapeutic approaches.

Liver cancer ranks No. 5 in the world among all types of cancer and takes 3^rd position among cancer-related deaths. Hepatocellular carcinoma (HCC) is a primary malignancy which does not include liver metastases from other sites. It is the most common form of liver cancers, and one of the leading causes of cancer-related deaths worldwide. HCC includes genetically and morphologically heterogeneous group of malignant tumors. HCC is characterized by a gender predisposition, namely, it occurs in men 1.5-fold more often, than in women. Viral infections such as hepatitis B and C are major risk factors for HCC. Moreover, non-alcoholic steatohepatitis (NASH) associated with metabolic syndrome and type 2 diabetes also becomes an increasingly common risk factor in developed countries. The mechanisms underlying the development of HCC are based on genetic changes in tumor cells and their microenvironment. Recently, the role of changes in the tumor microenvironment has drawn more attention, thus becoming the key characteristic in the HCC pathogenesis at all stages of the malignant process. Hepatocytes have a close relationship with immune cells, since in the liver, in addition to hepatocytes, there are Kupffer cells, myeloid cells (dendritic cells, monocytes and neutrophils) and other types of immune cells (T and B lymphocytes, NK and NKT, etc.). Cytokines released by various immune cells in the liver may influence liver processes, e.g., inflammation and carcinogenesis. Chronic inflammation results from persistent stimulation, or deficiencies of anti-inflammatory mechanisms. Its key features include immune cell infiltration, presence of inflammatory mediators, and imbalance of pro- and antiinflammatory cytokines leading to aggressive angiogenesis and tissue remodeling which, in turn, promotes the malignant process. Currently, there are several approaches to the HCC treatment which depend on the stage of the disease. Immunotherapy and its combinations have shown positive advances, and further research in this area will provide therapeutic options at the terminal stages of HCC. A variety of cytokines and their functions in HCC development are discussed in the present review article.

To date, there is no consensus explaining the relationship between varying concentrations of IFNγ and the severity of infection caused by SARS-CoV-2. The aim of this article was to analyze and formulate conclusions from the selected studies and publications, which, in sum, provide a potentially reasonable view on the role of IFNγ in COVID-19 pathogenesis. This article highlights current data on the immunological role of IFNγ which affects differentiation of naive T helper cells, acting as a polarizing factor. It activates the major histocompatibility complex (MHC) class I and II, by increasing the expression of MHC I/II subunits, inhibiting replication of the viral particles by initiating activation of interferon-stimulated genes followed by subsequent synthesis of antiviral proteins. Moreover, IFNγ activates the production of cytokines by T cells, enhancing cytotoxic activity of the T killers. IFNγ exerts immunostimulatory and immunomodulatory effects via STAT1, SOCS1 and PIAS genes, thus regulating activation of the JAK-STAT signaling pathway. A number of studies were considered where the patterns of changes in serum IFNγ concentration were examined in viral infections and SARS-CoV-2. We performed a systemic analysis of the results of studies that showed a relationship between high concentrations of IFNγ and COVID-19 severity. In a number of studies, the significantly high levels of IFNγ in COVID-19 patients were often associated with a poor outcome of the disease. The median values of the IFNγ concentration in severe COVID-19 were found to be significantly higher compared to the results obtained in the cases of moderate severity. It shows an increase, in parallel with viral load in the nasopharyngeal samples upon worsening of the clinical condition. Based on the data on the decreased IFNγ concentrations in convalescent patients, the mechanism of antagonism between IFNγ and IL-4 is considered, where the decreases serum concentrations of IFNγ along with increasing level of IL-4 may be an indirect proof of normal adaptive immune response with subsequent development of antibodies to SARS-CoV-2 and gradual elimination of the virus from the body. Moreover, the evidence is discussed that the patients harboring some parasitic infections (Toxoplasma gondii, Cryptosporidium, Blastocystis hominis, Giardia duodenalis, Entamoeba histolytica) with persistently elevated level of IFNγ are at reduced risk for severe course of COVID-19.

In this review, we discuss molecular and cellular mechanisms underlying cross-talk between immune cells and bone cells, both in healthy conditions and in some diseases. We provide short description of the main cell populations of bone tissue, i.e., osteoblasts, osteoclasts, osteocytes, bone marrow macrophages, OsteoMacs, and their effects on immune cells during bone modeling and remodeling. The data are presented on regulatory molecular pathways of bone marrow cell activity, T and B cells, macrophages, and formation of “endosteal niche” by the bone cells. We describe the key system of bone tissue homeostasis: RANK/RANKL/ OPG, which regulates differentiation of osteoclasts and bone destruction. In addition, RANK/RANKL/ OPG system modulates maturation and activity of various T and B cell subsets. We present the data on pleiotropic effects of T cells, B cells, dendritic cells, macrophage subpopulations, Tregs, NK cells, neutrophils upon differentiation and function of osteoblasts and osteoclasts. These effects promote accumulation and maintenance of the bone mass. We describe mechanisms of these effects based on direct cell-to-cell contacts and various soluble mediators and intracellular signaling pathways. A brief characteristic of some diseases is provided with concomitant dysfunction of immune cells and bone cells which play a decisive pathogenetic role (fractures, rheumatoid arthritis, periodontitis, postmenopausal osteoporosis, multiple myeloma). It was shown that the destructive bone inflammation, both in RA and periodontitis, leads to loss of bone mass, being featured by similar pathophysiological mechanisms involving immune and bone cell populations. Therapy of these diseases requires newer treatment strategies aimed not only at pro-inflammatory cytokines, but for increased bone resorption. We describe involvement of activated T cells, their cytokines into the pathogenesis of postmenopausal osteoporosis, thus providing a rationale for the novel term of “immunoporosis”, coined in 2018. The relationships between multiple myeloma cells and bone marrow microenvironment are provided. This cross-talk is based on contact cell-cell interactions, as well as due to effects of soluble mediators upon osteoclasts, stromal cells, and osteoblasts. These effects result in osteolysis, loss of bone mass, and myeloma progression. In conclusion, the relationships between the immune and bone cell populations suggest that they function as an entire regulatory system. This consideration provides a framework for the development of new therapeutic targets for the treatment of bone and immune system disorders.

GM-CSF and M-CSF, the hematopoietic colony-stimulating factors, induce various phenotypic changes in macrophage lineage populations and promote cell differentiation, respectively, into M1- and M2-like macrophages. The pro- and anti-inflammatory properties of macrophages generated by these colony-stimulating factors are well described, but the contribution of differentiation and polarization signals to the fibromodulatory activity of macrophages remains unexplored. To clarify the differences in the fibrogenesis regulation mechanisms inherent in differently activated macrophages, we studied the effects of macrophage-conditioned media on proliferation and differentiation of dermal fibroblasts. In this study, the human macrophages generated from peripheral blood monocytes were investigated. They were induced for differentiation by M-CSF or GM-CSF, being further polarized in the M1 direction with lipopolysaccharide and, in the M2 direction, with IL-4 or dexamethasone. Proliferative response of the fibroblasts was determined radiometrically by [3H]-thymidine incorporation. Differentiation into myofibroblasts was determined with flow cytometry technique, as expression of a specific marker α-smooth muscle actin (α-SMA). The level of macrophage TGF-β1 production was assessed using an appropriate ELISA kit. The data obtained indicate that the macrophages differentiated under the influence of “homeostatic” M-CSF are characterized by a moderate stimulating effect upon fibroblast proliferation, and the effects of M2 (IL-4) and M2 (Dex) macrophages exceed that of M1 (LPS), but do not differ significantly from each other. The M-CSF-induced M1 (LPS) and M2 (IL-4) macrophages, but not M2 (Dex), enhance the fibroblast differentiation and show similar level of stimulation. In contrast to M-CSF, the macrophages induced by “pro-inflammatory” GM-CSF exhibit a pronounced stimulatory effect on fibroblast proliferation, and the effects of M2 macrophages exceed those of M1 cells, being most pronounced for M2 (Dex). At the same time, only GM-CSF-induced M2 (IL-4) macrophages enhance fibroblast differentiation. Dexamethasone-polarized macrophages do not significantly affect fibroblast differentiation regardless of the CSF used (M-CSF or GM-CSF). The content of TGF-β1 in the supernatants of differently activated macrophages does not correlate with the level of stimulating effect of macrophage-conditioned media upon fibroblast differentiation. In general, the data obtained suggest the involvement of differentiation and polarization signals into modulation of pro- and anti-fibrogenic properties of macrophages.

Community-acquired pneumonia (CAP) is one of the most common acute infectious diseases. To date, the incidence of CAP among children was decreased significantly worldwide, mainly due to increasing use of effective preventive measures. Nevertheless, CAP remains a common cause of childhood morbidity and mortality. Pneumonia may develop at any age, but most often it occurs in young children, who are more likely to have a more severe course of pneumonia. Currently, early diagnosis and prognosis of the disease severity in children is an urgent issue. It was found that, in most cases, a panel of conventional biomarkers, including the number of leukocytes, procalcitonin, CRP is not sufficient for the diagnosis of pediatric CAP. There is a demand for new biological markers which, along with clinical evaluation, may significantly improve diagnostics and management of CAP in children, thus reducing the risk of adverse outcomes associated with this disease. Such markers could be found among the cytokines, which are active participants in the CAP pathogenesis. The aim of this study was to determine the level of several cytokines in blood serum of children with CAP and to assess changes in the cytokine profile depending on the patient’s age and severity of the disease. The study included 117 children aged 1 to 18 years with a diagnosis of CAP confirmed by X-ray examination. The comparison group included 28 healthy children who did not have CAP or other signs of acute respiratory viral infection at the time of examination, being free of any chronic pathology requiring outpatient observation. A number of cytokines were determined quantitatively in blood serum, i.e., IL-1β, IFNγ, IL-2, IL-4, IL-6, IL-10, TNFα, IFNλ2 (IL-28A), IFNλ3 (IL-28B), IL-8, MCP-1, IL-17AF, GM-CSF using test systems based on the “sandwich” method of solid-phase ELISA using peroxidase labeling. As a result, it was found that the content of IL-6, IL-17AF, IL-1β, IFNγ, MCP-1, IFNλ2 (IL-28A), IFNλ3 (IL-28B), GM-CSF was significantly higher in the group of children with severe community-acquired pneumonia. The levels of certain cytokines, e.g., IL-6, IFNλ2 (IL-28A), IFNλ3 (IL-28B), GM-CSF varied depending on the age of patients, thus, probably, reflecting the degree of immune system activation in the children of different age groups.

T lymphocytes type 2 immune response protect against helminths and toxins, and also contribute to the development of allergic inflammation. One of the most specific T cell surface markers T lymphocytes 2 is the CRTH2 molecule (CD294), which is an activating receptor for prostaglandin D2. The CD3⁺CD294⁺ population is negligible in the peripheral blood of healthy individuals; an increase occurs in patients with allergic diseases and an autoimmune nature of the response. The aim of the study was to study the quantitative and functional characteristics Т lymphocytes type 2 immune response in patients with rhinoconjunctival symptoms (n = 248) and drug hypersensitivity (n = 184). In 68 patients with an elevated and extremely high number of CD3⁺CD294⁺ cells, a detailed phenotype of this population was characterized by flow cytometry and the functional activity of the studied cell population in relation to the production of interleukin 4 and interferon γ was studied using enzyme immunoassay. The control group consisted of 34 volunteers. The relative number of CD3⁺CD294⁺ cells was significantly higher in the group of patients with drug hypersensitivity – 1.6% and rhinoconjunctival symptoms 1.2% compared to the control group – 1.0%. Elevated (1.6-3.6%) and extremely high (>3.6%) CD3⁺CD294⁺ cell number were significantly more frequently detected in patients with drug hypersensitivity. In both groups, an increase in the number of CD3⁺CD294⁺ cells were observed with severe damage to the skin. The phenotype of the population T lymphocytes type 2 CD45RA-CD3⁺CD294⁺CD2⁺CD5⁺CD7⁺CD27⁺CD28⁺CD57^-CCR7^- was determined, which corresponds to effector memory T lymphocytes. With a moderately increased relative amount of this population, T lymphocytes 2 were usually represented by T helpers 2. A pronounced increase in the population was observed due to T cytotoxic lymphocytes 2. Regardless of the predominance of the Т helper or Т cytotoxic 2 cells in patients revealed an increase in spontaneous production of interleukin 4 at a normal level of interferon. An increase in the peripheral blood T lymphocytes with CD294 expression contributes to the development, maintenance and exacerbation of allergic inflammation with the participation of IgEdependent and IgE-independent mechanisms. The CD3⁺CD294⁺ cell population should be determined as an additional parameter in assessing the presence of sensitization in the basophil activation test in patients with hypersensitivity reactions. The use of this laboratory biomarker to assess the dominant type of immune inflammation will make it possible to personalize the therapy of the examined patients. Identification of pronounced deviations of indicators from the average values of a population will influence the tactics of patient management.

Local allergic rhinitis, a new endotype of allergic rhinitis discerned by researchers of the Spanish Allergy School, is now in the focus of interest of international allergological community. A special feature of local allergic rhinitis, which, being similar to conventional signs of allergic rhinitis, is, however, characterized by absence of systemic atopy manifestations, e.g., an increased total serum IgE content and positive allergic skin tests. In order to assess the level of tolerance breakdown to allergens in local and classical allergic rhinitis, we have studyed concentrations of IL-4, IL-22, and IFNγ in three biological fluids, blood, nasal secretions, and skin exudate. The whole study cohort consisted of 82 patients aged 18 to 60 years with established allergic rhinitis. The diagnosis was based on counseling by allergologist/immunologist, including clinical case history and possible inheritance of atopy as well as videorhinoscopy performed by an ENT specialist. The procedure of videorhinoscopy allowed to specify allergic origin of rhinitis and exclude the patients with non-allergic forms of the disease, but it did not enable us to differentiate between the endotypes of classic and local allergic rhinitis. Subsequently, all patients have been divided into two subgroups based on the criteria of systemic atopy: (1) with a high content of serum total IgE and positive skin allergy tests (n = 41) and (2) with a significantly lower concentration of IgE and negative allergy tests (n = 41). It was concluded that the patients with classic allergic rhinitis prevailed in the 1^st subgroup, whereas local rhinitis predominated in the 2^nd group. The study of IL-4, IL-22 and IFNγ concentrations in the three biological fluids allowed us to presume that the 1^st subgroup was characterized by increased content of IL-4 and IL-22 in blood and skin exudate in comparison with controls, and the 2^nd subgroup showed a decrease in IFNγ to control values. The cytokine concentrations in nasal secretions were not representative for the subgroups studied. The result has been interpreted as the absence of tolerance breakdown to causal allergens in the patients with local allergic rhinitis at the systemic level. The obtained data could be used in development of a diagnostic biomarker system for this specific endotype of allergic rhinitis, thus avoiding potential diagnostic errors which occurred in the past, when this endotype was classified as non-allergic form of the disease, thus administering non-adequate treatment, e.g., allergen-specific immunotherapy, which could be prescribed in these cases.

In the context of the COVID-19 pandemic, scientific interest is growing in studying the impact of the proposed vaccination on women’s reproductive health. As is known, alterations in the state of the immune system and activation of an autoimmune response can lead to reproductive failure in women and potential complications of subsequent pregnancy. Objective: to evaluate the effect of the “Gam-COVID-Vac” on the immune status parameters, the relationship of their changes and the specific immune response to vaccination with the dynamics of the level of autoantibodies in women of reproductive age.

The prospective study included 120 women who were vaccinated against COVID-19 with the “Gam-COVIDVac”. The criteria for inclusion in the study were: the age from 18 to 49 years, the absence of COVID-19 in the anamnesis, a negative result of a study on SARS-CoV-2 by PCR and negative results of tests for antibodies of classes G and M to SARS-CoV-2 before vaccination, the absence of pregnancy and serious somatic diseases. The patients were examined twice: immediately before vaccination and 90-100 days after the introduction of the 1st component of the vaccine. The level of IgG antibodies to SARS-CoV-2 after vaccination was assessed using ELISA. Before and after vaccination, the levels of antiphospholipid, anti-nuclear, organ-specific and antihormonal autoantibodies were determined, peripheral blood lymphocytes were immunophenotyped to determine the main subpopulations (CD3, CD4, CD8, CD19, CD5, CD16, CD56), as well as the expression of activation markers of lymphocytes (HLA-DR, CD25, CD147) using monoclonal antibodies.

The effectiveness and safety of the combined vector vaccine against COVID-19 were high. Specific IgG antibodies to SARS-CoV-2 were produced in 98.3% of vaccinated women, no serious adverse reactions were observed. After vaccination, there was an increase in the level of some autoantibodies within the reference ranges, only IgM antibodies to phosphatidylethanolamine (PE) and IgG antibodies to DNA increased above the reference values. However, this increase was transient. After vaccination, the following changes in the parameters of the immunogram were observed: an increase in the content of cells with CD3⁺CD25⁺, CD19⁺ phenotype in peripheral blood and a decrease in the content of cells with CD56⁺CD16⁺ phenotype within the reference ranges, a decrease in CD147⁺/CD3⁺. Weak correlations were noted between these changes in immunogram parameters and the levels of some autoantibodies. The specific antiviral immune response to vaccination did not correlate with the autoimmune response.

Vaccination with “Gam-COVID-Vac” is effective and safe and does not lead to disorders in the immune system. The observed increase in the level of autoantibodies to PE and DNA is transient. Changes in the parameters of the immune status within the reference ranges may be due to vaccination and the development of a specific antiviral immune response.

Current therapeutic approaches to the treatment of endocrine ophthalmopathy (EOP) are based on nonspecific immunosuppression with glucocorticosteroids (GCs) and radiation therapy of the eye orbits. However, some patients exhibit resistance to the treatment. In a previous study, we have detected high levels of soluble cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R, and the TGF-β1 cytokine in euthyroid patients with long-lasting non-treated EOP and Graves’ disease (GD). TGF-β1 level was significantly higher in the patients with EOP compared to healthy individuals, and increased with prolonged EOP duration, thus suggesting activation of the factors regulating immune system which promote suppression of the autoimmune process. The aim of this work was to study the dynamics of TGF-β1 and cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R in the course of immunosuppressive therapy with high doses of GCs, as possible predictors of treatment efficacy. The study included 49 patients (98 eye orbits) with GD of euthyroid state and subclinical thyrotoxicosis, and the persons with EOP in active phase, who had not previously treatment for EOP. Concentrations of TGF-β1 cytokine, sTNFα-RI and sTNFα-R2, sIL-2R, antibodies to the thyroid-stimulating hormone receptor (rTSH), free fractions of thyroxine (fT4) and triiodothyronine (fT3), TSH in blood serum were determined in blood serum. Ultrasound examination of the thyroid gland (ultrasound of the thyroid gland), multi-layer computed tomography (MSCT)/magnetic resonance imaging (MRI) of the orbits were also performed. The patients were administered immunosuppressive therapy with high doses of HCs (methylprednisolone) in the course of pulse therapy, at a standard dosage of 4500-8000 mg, taking into account the severity and activity of the EOP clinical manifestations. The examination was carried out 3, 6, 12 months after starting the treatment. 3 and 6 months after the GC administration, more than 30% of patients remained resistant to treatment. The levels of TGF-β1 did not change significantly in the patients with positive EOP dynamics. In the patients resistant to GC treatment, the level of TGF-β1 was significantly decreased compared with patients who showed positive clinical dynamics. The level of sNFR1 and sNFaR2 did not change significantly. There were no significant differences in the levels of antibodies to rTSH, thyroid hormones in the patients resistant to GC treatment and with positive dynamics.

Immunosuppressive therapy with high-dose of methylprednisolone in pulse therapy regimen showed high efficacy and good tolerability, while some patients remain resistant to treatment. Lower levels of TGF-β1 cytokine at initial time and during the treatment allow usage of TGF-β1 levels as a biomarker of the activity of the process, treatment efficiency, and prognosis of the disease. Activation of TGF-β1, a fibroblast growth factor, may contribute to the development of fibrosis, strabismus, and diplopia.

The aim of the present study was to evaluate the subpopulation profile of T and B lymphocytes, and their relationships during therapy of the patients with Graves’ disease (GD) treated by means of radioactive iodine. We have examined 36 women with verified diagnosis of GD. The contents of thyroid hormones were determined by immunoradiometric analysis. The levels of thyroid-stimulating hormone receptor autoantibodies (rTSH) were evaluated by enzyme-linked immunosorbent assay. On the basis of comprehensive pre-therapeutic examination, all patients were exposed to the fixed-activity therapy with radioactive iodine-131 at a dose of 400 to 700 MBq administered orally in isotonic aqueous solution of sodium iodide. 56 practically healthy women were examined as a control group. The phenotype of T and B cells in whole blood was studied by flow cytometry using direct immunofluorescence. It was shown that the patients, prior to treatment with radioactive iodine, had high levels of cellular functional activity, as determined by expression of CD25 antigen on T cells and CD23-antigen on B lymphocytes. Higher functional activity of the cells responsive for adaptive immunity in the patients with GD manifests in the presence of increased levels of autoantibodies to rTSH. By means of correlation analysis, we found that the patients with GD examined before the therapy had the thyroid status may determine the functional stimulation of T and B cells, thus increasing the levels of autoimmune processes. One month after radioiodine therapy (RIT), the GD patients, along with transient hyperthyroidism with increased concentration of autoantibodies to rTSH, showed a reduction of activated T lymphocyte contents (including T helpers and cytotoxic T cells) to control values. However, the level of cytotoxic T lymphocytes in the blood remained low, and the content of Treg cells was significantly increased in the patients. Decreased contents of B cells activated memory B cell to the control levels were found in patients with GD over 1 month after RIT when studying the phenotype of blood B lymphocytes. In this case, increased levels of naive B lymphocytes and B2 cells were detected, as well as decreased numbers of activated B1 lymphocytes. The observed changes in the subpopulation composition of T and B cells, and in their phenotype developed against the background of complete absence of relationships between the studied parameters, thus suggesting loss of thyroid control of immune processes and cooperative cell interaction during the development of the immune response. Generally, the phenotypic changes of T and B lymphocyte subsets in the blood of patients with GD through 1 month after treatment with radioactive iodine may reflect a trend for decreased functional activity of adaptive cellular immunity which may also account for inhibition of autoimmune processes.

Rheumatoid arthritis (RA) ranks first among chronic joint diseases. The disease often affects people at their working age, being accompanied by significant decrease in the life quality of patients and their early disability. Rheumatoid arthritis is an immunoinflammatory rheumatic disease. Therefore, the immune system provides evolving focus of primary damage, its persistence and periodic exacerbation. Elucidation of intercellular relationships mediated by cytokines at various stages of the chronic inflammatory process is required in order to develop immunotherapeutic approaches, aimed for both recovery from exacerbations and maintenance of remission state. Purpose of our study was to evaluate cellular composition and cytokine profile of synovial fluid in the patients with rheumatoid arthritis at acute phase and in remission state.

We have studied the samples of synovial fluid taken in 60 patients with rheumatoid arthritis, with 30 subjects being at acute stage of the disease, and 30 patients in remission. Cellular composition and cytokine profile were assessed in the clinical samples. There were 21 women and 9 men at the acute stage (57.0±15.4 years old), with the disease duration of 8.55±6.9 years. The average age of 19 women and 11 men examined in remission state was 53.5±10.9 years, with comparable duration of illness (6.9±5.8 years). The leukocyte phenotyping was performed with a CytoFLEX flow cytometer (Beckman Coulter, USA). The cytokine contents were measured by enzyme immunoassay using a standard set of reagents from the “Proteinovy Contour” LLC (Russia). The results were registered by a Multiscan photometer (Labsystems, Finland).

During the disease exacerbation, the leukocyte contents in synovial fluid increased 2.4-fold, as compared to the remission values. The cellular infiltrate was represented by neutrophils, whereas the contents of lymphocytes and monocytes did not change. Increased migration of neutrophils was accompanied by an 8-fold increase in TNFα levels, compared with remission state, and IL-1β levels were increased by 6.3 times. The absolute number of CD3⁺T lymphocytes, CD16⁺CD56⁺B cells, and CD3^-CD19⁺NK during exacerbation was similar to the remission levels. However, the number of T cell subpopulations was changed, i.e., the number of CD4⁺ lymphocytes was decreased, and CD8⁺ cell counts were increased, like as numbers of Treg lymphocytes and NKT cells which showed a significant increase. A 4.3-fold increase in the IL-4 concentration during the RA exacerbation suggested the predominance of Th2 immune response. During remission, the concentrations of IL-6 and IFNγ in synovial fluid were increased, respectively, by 1.5 times and by 2.5 times, which is typical for activated Th1 response.

Primary immunodeficiencies (PID) are a heterogeneous group of hereditary diseases that lead to impaired immune defense. Often, the diagnosis cannot be made without identifying mutations that lead to the development of the disease. For many PIDs, there is no clear understanding of the etiology, pathogenesis, and genes involved. There is an obvious need to identify candidate genes potentially capable of leading to the development of PIDs.

Hereditary angioedema (HAE) is a rare genetically determined disease, accompanied by recurrent edema of soft tissues and submucosal membranes, posing a threat to the life of patients. Diagnosis is based on the clinical presentation, family history, laboratory values of C1-esterase inhibitor, complement component 4, complement component 1q, antibodies to C1 and genetic testing for a number of mutations in the genes SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6. However, pathogenesis may involve other genes in which the negative effect of mutations has not yet been studied. HAE is a non-monogenic disease that may involve an extensive network of genes. It seems important to determine the groups of the most probable candidate genes presumably involved in the development of pathology.

Aim – to identify, using bioinformatics analysis, candidate genes for the development/pathogenesis of HAE and to reveal their biological context.

The analysis was based on a group of genes, mutations in which are significantly associated with HAE: SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6. To analised genetic and protein–protein networks and identify the biological context of the selected candidate genes, a number of web resources were used: HumanNetv3, GeneMania, FUMA GWAS in the GENE2FUNC mode.

One hundred potential candidate genes in which mutations can be associated with HAE have been identified. The biological context of the identified genes was determined. The data of the biological context, genetic and protein-protein interactions made it possible to exclude a number of genes from the list of the most likely participants in pathogenesis and divide the remaining ones into groups with a greater or lesser potential for involvement. The group of the most likely HAO candidate genes includes PLAT, HRG, SERPINA1, SERPINF2, MASP2, GRB14, C1QBP, DOK2, KLKB1, F11, TEK, KLK10, KRT1, APOH, CPB2, F2.

The results obtained can provide significant assistance in the study of the HAE molecular mechanism, as well as in the diagnosis and prognosis of the disease course. The identified candidate genes have the potential to serve as diagnostic biomarkers for patients with unexplained angioedema.

The use of bioinformatic methods makes it possible to determine the list of candidate genes that are presumably involved in the disease pathogenesis or aggravate its course, and to obtain up-to-date information about the biological context of the identified genes. Understanding the genetic underpinnings and pathophysiology of PID may help define new diagnostic and therapeutic targets.

Efficacy of search for the unrelated compatible transplant donors depends on a number of factors. Of most importance are the standards of primary HLA typing, and the immunogenetic diversity of the donor pool. Timely donor selection guarantees the optimal timing for stem cell transplantation. This factor exerts positive influence upon the transplantation outcomes. In 2019, The Bone Marrow Donors Registry at the Russian Research Institute of Haematology and Transfusiology has implemented HLA-typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 genes as a standard for primary immunogenetic examination, in order to reduce the donor search period. The aim of our study was to evaluate the HLA typing results for potential stem cell donors at our Registry as compared with immunogenetic profile of donors at the Registries arranged in two Russian megapolises. All currently known groups of HLA-C, HLA-DRB1, HLA-DQB1 gene alleles, 19 of 21 open groups of HLA-A gene alleles, 34 of 36 known groups of HLA-B gene alleles were screened in the donors from our Registry. The most common HLA alleles groups were as follows: A*02 (0.2957), A*03 (0.1432), A*01 (0.1155), A*24 (0.1128); B*07 (0.1282), B*35 (0.1084), B*44 (0.0921), B*18 (0.0745); C*07 (0.2738), C*04 (0.1361), C*12 (0.1202), C*03 (0.1134), C*06 (0.1127); DRB1*15 (0.1445), DRB1*07 (0.1420), DRB1*13 (0.1271), DRB1*01 (0.1269), DRB1*11 (0.1216); DQB1*03 (0.3517), DQB1*06 (0.2269). A total of 1702 HLA-A*-B*-C*-DRB1*-DQB1*-haplotypes were revealed in our donor pool. The frequency of nine HLA-haplotypes exceeded 0.01: A*01-B*08-C*07-DRB1*03-DQB1*02 (0.0366), A*03-B*07-C*07-DRB1*15-DQB1*06 (0.0269), A*03-B*35-C*04-DRB1*01-DQB1*05 (0.0238), A*02-B*13-C*06-DRB1*07-DQB1*02 (0.0204), A*02-B*07-C*07-DRB1*15-DQB1*06 (0.0184), A*25-B*18-C*12-DRB1*15-DQB1*06 (0.0127), A*02-B*18-C*07-DRB1*11-DQB1*03 (0.0126), A*02-B*15-C*03-DRB1*04-DQB1*03 (0.0123), A*02-B*41-C*17-DRB1*13-DQB1*03 (0.0109). We carried out a comparative analysis of the HLA-haplotypes distribution for the donors of three Russian registers: Russian Research Institute of Haematology and Transfusiology (St. Petersburg); First St. Petersburg State I. Pavlov Medical University (St. Petersburg); National Medical Research Center for Hematology (Moscow). The six most common HLA-haplotypes among the donors from three Russian registers had the same rank positions and frequencies. The differences of some less common HLA-haplotypes distribution were determined. The results of our study indicate the immunogenetic diversity of the donor pool the Registry of Russian Research Institute of Haematology and Transfusiology. This fact, along with usage of international standards for primary immunogenetic examination is a prerequisite for effective donor search for the patients requiring stem cell transplantation.

Chronic psychosocial stress provokes anxious behavior and depressive disorders. The longitudinal stress-induced neuroendocrine signals may alter functioning of immune (central and peripheral) organs. Increased myelopoiesis is observed in bone marrow, being detrimental to lympho- and erythropoiesis, with increased emigration of monocytic bone marrow cells to the periphery and their acquisition of “inflammatory” phenotype. The subsequent migration of such monocytes to the brain with differentiation into the M1 type macrophages which form inflammatory signals, and their effect upon endothelial cells and microglia leads to increased production of cytokines, chemokines, and adhesion molecules, thus accelerating accumulation of bone marrow-derived monocytes migrating to the brain. The signals from bone marrow monocytes and activated microglia promote neuroinflammatory condition which leads to behavioral changes. Current data on the presence of non-resident bone marrow macrophages in the brain of depressed patients require studies of hematopoiesis in depression-like states. Pronounced plasticity is a characteristic feature of macrophages, i.e., their ability to acquire M1 or M2 phenotype depending on the microenvironment signals. M1 exhibit high pro-inflammatory activity and have neurodestructive properties, whereas M2 cells are characterized by low pro-inflammatory activity and pronounced regenerative potential, due to the production of multiple soluble mediators and cytokines, including neurotrophic and immunoregulatory factors, anti-inflammatory substances that provide neuroprotection, stimulate neurogenesis, synaptogenesis, growth and myelinization of axons, thus theoretically substantiating an opportunity of using the potential of M2 macrophages in the treatment of depression. In this work, we studied the effect of soluble factors of human macrophages, polarized into cells with M2 phenotype under the conditions of serum deprivation, upon bone marrow hematopoiesis and peripheral blood cells in a model of stress-induced depression. We have shown enhanced differentiation of hematopoietic stem cells into the granulocyte-macrophage (CFU-GM) lineage, along with increased monocyte population in peripheral blood in the depressive-like murine model. Development of a depressive-like state in the animals was associated with reduced amounts of both erythroid precursors in bone marrow and erythrocytes/hemoglobin in peripheral blood. Intranasal administration of soluble M2 macrophage factors (M2-SFs) for 7 days was accompanied by a corrective effect on the above parameters, being significant for peripheral blood monocytes. The data obtained suggest effectiveness of the M2-SFS anti-inflammatory effects in correcting changes in hematopoiesis caused by social stress in depressive-like animals.

Comparative analysis of antiviral protective mechanisms in protozoa and RNA interference of multicellular organisms has revealed their similarity, also providing a clue to understanding the adaptive immunity. In this article, we present the latest evidence on the importance of RNA-guided gene regulation in human antiviral defense. The role of neutralizing antibodies and interferon system in viral invasion is considered. The new concept has been introduced, i.e., antiviral protection of any living organism is based on the intracellular RNA-guided mechanisms. Simple and effective defense against viruses is that spacer segment of the viral DNA is inserted into the cellular chromosomes. Upon re-infection, the RNA transcript of the spacer directs nuclease enzymes against the foreign genome. This is a really adaptive immune defense that any cell potentially possesses. In humans, the interferon system provides an additional tool for early suppression of viral infections which shifts the cells to the alert regimen, thus preventing further spread of infection. The main task of the human central immune system is to maintain integrity and combat foreign organisms. Accordingly, a suitable index of acquired antiviral immunity should be a presence of specific spacer markers in DNA samples from reconvalescent persons, rather than detection of neutralizing antibodies, B and T memory cells.

This article is addressed primarily to general medical community, and its practical conclusions are as follows:

1. Presence or absence of specific antibodies to SARS-CoV-2 is not a prognostic sign of the disease. Detection of specific antibodies in blood simply reflects the fact that the person has contacted with the viral agent. Absence of antibodies does not mean a lack of such contact, and the persons with high titers of specific antibodies are not protected from re-infection with SARS-CoV-2.

2. PCR testing: The PCR results may remain “false positive” in those subjects who have had COVID-19, if the genetic material is taken from the site of initial virus contraction (mainly, nasopharynx). In our opinion, negative PCR tests for COVID-19 in blood plasma and urine will be a more correct index for the absence of the disease, even with positive PCR tests from the nasopharyngeal samples.

3. It is necessary to draw attention of general practitioners to potential usage of retinol in prevention and treatment of COVID-19, given the importance of RLR receptors in recognition of viral RNAs and positive experience of vitamin A administration in measles, another dangerous viral disease.