According to the results of recent studies, diabetic retinopathy can be considered not only as a vascular disease, but also as a neurodegenerative process. Study of the composition of the tear fluid is used to assess the state of local immunity in the development of eye diseases. However, studies examining the effect of tear composition in diabetic retinopathy are few. The aim of the study is to determine the levels of IL-1β, IL-10, TGF-β3, MMP-7, TIMP-2, protein S100b, BDNF and NGF in the tear fluid ofpatients with vascular and neurodegenerative manifestations of diabetic retinopathy. The study included 80 patients diagnosed with type 2 diabetes which were divided into 2 groups: the 1^st group included 40 patients who had no clinical signs of diabetic retinopathy on the fundus; the 2^nd group included 40 patients with initial signs of non-proliferative diabetic retinopathy. All those included in the study were examined on an optical coherent tomograph RTVue-100 (USA); the volume of focal losses of retinal ganglion cells (FLV) was determined. An increase in FLV above the normative base of the device was regarded as an OCT-sign of retinal neurodegeneration. According to the results of OCT, the participants of the first and second groups were additionally divided into 4 subgroups: 1A — patients without vascular changes in the fundus and without OCT signs of retinal neurodegeneration (n = 12); 1B — patients without vascular changes in the fundus and with the presence of OCT signs of retinal neurodegeneration (n = 28); 2A — patients with initial non-proliferative DR and without OCT signs of retinal neurodegeneration (n = 10); and 2B — patients with initial non-proliferative DR and with OCT signs of retinal neurodegeneration (n = 30). The levels of IL-1β, IL-10, TGF-β3, MMP-7, TIMP-2, protein S100 b, BDNF, and NGF in tear fluid were determined by enzyme-linked immunosorbent assay. Levels of IL-1β and IL-10 in tear fluid in all subgroups were comparable to controls throughout the study. TGF-β3 content in the tear fluid of patients in the group with initial signs of non-proliferative DR (group 2) was significantly (p = 0.001) lower compared with control and group 2. However, there was no significant difference (p > 0.05) between subgroups A and B within groups. The concentration of MMP-7 in the tear fluid in all subgroups was significantly lower than in the control (p < 0.05). However, in the subgroups with OCT signs of retinal neurodegeneration (1B and 2B), the deficiency of this metalloproteinase was more pronounced (p = 0.0001). The levels of the neuropeptides under study NGF, BDNF and S100 B in tear fluid did not differ from controls in all subgroups.

An increase in the incidence of optic neuritis among the working-age population, as well as an unpromising prognosis for vision due to the development of optic nerve atrophy, determines the high social significance of this problem. The aim of the work is to analyze the effect of Imunofan at the parameters of cellular immunity and clinical symptoms of the disease in the complex treatment of optic neuritis associated with herpes virus infection. The study involved 37 people (37 eyes) with acute optic neuritis associated with herpes infection. The treatment regimen included the appointment of a dexamethasone solution according to a decreasing scheme, a 1% solution of the drug Emoxipin 0.5 mL and a 12.5% solution of the drug Dicynone 0.5 mL through an irrigation system implanted in the retrobulbar space, in combination with the neuroprotection drugs (Pikamilon and Semax) for 10 days. All patients were divided into 2 groups. The main group consisted of 20 patients who received Imunofan to the treatment regimen in addition. The comparison group included 17 patients who were treated only according to the method described above. The course of treatment lasted 10 days. The analysis of the data showed a more significant positive dynamics of cellular immunity parameters in those who received immunotherapy. Our studies showed the effectiveness of this drug in the complex treatment of optic neuritis associated with herpes infection, what is confirmed by the acceleration of inflammation relief, a more significant increase in visual functions of patients treated with Imunofan, and a lower percentage of optic nerve atrophy. In this group of patients, changes in the parameters of the cellular link of immunity occurred earlier and remained stable throughout the entire period of observation. According to our data, an intergroup assessment of the immunoregulatory index showed its faster increase in patients of the comparison group who received Imunofan, and reached normal values already 6 months after treatment. The clinical effectiveness of Imunofan in the complex therapy of optic neuritis associated with herpes infection was characterized by a reduction in the period of relief of signs of inflammation in the optic nerve by 2 times or more, by an increase in the maximum corrected visual acuity by 4.5 times, and by a decrease in the incidence of recurrence of optic neuritis by 2 times over a 12 months observation period.

MS is a common disease of the central nervous system that leads to disability and reduced quality of life. The debut of disease in 3-5% of patients occurs in childhood and has a less favorable course compared to adults. MS is caused by the activation of autoreactive T cells in the breakdown of peripheral tolerance, which is normally controlled by regulatory T cells (Tregs). It is promising to study expression of CD39 and CD73 in Treg and Th17 populations to assess their suppressive activity. Aim is to evaluate content of major and minor lymphocyte populations and expression of CD39 and CD73 in CD4⁺ lymphocyte population in children with MS. 111 children with MS were examined, 66 with contrast-negative lesions on MRI (Group 1), 45 with contrast-positive lesions (Group 2). The comparison group consisted of 46 healthy children (Group 3). Content of T, B, NK lymphocytes, Treg (CD4⁺CD25^highCD127^low), Thact (CD4⁺CD25^highCD127^high), Th17 cells (CD3⁺CD4⁺CD161⁺); expression of CD39 and CD73 in Treg, Th17 and Thact was performed by flow cytometry. An increase in content of T helpers, a decrease in NK cells in patients in group 2 was revealed. An increase in number of Thact and Th17 lymphocytes was obtained in patients of both groups with MS. Number of Tregs in group 1 was significantly higher than in group 3. Ratio of cells expressing CD39 and CD73 in MS patients depended on lymphocyte population as well as in the group 3. The highest content of CD39⁺ cells was observed in Treg population, and the lowest in Thact population. For CD73 expression, on the contrary, the highest expression of CD73 was observed in Thact cells, the lowest in Treg. When comparing groups of patients, it was found that in patients of group 1, number of cells expressing CD39 ectonucleotidase was significantly increased, and number of supTh17 was comparable with group 3. In both groups of MS patients, an increase in CD73 counts in Treg, Thact and Th17 was observed. Thus, informative populations of lymphocytes (CD4⁺ cells, Treg, CD39⁺Treg, supTh17) have been identified, which can be used to monitor condition of children with multiple sclerosis.

Metalloproteinases (MMP) play a significant role in the mechanisms of maintaining chronic inflammation and tissue remodeling. The study of concentration changes in these enzymes in the blood serum of children with allergopathology is of great practical and scientific interest.

Objective: to study the role of MMP-9 in the pathogenesis of allergic diseases in children. 180 children aged from 1 to 18 years passed a comprehensive clinical and laboratory examination. This study included patients suffering from bronchial asthma (BA) (n = 54), atopic dermatitis (AD) (n = 54) and combination of these pathologies (n = 72). Serum levels of MMP9 were determined by enzyme immunoassay using Cloud-CloneCorp® test systems (USA).

The analysis of the obtained data showed that among patients with the established diagnosis of BA, the maximum concentration of this cytokine was registered in children with a moderate course of the disease. The conducted correlation analysis showed the presence of a significant correlation between the severity of asthma and the level of control over the disease (r = 0.63). Similar data was obtained in patients with a combination of BA and AD. In children of this group, there was also a significant increase in serum MMP-9 compared with healthy patients (p = 0.015). The concentration of this matrix metalloproteinase in serum was slightly higher among children with polyvalent sensitization than in patients with monoallergic etiology of the disease (p = 0.272). The values of MMP-9 in patients with only skin manifestations of atopy were significantly higher than in the control group (p = 0.025).

The data we obtained showed that all the patients we examined had a significant increase in the level of MMP-9 in the blood serum, which indicates an important role of this cytokine in the pathogenesis of allergic diseases in children.

The main mechanism for the occurrence of urticaria is the degranulation of mast cells. It has been proven that, regardless of the activation pathway, clinical manifestations will not differ. According to the literature, up to half of cases of chronic spontaneous urticaria are autoimmune in nature, can be combined with autoimmune thyroid disease, SLE, etc., and have a more severe course.

In therapy, antihistamines are traditionally used. However, some patients do not respond to the treatment, even with a multiple increase in doses. In the treatment of urticaria resistant to traditional antihistamines, the use of Omalizumab is recommended. The purpose of the study: to determine the profile of patients with chronic urticaria, as well as to evaluate the effectiveness of treatment with Omalizumab in patients with IgE- dependent and IgE-independent chronic urticaria.

Eight-one patients with chronic urticaria (60 adults, 21 children) were examined. Patients before the start of therapy had a long history of CU: from 1 to 20 years. Patients before the start of therapy were treated with antihistamines, but no control was obtained. An increase in the level of serum IgE was detected in 51.7% of cases in adults and 42% in children. Concomitant sensitization was determined in 48.3% of adults and 76.2% of children. In children, food, epidermal and pollen sensitization was the most common. Pollen and epidermal sensitization were more common in adults. The level of eosinophilia in the group with IgE-dependent was more pronounced than in other group (p = 0.0097). After 6 months, the group with IgE-dependent showed an improvement in the symptom score (UCT) from 3.1 CI (1.5-4.6) to 12.2 CI (10.8-13.7), (p = 0.0001). In other group, symptoms improved from 0.63 CI (0.36-1.6) to 8.1 CI (5-11.2) after 6 months (no control). After 6 months of genetically engineered biological therapy (GIBT), complete control over the symptoms of CU in group 1 was obtained in 66.7% of patients, partial — in 33.7%. In the second group, in 33.3% of cases, positive treatment results could not be achieved. Thus, genetically engineered biological therapy with Omalizumab increases the control over the course of CU. Treatment outcomes are higher in patients with an IgE-dependent disease profile.

Atopic dermatitis is a multifactorial genetically determined inflammatory skin disease characterized by itching, chronically relapsing dermatitis, age-related features of localization and morphology of lesions. The pathogenesis of atopic dermatitis is complex and includes epigenetic alterations, involved in the genomic adaptation, immune response reactions and dysfunction of the epithelial barrier that together trigger the development of atopic dermatitis. The aim of this study is to detect the expression level for IL4, IL13, IL33, TLR2, TLR9 genes in the biological materials of atopic patients.

The targeted genes for further expression evaluation were selected according to our previous findings on genome-wide methylation study. We detected the cascades with the differentially methylated genes that are most likely to take place in atopic dermatitis. Thus, we investigated expression levels for the IL4, IL13, IL33, TLR2, TLR9 genes in the skin, peripheral blood mononuclear cells and whole blood cells using RT-PCR on 55 pediatric patients and 26 healthy volunteers, and on 50 adult patients. Statistical analysis was performed with the use of Kruskal-Wallis H test and Mann-Whitney U test. Targeted expression analysis revealed that in the skin samples the expression of TLR9 and IL4 was 12 times significantly lower (p < 0.0001, p < 0.0005) in the lesional skin; and there was a 6-fold decrease in case of TLR2 (p < 0.01). The results for blood mononuclear cells differed and expression levels for most of the assessed targets were significantly higher before treatment. We have also found out that those differences were strongly pronounced especially in an elder age group (12-18 y.o.). Studying the IL33 gene expression in the whole blood samples of adults revealed that its level was significantly higher in case of patients with moderate form of AD. Besides, we concluded that locally in the affected skin inflammatory immune response may dominate; in the mononuclear cells Th2 immune response apparently takes place. New insights on immunological markers and links among them may shed a light on atopic dermatitis pathogenic mechanisms. The detected molecules could play role as potential therapeutic targets and form a management approach for patients with atopic dermatitis.

Toll-like receptors (TLRs) are the most studied among all Pattern Recognition Receptors, the main function of which is to initiate innate immune response by recognizing pathogen-associated molecular patterns of various microorganisms on the skin surface. TLR-mediated recognition plays an important role in linking innate and adaptive immunity that ultimately leads to the production of key cytokines, chemokines and antimicrobial peptides. Today, there is growing interest in research on single nucleotide polymorphisms (SNPs) in TLR genes and its influence on susceptibility to inflammatory disease, including atopic dermatitis. The aim of the research was to study the association of the rs5743708 gene polymorphism in the TLR2 gene, the rs4986791 gene polymorphism in the TLR4 gene and the rs352140 gene polymorphism in the TLR9 gene with the risk of developing severe cases of AD. A total of 100 patients with AD were included in the study (38 male and 62 female). The age range was from 18 to 65 years old. All participants were divided into 2 groups according to the SCORAD index (SCORing Atopic Dermatitis). The control group included 72 volunteers over 18 years old. The results of our study showed a statistically significant difference between the moderate AD group and healthy controls in the rs352140 gene polymorphism in the TLR9 gene (Figure 1). The frequency of the GG genotype of SNP rs352140 in TLR9 was 0.169 in the AD group versus 0.329 in the control group (p < 0.05; OR = 0.42; 95% CI = 0.18-0.97).

In conclusion, the results of our study showed that the TLR9 rs352140 gene polymorphism may be linked to an increased risk of atopic dermatitis. Moreover, it was found that the GG genotype of SNP rs352140 in TLR9 can be used as a predictor of the risk of developing moderate AD.

Immune cell hyperactivation along with cytokines they overproduce plays an important role in sarcoidosis and related disease pathogenesis. A central place in the immunopathogenesis of sarcoidosis is held by diverse cell-mediated reactions governed by T helper (Th) cell populations including Th17 subsets and relevant signature cytokines. We studied peripheral blood plasma samples of the patients with sarcoidosis (n = 123): 18% with acute and 82% with chronic course. The control group — samples from healthy volunteers (n = 43). T cell subset composition was assessed by flow cytometry. Cytokine concentrations (pg/mL) were measured by multiplex analysis using xMAP technology (Luminex). The level of “classical” Th17 turned out to be significantly reduced in acute vs chronic sarcoidosis: 28.3% vs 33.3% (p = 0.046). The level of “double-positive” Th17 (DP Th17) was significantly increased in chronic and acute vs control group: 31.7% and 34.2% vs 26.2% (p < 0.001 in both cases), without differences patient inter-group; “non-classical” Th17.1 were shown to have significantly reduced level only in chronic vs healthy subjects: 27.9% and 35.9% (p < 0.001). Clinical and laboratory diagnostic characteristics for blood DP Th17 levels in CD45RA-negative Th effector memory cells in sarcoidosis: in acute sarcoidosis vs healthy subjects, they were characterized by sensitivity — 82%; specificity — 71%, whereas in chronic: 67% and 56%, respectively. In patients with sarcoidosis vs healthy subjects were found to have significantly increased level of IL-12 (p70) — 1.3 vs 0.56, p = 0.028; IL-17A — 1.5 vs 0.43, p < 0.001; IFNγ — 4.1 vs 1.1, p < 0.001; TNFα — 21.7 vs 6.7, p < 0.001. Thus, CCR6⁺ Th17 and DP Th17 subsets and relevant signature cytokines are important in diagnostics of sarcoidosis of varying clinical course: a direct correlation was shown between the level of angiotensin-converting enzyme activity and percentage of memory DP Th17; disease progression vs regression had significantly reduced absolute number of total CD45RA^- memory and CM Th17; extrapulmonary manifestations had a significantly increased percentage of DP Th17 CD45RA^- and EM DP Th17; in chronic sarcoidosis are significantly increased concentration of IL-17A, IFNγ, IL-12 and positively correlation between IFNγ and the activity of angiotensin-converting enzyme.

The relationship between the processes of coagulation and inflammation protects the organism from potentially dangerous biological agents. However, hyperinflammation leads to an increase in the procoagulation potential, and activation of hemostasis factors maintains the inflammatory process. This phenomenon is called “immunothrombosis” or “ thromboinflammation”. The study of thromboinflammatory mechanisms is an actual problem of modern medicine, because in the future it will help to improve the therapy of diseases, in the pathogenesis of which thromboinflammation plays a significant role. The aim: to carry out a comparative analysis of the severity of the systemic inflammatory response in patients with immuno- inflammatory rheumatic diseases depending on the manifestations of hypercoagulation.

To achieve the aim, a comparative analysis of proinflammatory markers (IL-6, IL-8, IL-10, TNFα, sIL-2R, CRP, ECP, β2-microglobulin) in the blood of patients with immune-inflammatory rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, psoriatic arthritis, rheumatic heart disease) was performed. Based on these inflammatory markers according to the authors' original methodology, the integral index of systemic inflammatory response (SIR) — Reactivity Level (RL) — was calculated. The cohort was divided into 2 groups: with the presence of signs of hypercoagulation and without signs of hypercoagulation according to the presence of elevated D-dimer level (> 500 ng/mL). Control group — healthy blood donors.

The results of the study showed that SIR develops in patients with immuno-inflammatory rheumatic diseases regardless of the blood hemostatic potential. Patients with signs of hypercoagulation were characterized by higher values of most proinflammatory molecular markers, as well as increased integral level of SIR, which indicates a strong relationship between coagulation processes and inflammation at the systemic level. In addition, the probability of hypercoagulation increases with increasing severity of SIR (assessed by means of the integral index — RL). Thus, there is a transition of quantitatively more pronounced signs to a new qualitative level of pathological process development.

The pathogenesis of immuno-inflammatory rheumatic diseases is characterized by the development of SIR (hypercytokinemia, acute phase response, intravascular leukocyte activation), the severity of which is closely related to intravascular microthrombosis.

Considering the presence of immunomodulatory properties of human endogenous retroviruses, namely (i) the ability to activate the innate immune response by HERVs nucleic acids; (ii) the antigenicity of transcriptionally competent endogenous retroviruses envelope protein molecule, which causes polyclonal activation of lymphocytes; (iii) the absence of HERVs expression and protein production in the thymus during the immune tolerance formation, which allows us to consider these proteins as autoantigens or neoantigens, it seemed relevant to investigate the association of replication-competent human endogenous retrovirus HERV-E λ 4-1 with course of some of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. The aim of this work was a comparative study of the human endogenous retrovirus HERV-E λ 4-1 activation frequency in blood mononuclear cells in multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, as well as in chronic nervous system non-progressive diseases and the degenerative-dystrophic disease of the musculoskeletal system. The peripheral blood mononuclear cells were isolated by the venous blood centrifugation on Ficoll density gradient of 1.078 g/cm³. Expression of the HERV-E λ 4-1 envelope gene was detected by reverse transcriptase polymerase chain reaction. It was found that the HERV-E λ 4-1 envelope gene expression frequency in the chronic non-progressive diseases of nervous system, as well as in degenerative-dystrophic joint disease, is comparable to the expression frequency in conditionally healthy individuals. However, the HERV-E λ 4-1 envelope gene expression frequency in autoimmune diseases significantly exceeded that in conditionally healthy individuals and in non-inflammatory diseases. The maximum values of expression frequency were observed in active multiple sclerosis, significantly higher than in systemic lupus erythematosus and rheumatoid arthritis in the acute stage. Moreover, the expression frequency in the remission stage of multiple sclerosis was significantly lower than in the acute stage of the relapsing-remitted course, as well as in the progredient course. Estimation of HERV-E λ 4-1 envelope gene expression frequency at different severity levels of multiple sclerosis revealed its maximum rates at III and IV-V severity levels, both in relapsing-remitting and progressive course of multiple sclerosis. Thus, activation of the human endogenous retrovirus HERV-E λ 4-1 is associated with the course of autoimmune diseases, namely multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; it positively correlates with the activity and severity of multiple sclerosis.

Psoriasis is a chronic inflammatory skin disease characterized by increased proliferation of epidermal cells, impaired keratinization and an inflammatory reaction in dermis caused by activation of T lymphocytes and synthesis of pro-inflammatory cytokines. The pathophysiology of psoriasis is also associated with a decrease in anti-inflammatory functions of immunosuppressive cells. Recently, there are more cases of development of resistance to ongoing therapy with biologics in children, requiring cancellation of drug or its replacement. The aim of the study was to evaluate the content of T helper subpopulations in prognosis of effectiveness of biologics in children with psoriasis. Immunophenotyping of T helper populations was performed in 110 children with psoriasis vulgaris before appointment of biologics, at 16 and 52 weeks. Age of children ranged from 6 to 18 years. Severity of psoriasis and effectiveness of therapy were assessed by index PASI, which varied 0-68. Content of Tregs, Thact and Th17 was determined by flow cytometry. In group with a sufficient effect of biologics, a decrease in PASI was obtained, both at week 16 of therapy (p = 0.000) and by year of treatment, p = 0.017. In children with psoriasis, regardless of duration and effectiveness of biologics, percentage of Thact was increased relative to normal values. In group 1 before prescription of biologics was increased percentage of Thact (p = 0.005) and Th17 (p = 0.001). Analysis of dynamics of content of small populations of T helper during 1 year of use of biologics in children with different efficacy of therapy showed that significant changes were found in content of Th17 and Treg, as well as their Th17/Treg. ROC analysis showed that when Th17 deviation was above 53%, Thact above 181% and Th17/Treg above 2.6 before biologics were prescribed, insufficient efficacy of therapy could be expected in 75% of cases by year. By the end of induction course, with a Th17 deviation above 102% and a Th17/Treg above 2.6, probability of ineffective treatment was already 82%. The study shows the informative value of assessment of Thact before appointment of biologics, dynamics of Th17 by the end of induction course and Treg after 16 weeks of therapy in prognosis of effectiveness of biologics in children with psoriasis.

Innate immune cells, including myeloid cells — myeloid derived suppressor cells (MDSCs) — are supposed to play an important role in the pathogenesis of axial spondyloarthritis (AxSp). Myeloid derived suppressor cells represent a heterogeneous population of immature cells capable of suppressing innate and adaptive immune responses with the most pronounced suppressor activity against T cells. Biological disease-modifying antirheumatic drugs (bDMARDs) can reduce the clinical and laboratory disease activity, but their effectiveness varies widely in different patients with AxSp. The present study is aimed at studying MDSCs subpopulations and their suppressive function depending on the response to bDMARD therapy in AxSp. The study included AxSp patients with a disease duration of 16.5 years (median); HLA-B27 (+) status was detected in 79% of cases. All patients received bDMARDs at least the past 12 weeks, including TNF inhibitors (etanercept, certolizumab pegol, adalimumab, or golimumab) or IL-17 inhibitors (secukinumab, ixekizumab, or netakimab). Percentage of granulocytic MDSCs (G-MDSCs, Lin^-HLA-DR-CD33⁺CD66b⁺), monocytic MDSCs (M-MDSCs, HLA-DR^low/-CD14⁺), MDSCs of early stage differentiation (E-MDSCs, Lin^-HLA-DR^- CD33⁺CD66b^-), as well as intracellular expression of arginase-1 was assessed by flow cytometry. Frequency of circulating MDSC subpopulations of patients with a stable response to bDMARDs (responders) did not differ significantly compared to healthy donors. Patients not responding to bDMARDs therapy showed increased relative and absolute number of E-MDSCs compared to healthy donors (p_U = 0.01 and p_U = 0.02, respectively) and the responders (p_U = 0.03 and p_U = 0.07, respectively). Increased percentage of E-MDSCs was positively correlated to disease activity — ESR (R_s = 0.821; p = 0.023), CRP (R_s = 0.714; p = 0.07) and ASDAS_CRP (R_s = 0.829; p = 0.042) in the non-responder group. Responder patients exhibited no correlation between disease activity and circulating MDSCs. The suppressor potential of MDSCs was analyzed by the intracellular expression of arginase-1 molecule which is involved in the inhibition of T cell response. Patients with the stable response were characterized by increased expression of arginase-1 in E-MDSCs compared to donors (p_U = 0.02). Non-responders did not demonstrate significant changes in Arg-1 expression, however, the percentage of arginase-1-expressing G-MDSCs was positively correlated to indexes ASDAS_ESR (R_s = 0.857; p = 0.014) and BASDAI (R_s = 0.785; p = 0.036). Thus, E-MDSCs as well as arginase-1 expression in MDSCs may serve as biomarkers of effectiveness bDMARD therapy, and act as potential candidate predictors of response to therapy in AxSp.

Autoimmune diseases currently take a leading place in terms of frequency of occurrence in the population, among which 1 percent is occupied by rheumatoid arthritis (RA). Remission in this type of disease is extremely rare and requires constant use of pharmacotherapy. Studying the pathogenesis of RA is necessary to study to search for new drug targets. It is known that T helpers 1 (Th) and Th17 are involved in the development of RA. However, some researchers suggest that ILCs play a role in the development of RA. ILCs are “innate analogues” of Th, due to the fact that this subpopulation synthesizes the same cytokines. ILC1 is innate analogs of Th1, ILC2-Th2, ILC3-Th17. ILCs are tissue-resident innate lymphoid cells that have functional diversity and regulate the direction of the immune response through the production of cytokines.

We used peripheral blood mononuclear cells (PBMCs) from patients (n = 19) and conditionally healthy donors (n = 10) as material. The group of patients was divided biologic disease-modifying anti-rheumatic drugs (bDMARDs) and Metotrexate (MTX) and of stage of RA (early and very early arthritis, advanced and late). PBMCs were stained with monoclonal antibodies. ILCs were identified as Lin^-CD127⁺, CD294⁺ILCs (ILC2) were measured in the general population, CD117-CD294-ILCs were identified as ILC1, and CD117⁺CD294^-ILCs were identified as ILC3.

We obtained the following results: ILC1 was significantly reduced in patients treated with MTX comparison with patients on bDMARDs and healthy donors. However, patients on MTX with advanced RA had low levels of ILC2 and ILC3 compared to patients on bDMARDs. ILC2 significantly increased in patients with early stages of RA comparison with patients with advanced RA. However, ILC1 was significantly reduced in patients treated with MTX, and ILC3 increased significantly in patients treated with MTX comparison with bDMARDs. Expression of PD1 on ILC1 was increased compared to patients treated with bDMARDs. However, ILC3 patients with advanced stages on MTX had increased expression of PD1 comparison with patients taking bDMARDs. The ILC3 of donors was significantly increased comparison with patients on bDMARDs.

Arthropathy is one of the most prevalent diseases, which are based on the destruction and remodeling of cartilage and bone tissue. The inflammation that precedes destruction can be caused by mechanical stress on the joints, or by autoimmune reactions. Recently, IL-7 is considered as one of the key cytokines that promote the production of matrix metalloproteinases, catabolic enzymes, T cell-mediated activation of monocytes, and maturation of osteoclasts. The soluble form of the IL-7 receptor can help prolong the lifespan of IL-7 and thereby it ensures the bioavailability of the cytokine and mediates effect of IL-7 on cells. The aim of this study was to determine the soluble form of the IL-7 receptor (sIL-7R) in the blood plasma of patients with rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA) and psoriasis vulgaris (PS), as well as healthy individuals. The RA patients included in the study had moderate to high disease activity according to the DAS28 index. Patients with PsA predominantly had moderate and low disease activity (DAS28) and were characterized by mild to moderate disease severity (PASI). In accordance with the PASI index, patients with PS with mild and severe severity of the disease were included in the study. All patients with OA had a metabolic phenotype that is accompanied by an elevated body mass index.

sIL-7R was determined in blood plasma by enzyme-linked immunosorbent assay. It was found that in patients with arthropathy, the level of soluble form of IL-7 was increased relative to healthy individuals, with the exception of the group of patients with PsA. Also, a high concentration of sIL-7R was observed in patients with PS. Analyzing the clinical characteristics of the patients, we found that sIL-7R levels were elevated in RA and PsA patients with high disease activity by DAS28. In addition, positive correlations were found between the concentration of sIL-7R and DAS28 in RA and PsA. In patients with PsA with moderate severity of the disease (PASI), the concentration of sIL-7R was also increased relative to donor's values. On the contrary, in patients with PS, a high level of sIL-7R was noted regardless of the severity of the disease. In patients with OA, no relationship was found between sIL-7R levels and clinical parameters.

Thus, an elevated level of sIL-7R in patients with arthropathy may indicate the involvement of IL-7 and its receptor system in the pathogenesis of joint diseases. The IL-7 receptor may become a promising target both in the treatment of joint diseases and other autoimmune diseases, including psoriasis.

The aim of this study was to assess efficacy and safety of curcumin in metabolic syndrome- associated osteoarthritis (MetS-OA). All patients provided written informed consent. Knee OA was diagnosed according to American College of Rheumatology criteria; MetS was diagnosed according to Russian Scientific Society of Cardiology Guidelines. The study had before-and-after design. The main inclusion criteria were presence of knee OA and MetS, levels of global health assessment and pain assessment more than 50 mm using 0-100 visual analogue scale (VAS). The main outcome was VAS global. The other outcomes were VAS pain, Knee injury and Osteoarthritis Outcome Score (KOOS) consisting of five subscales: pain (KOOS pain), other symptoms (KOOS symptoms), activities in daily living (KOOS ADL), function in sport and recreation (KOOS Sport/Rec) and knee related Quality of life (KOOS QoL). The level of depression was measured using PHQ- 9. For pain, proportion of patients achieving minimal clinically important improvement (MCII) was assessed using the cut-offs of (a) 15 of 100 for absolute improvement and 20% for relative improvement.

The treatment consisted of C. longa extract 1000 mg/day for 4 weeks. The assessments were performed on baseline and 4 weeks thereafter. Eighteen women with MetS-OA of the knee were included in the study.

At the end of treatment, there were significant improvements in the VAS global scale by an average 33.9 mm (p = 0.001), VAS pain by 25 mm (p = 0.001). There was a trend towards improvement in PHQ-9 by 2.9 (p = 0.05). The mean improvement in KOOS pain was 11 (p = 0.001). KOOS symptoms improved by 9 (p = 0.025), KOOS ADL - by 12.4 (p = 0.001), KOOS Sport/Rec by 10.3 (p = 0.044), and KOOS QOL by 14.4 (p = 0.009). The proportion of patients achieving clinically significant improvement (MCII) were nine (56%) for both global health and pain. There were no adverse events during the study. The findings of this study suggest clinical efficacy and safety of C. Longa in MetS-associated knee OA. There is a need for large controlled studies to confirm these results.

Intraepithelial lymphocytes (IEL) play a critical role in maintaining the immune balance of the gut and provide the first line of mucosal defense against luminal antigens as well as rapidly respond to epithelial injury. Recently, IEL have received a lot of attention as key mediators of aberrant immune response resulted in persistent immune activation, inflammation and altered intestinal barrier function, seen in Crohn's disease (CD). This study describes for the first time subsets of colonic IEL in CD patients as compared to healthy controls aimed at characterization of altered IEL contribution to the pathogenesis of Crohn's disease.

The peripheral venous blood and colon tissues were obtained from 10 CD patients and 6 donors. IEL were isolated from the mucosa by incubation the tissue in a predigesting solution. Lymphoid cells phenotype was investigated using monoclonal antibodies and flow cytometry.

The majority of colonic IEL was identified as СD3⁺T lymphocytes and no significant differences were found in their numbers in investigated groups. However, changes in T cell subsets composition have been shown: the ratio of СD3⁺СD4⁺IEL and СD3⁺СD8⁺IEL was 1:1 in colon of CD patients and correlated with T cells in peripheral blood (R = 0.7; p < 0.05) while donor tissues were characterized by expected СD3⁺СD8⁺T killers prevalence and the ratio reached 1:2 (p < 0.05). The increase of unconventional γδIEL (mainly due to V81+T cells) and СD161⁺T cells in association with TNK cells decrease were revealed in colon (p < 0.01) as well as in peripheral blood (p < 0.05) of CD patients as compared to donors. Moreover, the number of colonic γδIEL was correlated with disease location (R = -0.6; p < 0.05), and disease behavior (R = 0.7; p < 0.01) according to Montreal classification.

The observed data indicates changes in colonic IEL composition in CD patients that may provide valuable insight into the contribution of T helpers, γδT cells and mucosa-associated СD161⁺T cells in autoimmune intestinal inflammation but need further possible mechanisms discussion.

Neutrophilic granulocytes have a wide spectrum of functional activity. In recent years, the functional significance of neutrophils in the development and course of malignant neoplasms has been discussed. It has been shown that neutrophilic granulocytes can play pro- or antitumor activity. The aim of the study was to assess the structural and functional features of neutrophils in patients with varying degrees of prevalence of cancer of the larynx and laryngopharynx. Forty-one patients (aged 35-67) with newly diagnosed cancer of the larynx and laryngopharynx were examined and divided into subgroups according to the TNM classification: the first subgroup (14 patients) with a localized tumor process consisted; and the second subgroup (27 patients) with a widespread tumor process. The relative and absolute number of neutrophils was assessed, and the neutrophil-lymphocyte ratio (NLR) was determined. The content of neutrophils with varying degrees of nuclear segmentation in the blood was calculated, the activity of myeloperoxidase, cationic proteins, alkaline phosphatase, and the degree of neutrophil activation in the NBT test was determined cytochemically. Concentration of interleukin-8 was determined using ELISA. In patients with cancer of the larynx and laryngopharynx the number of neutrophils (p = 0.045) and NLR (p = 0.033), as well as serum concentration of interleukin 8 (p = 0.011), increased compared to healthy individuals. The proportion of cells with hypersegmented nuclei in the neutrophil population (p < 0.001) and cytotoxic potential increased with the spread of tumor process. A direct correlation (r = 0.42, p = 0.03) was found between the T index, which reflects the volume of the tumor, and the content of hypersegmented neutrophils. It can be argued that such a simple and accessible laboratory parameter as the degree of segmentation of the nuclei of neutrophilic granulocytes can be used as one of the criteria to assess and predict the course of the tumor process.

Stomach cancer is in the top ten in terms of prevalence and ranks 4th in terms of causes of death worldwide. The most common and most aggressive variant of gastric cancer is adenocarcinoma. The monocytic link of immunity provides the main line of the body's fight against malignant cells, while in patients with adenocarcinoma it is insufficiently studied. The purpose of the study was to evaluate the functional activity of monocytes in patients with gastric adenocarcinoma at different stages of the disease.

Individuals (n = 164) were examined, among whom 85 were diagnosed with stage I-IV stomach adenocarcinoma. The study also involved 79 apparently healthy donors. The functional activity and oxygen-dependent phagocytosis of monocytes were assessed by the chemiluminescent method. Luminol was used as a chemiluminescence inducer. The respiratory burst was activated with opsonized zymosan.

In patients with stomach adenocarcinoma, at rest (spontaneous chemiluminescence), an increase in the time the curve reached the maximum intensity of chemiluminescence (Tmax = 7957 s), the area under the chemiluminescence curve (Squr = 0.2 x 10⁶), the activation index (1.89 c. u.) and a decrease in the maximum value of chemiluminescence intensity (Imax = 424 c. u.) relative to the control group (Tmax = 5533 s, Squr = 0.011 x 10⁶, activation index = 0.88 c. u., Imax = 424 c. u., p < 0.05) were seen. When chemiluminescence is induced in patients with stomach adenocarcinoma, a statistically significant predominance of Squr is fixed (0.46 x 10⁶, in the control group Squr = 0.031 x 10⁶). Also, in the group of patients with stomach adenocarcinoma, monocytic phagocytosis was reduced by more than 2 times (29% vs 84% in the control group, p < 0.05). When analyzing the studied parameters, depending on the stage of the disease, it was found that the violation of the chemiluminescent reaction in patients with stomach adenocarcinoma is fixed already at an early stage. At the same time, in patients with stage IV stomach adenocarcinoma, the indicators of spontaneous and induced chemiluminescence are more than 2 times different from those in the control group and patients at stage I of the disease. The identified features indicate a decrease in the effectiveness of immune reactions of the monocytic link in stomach adenocarcinoma already in the early stages of the disease and can be used to detect early signs of immune disorders and optimize therapeutic approaches in this disease.

The role of neutrophils in kidney cancer is currently being studied. Their role in carcinogenesis is ambiguous. As one of the most abundant blood leukocytes, neutrophils play an important role in cancer progression through multiple mechanisms, including promotion of angiogenesis, immunosuppression, and cancer metastasis. Neutrophils synthesize and release pro-angiogenic factors that are able to directly or indirectly stimulate the growth and migration of endothelial cells, which in turn causes the formation of new blood vessels from pre-existing ones. The production of various factors by neutrophils, including proangiogenic ones, is mediated by the expression of the genes of these molecules. Functional heterogeneity is characterized by differences in neutrophil gene expression patterns. The aim of this study was to evaluate the angiogenic potential of circulating neutrophils in kidney cancer. The object of the study were blood neutrophils of patients with verified clear cell kidney cancer at stage I (T1N0M0G1, n = 28, median age 60), stage II (T2N0M0G2, n = 15, median age 61) and stage III (T3N0M0G2, n = 15, median age 63) before surgery. The control group consisted of apparently healthy donors (n = 15, median age 54). Serum levels of IL-8 and VEGF-A were assessed by enzyme immunoassay. Expression of the CXCL8 and VEGF-A genes in circulating neutrophils was determined by reverse transcription quantitative PCR. As a result of our study, an increase in the level of IL-8 and VEGF-A in the blood serum of patients with kidney cancer in all studied groups compared with the control group was revealed. We observed a direct correlation between serum levels of IL-8 and VEGF-A in patients with kidney cancer (r = 0.429; p = 0.016), which confirms the relationship of these angiogenic factors. A significant increase in CXCL8 gene expression by circulating neutrophils was found in patients on II (2.91, Q_0.25-Q_0.75: (1.296-4.99), p = 0.02) and III (1.93, Q_0.25-Q_0.75: (0.755-11.36, p = 0.014) stages of kidney cancer compared with the control group (1.50, Q_0.25-Q_0.75: (0.80-4.05)). However, VEGF-A gene expression by circulating neutrophils did not differ from those in the control group. Blood neutrophils in kidney cancer exercise their angiogenic potential through the production of IL-8.

The transition of cervical neoplasia (CIN) to cervical cancer occurs with the active participation of IL-4, for which both pro- and antitumor effects have been shown with tumors of various localizations. The expression of cytokines is regulated at the transcriptional level in the promoter region of the gene. It has been shown that the genotype IL4 (589C/T) (rs2243250) is associated with the development of gastric and breast cancer. The contribution of IL-4 genotypic variations to the development of CIN has not yet been studied. The aim of the study was to assess the risk of developing cervical neoplasia by the presence polymorphism of IL4 (589C/T) and the level of IL-4. The object of the study was circulating neutrophils, serum and genomic DNA of 36 patients with CIN and 20 women without dysplasia (comparison group). Using ELISA, the level of IL-4 was determined in neutrophil lysate and serum. Phagocytic activity and adhesive ability (CD11b) of neutrophils were assessed. Allele-specific real-time PCR using Taq-Man probes was used to analyze of the IL4 589C/T (rs2243250). Statistical processing was carried out using Statistica 13 and Jamovi 1.6.5.0. As a result of the study, it was found that the level of IL-4 in serum and circulating neutrophils in patients with CIN is significantly higher than in the comparison group. The -589C* allele of the IL4 gene and the TT genotype are more common in the group with CIN (55.5%) than in the control (25%). At the same time, a direct relationship was established between the presence of polymorphism and increased adhesive ability and with indicators of the phagocytic number of circulating neutrophils. Analysis of the incidence of IL4 C589T by the «case-control» method showed that the chances of CIN formation in carriers of the -589C allele and the TT genotype were 3.75 (95% CI: 1.013 - 13.880, Chi-square = 4.161, p = 0.042). The -589C* allele and TT IL4 genotype, neutrophil and serum IL-4 levels are associated with HPV infection. Using a binary logistic regression model, we demonstrated the possibility of using IL-4 levels in circulating neutrophils and IL-4 gene polymorphism (589C/T) for the differential diagnosis of patients with CIN (χ² = 15.6, p = 0.001). Significant significance for their combination was assessed by ROC-curve analysis (IL-4 in neutrophils; IL4 (-589С*), 75% probability. Thus, the IL4 (589C/T) is associated with the adhesive and phagocytic activity of circulating neutrophils. In HPV-infected patients, IL4 gene polymorphism (589C/T) can serve as a marker for early detection and prognosis of CIN.

The aim of our study is to assess the local cytokine levels as prognostic factors for early relapse in NMIBC patients. 75 patients with NMIBC were enrolled in the study: 51 with primary NMIBC and 24 with initially recurrent NMIBC, LG and HG tumors were diagnosed in each group. Patients with primary NMIBC were monitored during 9 months after treatment: TURB and chemotherapy (No. 6). During TURB samples of tumors were taken, supernatants were obtained and tissue cytokine levels were measured (IL-1β, IL-6, IL-10, IL-18, TNFα, IFNγ, IL-8) by ELISA test. The results showed that in patients with primary NMIBC early relapses were diagnosed in 15 (46.8%) of LG tumors and in 11 (45%) of HG tumors matching that there was no difference depending upon tumor grade. In initially recurrent tumors of both LG and HG NMIBC the amounts of cytokines were maximal: in LG tumors they exceeded the primary ones from 7.1 (IFNγ) to 300 (IL-6) while in HG - from 2.0 (IL-10) to 9.7 (IL-6). The amounts of IL-1β, IL-6, IL-10, IFNγ, IL-8 were higher in those LG primary tumors which relapsed in 6-9 months compared to the ones which didn't, though their levels were much lower than in initially manifested relapse (from 2.6 times for IFNy to 150 times for IL-6). A similar trend, though not for all the same cytokines, was observed in HG tumors: tissue levels of IL-6, IL-10, IL-18 and TNFα were higher in tumors which relapsed in 6-9 months after treatment. The increase of 2 cytokines' levels were common for both LG and HG tumors (IL-6 and IL-10). This finding might be considered as a new prognostic factor of the early relapse. We conclude that relapse of LG and HG NMIBC is related to some immune mechanisms, namely to local hyperproduction of cytokines, especially IL-6 and IL-10, though IL-1β, IL-8, IFNγ could have an impact on LG and IL-18, TNFα — on HG tumors. Taking into account common signaling pathways of IL-6 and IL-10 like JAK/STAT, these transcription factors might be potential targets for new effective approaches to treatment.

Molecular classification, immuneheterogeneity, and the existence of distinct immunophenotypes of virus-associated cervical cancer (CeCa) remain as-yet weakly explored issues, and this is particularly true of its earliest clinical stages and pre-invasive forms: cervical intraepithelial neoplastic (CIN) lesions. The goal of the study was to identify transcriptomic landscapes of invasive CeCa at its initial progression that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment. Transcriptome profiling was carried out using RNA-sequencing on Illumina platform. A panel of surgical-derived tissue samples comprised human papillomavirus-positive CIN grade 1-3, cancer of FIGO IA1-IIB stages, and morphologically normal epithelium. Transcriptomic profiles were analyzed with the use of bioinformatics tools, such as gene set enrichment (GAGE) for signaling pathways, xCell enrichment for cell composition identification, and PREDA positional analysis of genomic data. Hierarchical clustering revealed heterogeneity of transcriptomic profiles within the early-stage CeCa, namely, the existence of two clusters of tumor samples and three functional patterns of genes showing coordinately altered expression. Pathway enrichment analysis on genes differently expressed between the two clusters/groups of CeCa samples (‘A' and ‘B') and CIN (group ‘C') suggested that invasive tumor progression in groups ‘A' and ‘B' might rely on immunologically dissimilar mechanisms. xCell analysis confirmed heterogeneity of changes in the abundancies of cell populations when comparing CeCa sample groups and CIN, along with differences in immune and stromal scores. PREDA demonstrated that these transcriptomic differences could be linked to different chromosomal regions and co-localized with particular gene families and potentially the reported virus integration hotspots. Overall, the existence and detectability of different transcriptomic immune-based phenotypes of invasive CeCa at its initial stages of progression is shown, which may provide new options to broaden the knowledge and applicability of target and immune anti-cancer therapy.

The avoidance of immune surveillance by malignant plasma cells (PCs) in multiple myeloma (MM) is mediated by different mechanisms, among which an induction of T cell exhaustion and expansion of myeloid-derived suppressor cells (MDSCs) appear to play substantial roles, but it is still a lack of data on possible MDSC-mediated induction of T cell exhaustion. The aim of the present work was to evaluate possible relationship between frequencies of MM PCs, MDSCs and phenotypically exhausted PD-1⁺ and TIM-3⁺ T cells in bone marrow (BM) samples and peripheral blood (PB) of MM patients at various disease stages. Peripheral blood (n = 88) and BM samples (n = 56) were obtained from MM patients (newly diagnosed (n = 6), patients in remission (n = 71) and with progressive disease (n = 11)). Frequencies of T cells expressing checkpoint receptors PD-1 and TIM-3, polymorphonuclear MDSCs (PMN-MDSCs, Lin^-CD14^-HLA-DR^- CD33⁺CD15⁺/CD66b⁺), monocyte MDSCs (M-MDSCs, CD14⁺HLA-DR^low/-), early MDSCs (E-MDSCs, Lin^-HLA-DR^-CD33⁺CD15^-/CD66b^-), and MM PCs (CD45^dimCD38⁺CD138⁺CD56⁺CD19^-CD117⁺CD27^- CD81^-) were assessed with flow cytometry. Circulating and BM-resident PD-1⁺/TIM-3⁺T cell subsets, BM E-MDSCs, as soon as MM PCs and serum beta2-microglobulin (B2-M) levels were gradually increased in patients at different stages. Despite that, there were no associations between the markers of tumor load and the studied cell subsets. In patients in remission, BM PMN-MDSCs negatively correlated with CD4⁺T cells, CD4⁺PD-1⁺ and CD8⁺TIM-3⁺T cell subsets; there were positive correlations between BM E-MDSCs and CD4⁺PD-1⁺TIM-3⁺ cells and PB M-MDSCs and CD8⁺PD-1⁺ and (as a trend) CD8⁺TIM-3⁺T cells. We found no associations for the samples of patients at diagnosis and with progression. We can conclude that a possible mutual influence of malignant PCs, MDSCs and PD-1⁺/TIM-3⁺T cells is nonlinear, especially during a manifest tumor growth at diagnosis and progression. The detected negative correlations between resident PMN- MDSCs and T cell subsets might be associated with MDSC suppressive function, affecting both predominantly activated PD-1⁺ cells and exhausted TIM-3⁺ subsets. The positive correlations between BM E-MDSCs and CD4+PD-1⁺TIM-3⁺ cell subset and circulating M-MDSCs and PD-1⁺ and TIM-3⁺ CD8⁺T cells might confirm an ability of MDSCs to induce T cell exhaustion.

Myeloid-derived suppressor cells (MDSCs) play an important role in the immune response regulation in many pathologies, primarily in malignant tumors, but their role in the hematopoietic stem cell engraftment and the hematopoietic recovery after high-dose chemotherapy and autologous stem cell transplantation remains practically unexplored. This study is aimed at studying the correlation between the number of MDSC subpopulations and blood parameters at the stage of hematopoietic recovery after high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with multiple myeloma (MM). Circulating MDSCs were assessed at the stage of leukopenia recovery (absolute leukocyte count in peripheral blood (PB) > 1 x 10⁹/L) by flow cytometry. The number of transplanted CD34⁺CD45⁺ hematopoietic stem cells was 4.38 x 10⁶/kg (IQR (3.1—5.6) x 10⁶/kg). The duration of recovery from leukopenia varied from 8 to 18 days (Me 12 days). The number of MDSCs at the engraftment was not associated with the number of CD34⁺ cells/kg in the graft. The relative number of monocytic MDSCs (M-MDSCs, CD14⁺HLA-DR^low/-) directly correlated with the number of monocytes at the stage of recovery from leukopenia (R = 0.417, p = 0.002). Granulocytic MDSCs (PMN-MDSCs, Lin^-HLA-DR^-CD33⁺CD66b⁺) were characterized by an inverse correlation with the number of monocytes (R = -0.493, p = 0.0003) while the association with the absolute number of neutrophils was weak (R = 0.273, p = 0.048). The number of lymphocytes at the stage of recovery from leukopenia had an inverse correlation with PMN-MDSCs (R = -0.347, p = 0.014) and did not correlate with M-MDSCs. When analyzing the duration of leukopenia, an inverse correlation with this indicator was revealed for the percentage and absolute number of M-MDSCs (R = -0.347, p = 0.018 and R = -0.469, p = 0.0008, respectively). Multiple regression analysis showed dependence of the lymphopenia duration on the proportion of circulating M-MDSCs (p = 0.014) and the number of transplanted CD34⁺ cells/kg (p = 0.032). According to the data of multivariate analysis of variance, the number of transplanted CD34⁺ cells/kg and the number of M-MDSCs were significant factors for the duration of leukopenia. At the same time, such clinical parameters as the depth of response and minimal residual disease status before high-dose chemotherapy and hematopoietic stem cell transplantation, as well as the MM stage, did not affect the duration of hematopoietic recovery. Thus, the obtained results indicate the association of a higher number of M-MDSCs with a shorter duration of leukopenia after high-dose chemotherapy with autologous stem cell transplantation and indicate a positive role of M-MDSCs in hematopoietic recovery in the early post-transplant period in patients with MM.

Hematopoiesis is a complex process that requires a specific set of blood components to function properly. Blood diseases can result from imbalances or deficiencies in these components. The body has physiological sensors that respond to environmental changes by maintaining elemental homeostasis. A deficiency in one micronutrient can lead to imbalances in others. The purpose of this study was to investigate the role and interaction of copper, cobalt, and iron in hematopoiesis and to determine the prevalence of anemia in children living in the Aral Sea region.

A total of 1120 children and adolescents were examined, and their physical development was measured using anthropometric measurements and laboratory tests. Hair samples were analyzed to determine the children's micronutrient status. The results revealed that 78% of the children had a decrease in hemoglobin, and anemia was more prevalent in adolescents. A correlation was found between high growth and increased levels of erythrocytes and hemoglobin. The study also identified the most common hypomicroelementoses in the Aral Sea region, including copper deficiency in 98.4% of cases, cobalt deficiency in 92.1%, and zinc deficiency in 57.8%.

The study also analyzed the ratio of trace elements, revealing an increased Fe/Cu and Fe/Cu ratio in all age groups. Imbalances and deficiencies in copper, cobalt, zinc, and manganese were found to contribute to the development of anemia in children. Hair analysis for trace elements was shown to be significant in the differential diagnosis and treatment of children with anemia.

In conclusion, the study highlights the importance of maintaining a proper balance of trace elements in hematopoiesis. Deficiencies in copper, cobalt, zinc, and manganese can contribute to anemia in children, and hair analysis can be used to diagnose and treat the condition. Further research is needed to better understand the role of trace elements in hematopoiesis and their impact on human health.

In premature birth and postpartum damage to the developing lung, the processes of the formation of pulmonary vessels and alveoli are disrupted, leading to bronchopulmonary dysplasia (BPD). BPD is a multifactorial disease and the pathogenesis of lung tissue damage is still not fully understood. Studies of angiogenesis biomarkers can be informative for assessing the development of BPD. In this study we examined the blood serum of 65 premature infants aged 6 to 180 days of life; gestational age at birth was 23-33 weeks, body weight 480-1840 g, APGAR score 5-6. All children in the early neonatal period had respiratory distress syndrome, then 46 children formed and 19 did not form bronchopulmonary dysplasia. The concentration of the factors of angiogenesis and fibrosis was determined in blood serum by ELISA. There were no differences in the levels of angiopoietins 1 and 2, vascular endothelial growth factor VEGF-D, transforming growth factor beta TGF-β, thrombospondin-1. We observed a tendency to increasing the level of VEGF-A, which is a key regulator of angiogenesis and lung maturation; we regard this tendency as a favorable sign of lung formation. We found tendencies to increase of the adhesion molecule of endothelial platelet cells PECAM-1, interleukin 8 and connective tissue growth factor CTGF. CTGF expression is enhanced by artificial lung ventilation and exposure to high oxygen concentrations. We consider an increase of CTGF in BPD to be an unfavorable change, since the binding of CTGF to VEGF inhibits VEGF-induced angiogenesis. In children with BPD, we found a decrease in the level of platelet derived growth factor PDGF-BB, the median concentration was 3180 pg/mL in BPD versus 4782 pg/mL without BPD (p = 0.024). PDGF is an important factor in tissue regeneration and plays an important role in the formation of blood vessels. We assume the decreasing of PDGF concentration in BPD can lead to a violation of the alveolarization necessary for the formation of the structure of healthy lungs. Studies of angiogenesis factors will help to better understand the pathogenesis of lung damage in BPD.

Monocytes play an important role in the systemic immune defense against pathogens and maintaining physiological pregnancy. During pregnancy peripheral monocytes migrate into the decidua and form the pool of decidual macrophages which participate in the formation and development of placental tissues. The population of peripheral blood monocytes is phenotypically and functionally heterogeneous. In humans, there are different monocyte subsets depending on the expression of CD14 and CD16. CD56-positive monocytes are found in healthy women. Their number is positively correlated with body mass index, body fat. Tim-3 (T cell Ig and mucin domain-containing protein 3) expression is observed in peripheral monocytes during pregnancy. It is known that peripheral monocyte functions effectively change at pregnancy to form the immune tolerance at the maternal-fetal interface and the systemic immune defense against pathogens. However, the monocyte phenotype shift during pregnancy remain poorly understood. Therefore, the aim of the study was to evaluate the CD56 and Tim-3 expressions in monocyte subsets in human pregnancy. Peripheral blood mononuclear cells were isolated from peripheral blood of pregnant women (gestational age 29 weeks (28-31) by density gradient centrifugation and analyzed by flow cytometry. Peripheral blood of healthy non-pregnant fertile women (in follicular phase of the menstrual cycle) aged 21-29 years was studied as control. Pregnant women had a lower percentage of classical CD14^hi/CD16^- monocytes in comparison with non-pregnant. The percentages of intermediate (CD14^hi/CD16⁺) and non-classical (CD14^low/CD16⁺) monocytes did not change. The CD56 molecule expression was observed in all monocyte subsets in pregnant and non-pregnant women. Pregnant women had a higher percentage of CD56-positive classical (CD14^hiCD16^-) and non-classical (CD14^lowCD16⁺) monocytes than non-pregnant. The percentage of CD56-positive intermediate (CD14^hiCD16⁺) monocytes did not change. The percentages of double-positive CD56⁺Tim-3⁺ classical (CD14^hiCD16^-) and non-classical (CD14^lowCD16⁺) monocytes were increased in pregnant women. The numbers of double-positive CD56⁺Tim-3⁺intermediate (CD14^hiCD16⁺) monocytes did not change. Thus, the CD56 and Tim-3 expressions in different monocyte subsets were changed in human pregnancy.

Systemic inflammation alongside endothelial dysfunction is considered to play a crucial role in PE pathogenesis. Endothelial dysfunction can be assessed by endothelial glycocalyx (eGC) damage. eGC is a superficial layer of cells associated with endothelial membrane that provides all endothelial cells functions. Its damage can be evaluated by the levels of its circulating components in blood. Patients with PE generally receive methyldopa (Dopegyt) solely or in combination with nifedipine (Cordaflex), and there is no understanding of their effect on proinflammatory state of blood vessels. Our study aimed to assess levels of IL-6, IL-18, TNFα, galektin-3 and homocysteine as well as levels of syndecan-1, eCG structural component, representing system inflammatory response and endothelial dysfunction development in blood of women with early- and late-onset PE receiving different antihypertensive treatment strategies. Eighty-two patients were enrolled into this interventional longitudinal pilot study. The comparison group included 15 patients before 34 gestational weeks and 15 patients after 34 weeks. Study subgroup 1 included 12 patients with early- onset PE receiving Dopegyt solely and 16 patients with early-onset PE receiving Dopegyt together with Cordaflex. Study subgroup 2 included 12 patients with late-onset PE receiving Dopegyt solely and 12 patients with late-onset PE receiving combined therapy. As for early-onset PE, only IL-6 demonstrated statistically significant differences in patients receiving both treatment strategies compared to control. Proinflammatory state was more profound in late-onset PE. IL-6 levels were significantly increased in late-onset PE treated with Dopegyt. IL-6 and TNFa levels were significantly higher in late-onset PE patients treated with Dopegyt + Cordaflex compared to control. Syndecan-1 levels were statistically significantly higher in patients with early-onset PE treated with Dopegyt solely. There were no statistically significant differences between the groups despite elevated mean values of syndecan-1 in late-onset PE. Galectin-3 and homocysteine levels did not differ significantly between the groups, representing lack of pronounced inflammatory response and endothelial dysfunction.

External genital endometriosis (EGE) is one of the common gynecological diseases of women of reproductive age with a relapsing, progressive course that worsens the quality of life of patients due to pain, emotional imbalance, fear of relapse and possible surgical intervention. Currently, endometriosis is recognized as one of the most common diseases associated with infertility. Thus, among fertile women with preserved childbearing function, the disease is generally diagnosed in approximately 6-7%, while among patients suffering from infertility, its frequency can reach 20-48%.

However, the causes that determine reproductive dysfunction in patients with EGE are not well understood. Much attention is currently paid to the role of immunity in the formation of endometriosis. Patients with EGE show changes in both local immunity factors and immunological components of circulating blood.

Purpose of the study: the study of factors of innate and adaptive immunity in patients of reproductive age with external genital endometriosis (EGE).

The study included 71 patients with various stages of external genital endometriosis, the control group included 24 patients without endometriosis. Determination of the population composition of peripheral blood lymphocytes, the level of monocytes expressing TLR, activation markers, was carried out by laser flow cytometry — Immunotex (France), Caltag (USA), FITC (fluorescein isothiocynate) — labeled CD3, CD4, CD8, CD16, CD19, HLA-DR, CD282, CD284 and PE (phycoerythrin) - labeled with CD25, CD69, CD95, CD107a, CD14.

External genital endometriosis is characterized by: at stages I-II of the disease - a violation of the early stages of the innate immune response (an increase in the number of monocytes expressing TLR-4, a violation of the activation and differentiation processes of immunocompetent cells, which is reflected in a decrease in the expression of CD16, CD8, CD16⁺HLA-DR⁺, CD16⁺CD107a⁺, CD8⁺CD107a⁺, at III-IV stages of the disease, there is a decrease in the level of CD16 and activation markers CD69, HLA-DR, CD107a on their surface, which is combined with a decrease in the expression of CD8, CD16, HLADR and CD107a on their surface. CD95⁺ and CD8⁺CD95⁺ were found at various stages of EGE.

The results obtained allow us to understand the features of the functioning of innate and adaptive immunity at various stages of external genital endometriosis, and the studied immunological parameters can be used as diagnostic criteria for the formation of various stages of EGE. These data can serve as a theoretical basis for further identification of markers of EGE progression, as well as the mechanisms underlying immune inflammation.

C1 inhibitor of serine proteases (C1-INH) performs a regulatory function in the complement system and vascular permeability. Deficiency of C1-INH leads to various forms of angioedema, including hereditary angioedema (HAE). The cause of HAE is a genetically determined violation of the synthesis of C1-INH. A decrease in the level of C1-INH to 50% relative to the norm leads to an increase in the production of bradykinin, which is the basis for the diagnosis of HAE. The development of affordable ELISA for the quantitative determination of C1-INH is a popular direction for clinicians. During the development of a new kit for quantitative determination of C1-INH, two mouse monoclonal antibodies (mAb) with different epitope specificities were obtained. On their basis, a sandwich-type ELISA was developed. The specificity of the obtained mAb's was confirmed using the medical device “Berinert”. To prepare calibrators, C1-INH was affinity purified from human blood plasma using a sorbent with immobilized mAbs. The identity of the C1-INH protein was confirmed by PAGE electrophoresis, immunoblotting, and mass spectrometry on MALDI-TOF/TOF UltrafleXtreme mass spectrometer. To assess the quality indicators of developed reagents kit, studies were carried out in accordance with GOST R 51352-2013 and TU 21.20.23-041-01967164-2022. Values of quality indicators: accuracy — 93.53%; measurement linearity interval — 22.00-176.07 ng/mL. Using the developed ELISA test system, we examined 28 blood sera from healthy donors and 7 blood sera from patients with confirmed HAE. In the same samples, the content of C1-INH was determined by turbidimetric method, using the "Diagnostic reagents for in vitro immunochemical studies of specific blood proteins. Model: C1-esterase inhibitor (C1 EsteraseInhibitor)" (Aptec, Belgium). The correlation coefficient was 0.94 (p < 0.05). It was found that the diagnostic sensitivity and specificity of the developed ELISA is 100%. As a result of the study, an original ELISA test system for the quantitative determination of C1-INH was developed "Reagent kit for enzyme-linked immunosorbent assay of human C1-inhibitor (C1-inh PS)".

Wilson's disease (WD) is a rare hereditary disease caused by a deficiency of the ATF7B transporter. The accumulation of copper can cause damage to organs and cells, mainly the liver. Copper exposure can modulate cytokine synthesis through molecular and cellular signaling pathways, including the nuclear transcription factor NF-kB pathway. NF-kB is the main regulator of inflammation and cell death, acts as a central link between liver damage, fibrosis and hepatocellular carcinoma. An excess of NF-kB-dependent cytokine response stimulates inflammatory reactions, but excessive inhibition of NF-kB can negatively affect the viability of hepatocytes. Method of flow cytometry with visualization — Amnis ImageStream^X allows to evaluate the activity of NF-kB (% of activated cells in cell populations). The aim: to evaluate the activity of NF-kB in lymphocyte populations in children with WD disease. Immunophenotyping of lymphocytes and assessment of the level of translocation of NF-kB were performed in 52 children with WD and in 25 children of comparison group. The mass concentration of copper in daily urine was determined by atomic absorption method using the AAnalyst 800 spectrometer. In children with WD, the content of cells with NF-kB translocation varied from 5 to 90% depending on the lymphocyte population; the highest level was detected in B cells — 57.5 (37-68) %. A significant difference in distributions of the number of cells with NF-kB translocation between WD and healthy children was shown (F-criterion, p < 0.01). In most cases, children with WD are characterized by a decrease in the activity of NF-kB in populations of B cells (in 43% of cases), T helper cells (48%), T cytotoxic (44%) and Th17 lymphocytes (41%). In children with WD, the concentration of copper varied from 9.7 to 2582 mcg/day, Me = 616 (210-1173). A direct relationship was obtained between the copper content in urine and the level of translocation of NF-kB in B lymphocytes, r = 0.34, p = 0.016. The activity of the NF-kB correlates with biochemical markers of the severity of liver damage (ALT, AST, GGT) and with copper content in urine. The study of the NF-kB signaling pathway seems promising for a better understanding of the pathogenetic mechanisms of the formation of inflammation and liver fibrosis in children with WD.

The autism spectrum disorders (ASD) are now widely accepted as a pervasive, complex, heterogeneous neurodevelopmental disorders with multiple etiologies, subtypes, and developmental trajectories. There are no available and effective biomarkers for them. Immune dysfunction is seen as an important risk factor contributing to the neurodevelopmental deficit in ASD, and is signified, among other things, by an imbalance of cytokines in the brain and on the periphery. In recent years, saliva has been proposed as a biological material for diagnosing ASD, due to the accessibility and non-invasiveness of the method for its production. However, the question of whether salivary cytokine levels may be used as effective early biomarkers for autism requires further research, including saliva versus plasma/serum comparisons.

Aim: a comparative analysis of the levels of cytokines: IL-6, IFNγ, TNFα, IL-1β, IL-4, IL-10, in saliva and blood plasma to identify possible markers of ASD and their severity in children.

The study included 11 children with typical neurodevelopment (TDC) and 55 children with ASD, among whom 37 children had mild or moderate autism (according to CARS), and 18 children had severe autism. Samples of unstimulated mixed saliva and venous blood were simultaneously collected from all children. Salivary concentrations of cytokines: IL-6, IFNγ, TNFα, IL-1β, IL-4, IL-10 were determined by multiplex Luminex™ analysis. Plasma levels of cytokines were assessed by ELISA. Differences between groups were tested using the Kruskal-Wallis U-test with post-hoc Conover-Inman comparisons, between samples (saliva/ plasma) are using the Wilcoxon signed-rank test. The correlation between the concentrations of cytokines in plasma and saliva was determined using linear regression by the RMA method.

In all examined groups, the levels of IL-6, IFNγ and IL-10 in saliva were significantly lower, and TNFα, IL-1β and IL-4 were higher than the corresponding levels of the same cytokines in plasma. Regardless of health/ disease status, no significant correlations were found between salivary and plasma cytokine levels in children. IL-1β levels were significantly lower and IL-10 levels were higher in the saliva of both groups of children with ASD compared with TDC. No significant differences in salivary cytokine concentrations were found between children with mild and severe ASD.

Thus, salivary cytokines can be used as markers of ASD in children, but not the severity of the condition. The absence of correlations in the levels of some pro/anti-inflammatory cytokines between saliva and blood plasma may probably indicate a special immunological status of an ecological niche, the oral cavity.

Traumatic brain injury (TBI) results in a significant inflammatory burden that increase the production of inflammatory mediators and biomarkers. The immune system plays a key role in the pathogenesis of traumatic brain injury. Neuroinflammatory mediators released from resident glia (activated microglia and astrocytes) inside the brain recruit immune cells where cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. Interleukin-6 (IL-6) is a proinflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. The purpose of the current study was to assessment of cerebrospinal fluid (CSF) interleukin-6 (IL-6) and MBP levels in patients with TBI. Samples of cerebrospinal fluid of 85 patients with TBI were examined. Concentrations IL-6 were measured via xMAP multiplexing technology. The control was the course of CSF in patients with concussion. An increased content was found in all patients with traumatic brain injury: 19.59 pg/mL in the group with mild traumatic brain injury; 103.6 pg/mL in the group with moderate traumatic brain injury; and 2225 pg/mL in the group with severe traumatic brain injury load versus 2.58 pg/mL in the control group. A direct correlation was found with the presence of basic myelin proteins in the cerebrospinal fluid, which indicates the degree of damage and neurodegeneration processes. Identification of the features of IL-6 content in patients with brain injury may indicate its important role in the course of disease. It also requires additional more detailed study, including comparison with IL-6 content in peripheral blood.

Schizophrenia is a chronic mental disorder that is caused by a complex palette of genetic, epigenetic and environmental factors. Some of the important components of its pathogenesis are systemic inflammation and the dysfunction of immunity, which lead to neuroinflammation, contributing to development of structural brain changes. Earlier we have shown that increase in interleukin-17A levels is associated with morphometric changes and immune dysregulation in schizophrenia. IL17A G-197A (rs2275913) genetic polymorphism is involved in determining interleukin-17A secretion. The goal of this work was to investigate the associations between rs2275913 polymorphism, immune disorders and structural neurovisualization findings in schizophrenia to provide new insights into the immunopathogenesis of this disease. 60 patients aged 18 to 42 years diagnosed with schizophrenia were enrolled. 85 healthy volunteers were included into the control group. Multiplex assay was used to determine cytokine and chemokine serum levels. Rs2275913 polymorphism was assessed by polymerase chain reaction with electrophoretic detection of amplification products. A number of relationships between rs2275913 polymorphism and the immune parameters in schizophrenia were revealed. Carriers of G allele showed significant increase in IFNY, a key cytokine of Th1-link of adaptive immunity, and IL-8, an inflammatory chemokine. Also, increased levels of CXCL16 were observed in patients carrying the G allele. CXCL16 activates secretion of other proinflammatory chemokines and is involved in activation of Th1 adaptive immunity. Associations of heterozygous GA genotype with reduced cortical thickness in a number of areas of the frontal cortex in schizophrenia were found. Changes in cortical thickness in some of these areas, including middle frontal gyrus and orbitofrontal cortex, can be relevant to the pathogenesis of schizophrenia. The results highlight the importance of immunogenetic factors in the pathogenesis of schizophrenia and indicate that the rs2275913 polymorphism requires further studies as a potential biomarker of immune dysregulation and morphometric brain changes in schizophrenia.

Alzheimer's disease is the most common neurodegenerative disease in old age. In some cases, it is preceded by mild cognitive impairment (MCI). One of the important components in the pathogenesis of neurodegeneration is chronic neuroinflammation (inflammatory activation of microglia and astrocytes in the brain). Systemic inflammatory response and immune dysregulation may contribute to neuroinflammation. The purpose of this study was to investigate the level of chemokines and other inflammatory mediators in patients with MCI who underwent medical rehabilitation, and to study its associations with the severity of cognitive impairment. The study group included 48 patients with MCI undergoing rehabilitation. Rehabilitation included cognitive therapy, psychotherapy and tasks for unaided performance. Repeated examination was conducted 6 months after the completion of rehabilitation. The control group included 46 healthy volunteers. Multiplex assay was used to determine serum cytokine and chemokine concentrations. Student's t-test was used to assess the significance of differences. Assessment of cognitive functions was performed using international neuropsychological scales. In patients with MCI, we have found an increase in the levels of several cytokines and chemokines (TNFα, CXCL10/IP10, MDC) that regulate systemic inflammation, cellular and humoral mechanisms of adaptive immunity. After the rehabilitation course their levels returned to normal. It was also found that decrease in CCL7 level in the patients before the rehabilitation course is associated with the severity of cognitive impairment. The findings contribute to understanding the role of chemokines in the pathogenesis of MCI, and indicate that their levels can be potential biomarkers of the severity of cognitive impairment. For translation of the findings into clinical practice, their validation in larger studies is needed, as well as assessing the associations between chemokine levels and the severity of cognitive impairment in MCI over long-term follow-up.

According to modern ideas, changes in the functioning of the immune system affect the immune processes in the nervous system, contributing to the development of neuro-immuno-inflammation and thereby indirectly affect the rate of progression of neurodegenerative processes. The aim of our study was to investigate the prevalence of post-viral chronic fatigue syndrome and cognitive impairment (aMCI) among patients with atypical, chronic active herpesvirus infections (ACA-HVI).

Under our supervision were 126 patients of both sexes aged 18 to 60 years with ACA-HVI.

It was established that mono-EBV infection affects 27.7%; mixed EBV infection is observed in 72.3% of patients. When assessing cognitive functioning using CGI, MMSE scales, the incidence of aMCI was found to be 68.3%: with mixed HVI — 87.4%, with mono HVI — 38.8%. During the study, significant limitations were identified in the use of standard scales due to the impossibility of conducting a comprehensive assessment of clinical status parameters and cognitive dysfunctions, as well as correlation of these parameters and assessment of dynamics of the immunocorrection. To achieve this goal the Scale of assessment of the criterion clinical symptoms of patients with ACA-HVI with CFS was used. It was shown that in mixed-HVI, the severity of symptoms exceeded the severity of symptoms of patients with mono-HVI and was 52.7 (43.1-62.2) and 38.0 (31.9-42.8) points, respectively (p > 0.05). Thus, it was found that patients suffering from mixed HVI have more pronounced, severe manifestations of CFS and aMCI, which are 1.5 times higher than similar manifestations in patients with mono-HVI, significantly reducing the quality of life of these patients, worsening their social adaptation.

Prolonged persistence of herpes viruses in immune-compromised people creates conditions for constant antigenic stimulation and immune imbalance with the onset of secondary immunodeficiency or clinical manifestation of existing primary disorders in the immune system, which creates the prerequisites for the development of neuro-immuno-inflammatory changes in nervous system, followed by the formation of clinical manifestations of ME/CFS with different cognitive impairments that may be classified as aMCI.

Mental disorders often accompany autoimmune diseases, for example, since 1949 it has been known about “myxedematous madness”, a psychosis caused by hypothyroidism. The most common cause of hypothyroidism is Hashimoto's autoimmune thyroiditis. It is also known about another neuropsychiatric disorder associated with autoimmune thyroiditis, Hashimoto's encephalopathy. It is a severe dysfunction of the central nervous system, the pathogenesis of which is not associated with hormonal disorders. Cytokines are regulators and participants of inflammation, including autoimmune. Certainly, when we are talking about high concentrations cytokines, we mean systemic inflammation. The minimal or mediocre fluctuations in cytokines within the ranges that are characteristic of healthy status or normergic acute phase response in disease cannot be interpreted from the point of view of binary endocrinological logic. In the CNS, cytokines are able to influence on the neuroendocrine control of systemically regulated functions. It is also important that glial cells (astroglia, microglia) are capable of producing a number of cytokines and can affect neurons and develop behavioral changes. In addition, the ability of a number of cytokines outside the CNS itself to act on vagal afferents and through them to convey information to the CNS, affecting its state and functions, has been proven. It is reasonable to assume that minimal fluctuations in cytokine levels may also affect the state and function of the CNS. The aim of the study was to investigate the levels of cytokines in patients with thyroiditis; in patients with thyroiditis associated with mental disorders; in a group of healthy individuals; and evaluate the effect of cytokine levels on clinical manifestations. In the group of patients with thyroiditis and mental disorders, the levels of CCL20/MIP3α, IL-13, IL-2, IL-27, IL-5 were significantly higher than in other groups. At the same time, no positive correlation was found between the clinical manifestations of mental disorders and the levels of cytokines. A positive correlation was found between the levels of some cytokines and free triiodothyronine, as well as the level of antithyroid antibodies. Mental disorders associated with autoimmune thyroiditis may be associated with changes in the cytokine profile and result from neuroinflammation.

Bruton's tyrosine kinase (BTK) inhibitors represent a class of drugs that have demonstrated their efficacy and safety in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphomas who were considered refractory to any previously used type of therapy. BTK plays a key role in all stages of B lymphocyte development, but in recent years, there have been data indicating that BTK is also involved in the activation of myeloid cells.

The aim of this study is to analyze and systematize all published materials on the immunomodulatory effects of BTK inhibitors (ibrutinib, acalabrutinib, etc.).

A systematic review of the scientific literature was performed using a step-by-step search process in electronic databases (PubMed, Web of Science, ScienceDirect, and Scopus). The following keywords were used in the database search: “CLL”, “BTK”, “ibrutinib”, “COVID-19”, “allergy”, “inflammation.” The search for studies was conducted from the time of the first BTK inhibitor drug (ibrutinib) appearance in 2009 until December 2022.

The results of the study on the influence of BTK inhibitors on the functional state of B and T lymphocytes, neutrophils, and monocytes/macrophages are presented. The immunomodulatory effects of ibrutinib on adaptive and innate immune system cells, including CD4⁺ and CD8⁺T lymphocytes and NK cells, are described. Since BTK inhibitors alter the functional activity of phagocytic cells and the ratio of T cell populations, there is a suggestion about the possibility of using these drugs for the treatment of other nosological forms, not only B cell malignancies, which is currently being studied in clinical trials. Data on the use of BTK inhibitors to combat hyperacute inflammation and to suppress allergic reactions, including anaphylaxis, are summarized. In addition, the expediency of short-term use of BTK inhibitors to reduce the risk of side effects during oral immunotherapy and for desensitization to drugs is discussed.

The presented data indicate that BTK inhibitors are promising drugs with immunomodulatory effects. However, BTK inhibitors need to increase selectivity to reduce off-target effects on other kinases.

Currently, a large number of studies on genetic modification of cord blood NK cells (UCB-NK) are carried out at both clinical and preclinical levels. Immunotherapy based on UCB-NK cells has great potential for antitumor therapy. However, despite having known several advantages over peripheral blood NK cells (PB- NK), including a high concentration in cord blood and low virulence rate, UCB-NK cells are predominantly characterized in the scientific literature as immature and low-functioning NK cells. In this work, we studied the phenotypic characteristics of UCB-NK cells and the possibility of stimulatory compensation of the decreased functional activity of UCB-NK cells. Our studies revealed UCB-NK cells can be characterized as poorly differentiated and weakly activated cells with high level of inhibitory receptor NKG2A and low level of activating receptor NKG2C and HLA-DR, accordingly with the literature data. Two types of stimuli were chosen to stimulate freshly isolated UCB-NK cells: 1) 100 units of IL-2; 2) combinations of 100 units IL-2 and K-562 feeder cells expressing membrane-bound IL-21 (K562-mbIL21). It was shown the degranulation (LAMP-1) and proliferative activity was higher than for parallel cultured ex vivo PB-NK cells under the same conditions for UCB-NK cells stimulated for 7 days with IL-2 + K562-mbIL21. Moreover, stimulation in the way of IL-2 + K562-mbIL21 seemed to be a more perspective way to obtain a large number of proliferatively active UCB-NK cells compared to stimulation with IL-2 only. Since genetic modification of NK cells is a promising way to improve the antitumor properties of NK cells, retroviral transduction procedure was performed to study of the stimulated UCB-NK cells. UCB-NK cells stimulated with IL-2 + K562-mbIL21 were transduced on day 8 of cultivation. In this study, we used targeted overexpression of the adaptor molecule DAP12, which is involved in the signaling of activating NK cell receptors. PB-NK cells and UCB-NK cells were transduced under the equal experimental conditions in same volume of viral particles. As a result, the transduction efficiency was found to be more than 4-fold higher for UCB-NK cells compared to PB-NK cells. Thus, UCB-NK cells appear to be a promising tool for further research in cancer immunotherapy.

Among the causes of male infertility, enough attention is paid to oxidative stress, which in turn is a pathogenetic link in the inflammatory process. However, there is practically no information on the content of oxidized modified proteins in the semen, which makes it difficult to study the pathogenesis of diseases of the male reproductive system. In part, protein oxidation may be due to the production of reactive oxygen species by microorganisms, both directly and indirectly through the activation of immune system cells. The aim of the research was to study the level of oxidized modified proteins and changes in immunoglobulin concentrations in the semen under bacteriospermia. A study was made of the ejaculate of 48 men who applied to the clinic for infertility in marriage. The comparison group consisted of 32 practically healthy men who had no growth of microorganisms in the ejaculate samples. When conducting bacteriological analysis, the studied samples were diluted 10 times and used the generally accepted method. The concentration of albumin, immunoglobulins A, M, G, E was determined in the spermatic fluid. The oxidative modification of proteins was evaluated in the reaction with 2,4-dinitrophenylhydrazine. The concentration of oxidized proteins was expressed in nmol/mg of the total protein of the studied biological fluid. The biuret method was used to determine the protein concentration. Statistical analysis of the results was performed using descriptive statistics and Student's t-test for paired data. The concentration of protein in the seminal fluid did not differ significantly among the studied groups. The albumin concentration (16.96±1.28 mg/mL) was statistically significantly lower in the absence of microorganism growth than in bacteriospermia. With bacteriospermia, a decrease in the concentration of IgM and IgA and an increase in the level of IgG were noted. The degree of protein oxidation is maximum when enterobacteria are isolated from seminal fluid. Thus, during the studies it was found that, despite the absence of a clinic, with asymptomatic bacteriospermia, the secretion of immunoglobulins G into the semen is observed. The accumulation of oxidized proteins in the seminal fluid in bacteriospermia has been shown.