The review deals with modern ideas of neuroimmunoendocrine regulation of physiological and pathophysiological processes in skin. The present data are provided which indicate to composite mechanisms of intercellular interactions in complex regulating systems (nervous, immune, endocrine) acting at the level of skin in normal conditions, as well during the posttraumatic period. We describe different modes for participation of endocrine and nervous systems in immunologically induced skin inflammation. The data are provided confirming localization of adrenergic receptors on membranes of immunocompetent cells and leukocytes, on regulatory effects of hypothalamus upon immune functions, about multidirectional actions upon inflammation of sympathetic and parasympathetic nervous system etc.

There are sufficient data on promotion of pathophysiological changes and reconstitution processes in the skin due to effects of local immune cells and bioactive substances expressed by them. The course of skin wound regeneration depend on the type of damage, degree and a phase of healing process. Posttraumatic reparative potential of skin is often limited by the infectious processes initiated by local microflora, products of cell disintegration and necrotic tissues. The cause-effect relationship is proven by arising inflammation which is implemented by inclusion of immune protection responses. The increased necrotic area and suppuration of the wound occurs die to inhibition of system of the phagocytizing macrophages. However, activation of this system brings about formation of the connective tissue capsule around the inflammation focus within early terms.

We also discuss the issues of reparative skin regeneration which of great medico-social value, in connection with considerable prevalence of traumatic events and their social consequences, followed by expressed cosmetic defects. Evolving neurocognitive problems lead to decreased quality of the patient’s life, development of social disadaptation and further deprivation. The role of nervous system and psychological frustration in genesis of skin manifestations requires future development of the modern scientific direction, i.e., psychodermatology.

Understanding of molecular mechanisms regulating the neuroimmunocutaneous interactions offers new prospectives in treatment of some skin diseases, as well as activation of the damaged skin recovery. According to the data presented in the review article, one may conclude on relevance of further studies on reparative potential of skin under interactions of homeostatic regulatory systems.

Summary.

Changes in the state of gut-associated lymphoid tissue (GALT) and the composition of the intestinal microbiome, both in experimental STZ-induced diabetes and in development of type 1 diabetes in humans as well as chronic inflammation due to stimulation of innate immunity are crucially important in the development of type 1 diabetes mellitus. One of the most important mediators for interactions between the intestinal microbiome and GALT are specialized M cells of the follicle-associated epithelium, providing transcytotic delivery of antigens to the underlying lymphoid structures. TNFα-signaling also plays a supporting role in the formation of M cells. Therefore, the aim of our work was to study some features of TLRs expression and transcriptional activity of the Gp2, Spi-B, Nf-kB1, c-Rel, TNFα and TNFr genes in GALT in experimental diabetes mellitus (EDM), and after pentoxifylline administration. To identify TLR2⁺ cells and TLR4⁺ cells, an immunofluorescence method was used with monoclonal antibodies to corresponding pattern-recognizing receptors. To study the transcriptional activity of genes, the method of real-time reverse transcription polymerase chain reaction (RT-PCR) was used. In the course of developing experimental pathology, at the terms of 2 and 4 weeks, a decrease in the total density of TLR2⁺ and TLR4⁺ lymphocytes was observed in lamina propria of villus (villus) and subepithelial zone isolated lymphoid follicles (ILF) of rat ileum. At the same time, the density of TLR2 on the membrane of immunopositive cells was increased for small lymphocytes, and TLR4 density has became higher in medium and small lymphocytes. The pentoxifylline administration to diabetic rats resulted in a decrease in the total density of TLR2⁺ cells at the 2nd week of development of the pathology, and an increase in this index at the 4th week. The total density of TLR4⁺ cells showed changing growth rates only in villus at the 2nd week of EDM development in the presence of pentoxifylline. Changes in the density of TLR2 and TLR4 on the surface of lymphocytes were multidirectional. The development of diabetes is also reflected in the transcriptional induction of genes of the key transcription factors NF-kB1 and c-Rel in GALT cells at both the 2nd and 4th week of the development of EDM. Meanwhile, administration of pentoxifylline resulted in a significantly reduced level of normalized expression of NF-kB1 mRNA during the entire observation period and increased this indicator for c-Rel mRNA at the 2nd week. The growth of normalized expression of markers of M cells Gp2 and Spi-B was observed both on the 2nd and on the 4th week of the development of experimental pathology. Administration of pentoxifylline to diabetic animals was largely reflected in the change in the intensity of mRNA expression of the mature M cell Gp2 marker. This parameter was increased during the 2nd week of developing pathology, and on the 4th week, a downward trend was shown. The development of EDM led to a significantly increased level of near-normalized expression of proinflammatory TNFα cytokine and its receptor TNFr, and demonstrated a trend towards their decrease following pentoxifylline administration in diabetic animals.

Dendritic cells (DCs) play a key role in maintaining the peripheral tolerance of lymphocytes to autoantigens. Recovery of immunological tolerance in autoimmune diseases, particularly, in rheumatoid arthritis (RA) is considered a new therapeutic strategy. The aim of this work was to study the effect of dexamethasone-modified DCs generated from monocytes of RA patients in the presence of IFNα (DCs_Dex), upon autologous T lymphocytes in mixed leukocyte culture (auto-MLC), and to investigate possible mechanisms of the DCs_dex tolerogenic effect upon autoreactive T cells. We have shown, that DCs_Dex from RA patients induce T cell hyporeactivity in auto-MLC. Hyporeactivity of T cells is associated with cell cycle blockage in CD4⁺T lymphocytes and decreased IFNγ, IL-17, IL-4 and IL-13 production, which indicates the induction of CD4⁺T cell anergy. In this case, inhibition of Th1/Th17 has been more pronounced than the suppression of Th2 cells producing IL-4 and IL-13. Along with T cell anergy, the decrease of proliferative response in auto-MLC is associated with increased CD3⁺T lymphocyte apoptosis. In addition, the DCs_Dex of RA patients suppresses the proliferation of autologous T cells stimulated by unmodified DCs. This effect is associated with enhancement of IL-10-producing CD4⁺T cells in the auto-MLC, thus being indicative for an ability of DCs_Dex to induce conversion of CD4⁺T lymphocytes into regulatory T cells (Tr1). The data obtained characterize a new type of tolerogenic DCs, generated from blood monocytes of RA patients in the presence of IFNα and modified by dexamethasone, thus revealing a mechanism for tolerogenic effect of DCs_Dex upon T cells that recognize self-antigens in auto-MLC.

Hematopoietic stem cell transplantation (HSCT) from healthy donors is used for blood cancer treatment. Alloreactive graft-versus-host disease (GvHD) is one of the post-transplant detrimental side effects, and the main reason for GVHD after HSCT fully matched for human leukocyte peptide antigens (HLA) presented by HLA molecules on cell surface. These polymorphic peptides, minor histocompatibility antigens (MiHA), arise from any genes, including those expressed at hematopoietic tissues. The latter may lead to the s.c. graft-versus-leukemia effect (GvL), thus preventing relapse of a malignancy. A*02:01 is one of the most frequent HLA alleles for European part of Russia. We assessed frequencies for 20 MiHA-encoded genetic polymorphisms, presented via A*02:01 allele, for plausible bone marrow donors, or hematopoietic stem cells (HSC) from the Donor Registry at Russian National Research Center for Hematology, we have also determined a number of immunogenic mismatches for these 20 MiHA in real donor – recipient pairs. A total of 608 potential donors, 90 donors and 92 recipients were genotyped. Using public data, we have shown that frequencies for MiHA coding genes are most close to appropriate frequencies among the European population. We have calculated probability of MiHA-specific alloimmune response after HSCT: there are chances of 33 and 75% for three or more immunogenic mismatches (IM) for related and unrelated HSCTs, respectively. Real frequencies for immune mismatch in 20 related and 20 unrelated donor – recipient pairs are in accordance with estimated theoretical probabilities. As based on the calculated frequencies, we suggest the LB-NDC80- 1P/A, LB-CCL4- 1T, and HA-1 MiHA to be the most promising minor antigens for targeted cell therapies of hematopoietic tissue malignancies. The data obtained could be used for planning allo-HSCTs in Russian patients.

Erythropoietin (EPO) is mainly used to stimulate erythropoiesis. Its cytoprotective effects upon other cells of the human body and animals were recently shown, in particular, anti-apoptotic effect was observed. EPO effect upon the cells is mediated by interaction with erythropoietin receptor, with a complex forming a heterodimeric bond with β-common chain (CD131). In the present work, we studied the changes in erythropoietin receptor expression, and production spectrum of biologically active molecules in bone marrow mononuclear cells (BM-MNC) of patients with coronary heart disease. The flow cytometric assays showed that short-term incubation of BM-MNC with erythropoietin caused increased expression of the erythropoietin receptors on hematopoietic stem cells and tended to reduce the number of endothelial progenitor cells carrying the erythropoietin receptors. Solid-phase enzyme immunoassay in conditioned media from BM-MNC revealed that long-term (72 hours) exposure of BM-MNC to erythropoietin promoted increased production of IL-1β, PDGF-AB, and Epo, if compared to the basal production level (p < 0.05). Short-term incubation of BM-MNC with erythropoietin (60 minutes) caused a significant increase in the IL-1β, PDGF-AB and CXCL-12 / SDF-1α production levels, as well as significant reduction in the IL-10 production levels compared to the basal levels (p < 0.05).

Specific antibodies against estradiol (Es) and progesterone (Pg) are known to modulate blood serum concentrations of these hormones and their biological effects after immunization of animals. It was suggested that specific IgA-Es and IgA-Pg could influence on Es and Pg levels in human blood serum. The purpose of this study was to identify the suggested correlations between serum Es and Pg and specific IgA-Es and IgA-Pg in postmenopausal healthy women (HW) and breast cancer patients (BCP). The serum levels of Es, Pg, IgA-Es and IgA-Pg were studied in 226 HW and 633 BCP by means of solid-phase immunoassay. The following results were obtained. The levels of Es in BCP (0.25 nmol/l) were higher than in HW (0.16; р < 0.0001). The levels of Pg were lower (0.79 vs 0.87; р < 0.0001), and individual Pg/Es ratios were lower (3.19 vs 6.64; р < 0.0001). Individual IgA-Pg/IgA-Es ratios correlated with decrease of Es (r_s = -0.15; p = 0.029), with increase in Pg (r_s = 0.38; р < 0.0001), and with increased Pg/Es ratio (r_s = 0.29; р < 0.0001) in healthy women. Similar correlations were determined in BCP (correspondingly: r_s = -0.14, р < 0.001; r_s = 0.1, р = 0.009; r_s = 0.15, р < 0.0001). The decrease of Es and increase of Pg and Pg/Es in BCP were less significant than in HW: the a quotients in regression у = ах+b (y = hormones levels and x = antibodies levels) in BCP were 3 to 4-fold lower than in HW. These peciliarities of interrelations between hormones and specific antibody levels were revealed only in ER⁺/PR⁺ BCP but not in ER⁺/PR^- and ER^-/PR^- BCP. In conclusion, we have confirmed a suggestion about participation of specific antibodies in regulation of steroids levels in human blood serum. The immune regulation of hormonal status was weakened in BCP.

Angiogenesis factors (VEGF, Ang-1, TGF-β) influence production, development and functioning of vascular endothelium that are part of the placental barrier structure and are involved into transplacental transfer of different substances. The aim of this study was to study the relationship between VEGF, Ang-1, and TGF-β concentrations, and the levels of transplacental IgG-antibodies to the measles virus in cord blood of children born to mothers with placental insufficiency. Patients and methods: venous blood was taken from 32 women with uncomplicated pregnancies, and 34 samples from pregnant women with placental insufficiency, as well as umbilical blood of their newborns, the level of IgG-antibodies to measles and the concentration of some angiogenic factors (VEGF, Ang-1, TGF-β) examined by ELISA techniques. The following results were obtained: in a cord blood of infants seronegative for the measles virus, born to women with placental insufficiency, showed uniformly low VEGF levels, decreased Ang-1 concentration (1.6) and increased TGF-β concentration (2.7) as compared to seropositive newborns. In a similar group of children from mothers with physiological pregnancy, the level of these factors did not differ from those in newborns with protective antibodies to measles. Conclusion: in physiological pregnancy, transplacental transmission of IgG-antibodies to the measles virus is directly dependent on the presence of specific antibodies in a woman; in case of placental insufficiency, an imbalance in the system of angiogenic factors may promote disturbances of transmission mechanisms for IgG measles-specific antibodies from mother to the fetus.

The problem of rehabilitation of children with congenital cleft lip and palate (CCLP) is a difficult task and doesn’t lose its relevance. Children with CCLP often suffer from repeated acute viral and bacterial infections of the respiratory tract and upper respiratory tract, which leads to a forced delay in surgical, orthodontic treatment, adequate speech therapy and complications after staged surgical operations. The development of inflammatory processes in children with CCLP is associated with anatomical and topographic features that facilitate the penetration of pathogenic microflora in oral and nose mucosa and, consequently, negative changes in the immune system (IS). The key cells of IS in maintaining homeostasis and ensuring oral health are neutrophil granulocytes (NG). NG dysfunctions in CCLP interfere with the elimination of pathogens and support their persistence. This can occur against the background of previously existing defects in the functioning of the NG system and is aggravated by the significant pathogenicity and massiveness of the impact of various infectious agents. Full diagnostics of NG dysfunctions is necessary for the further implementation of their timely immune correction and prevention of the development of pathological chronic inflammation in response to the pathogenic microflora long-term on the mucous membrane of the mouth and nose. For this purpose study was conducted of the functional activity and phenotypic characteristics of NG in children with CCLP at different stages of complex rehabilitation. Blood samples of 56 children with CCLP 1-3 years (n = 20, group 1), 4-6 years (n = 20, group 2), and 7-12 years (n = 20, group 3) at different stages of complex rehabilitation and 30 conditionally healthy children (control groups) of the corresponding age was studied. A violation of the microbiocenosis of the mucous membranes of the oral and nasal cavities was revealed, which may be a cause or a consequence of a decrease in antibacterial immunity, first of all NG dysfunctions. Common for all age groups children with CCLP NG dysfunction was found: the appearance of NG expressing CD14 receptors that are absent in children of all three control groups, which indicates the presence of viral and bacterial load; defects of phagocytosis associated with a decrease in the number of actively phagocytic NG, impaired NG capture functions; impaired NADPH oxidase release with partial or complete blockade of the response to additional antigenic load, even in the absence of acute clinical manifestations. Comparative analysis of the studied indicators of the expression level of the receptors CD64, CD16, CD32, CD14 NG in children with CCLP demonstrates different equipment, which determines the inconsistency of the phagocytic and microbicidal function of NG in different age periods. Thus, an increase in the expression of these membrane markers, especially CD64 and CD14, in older age groups is accompanied by more significant defects in phagocytic and killing functions of NG, which is associated not only with recurrent viral respiratory infections, but also with a high frequency of associated bacterial infections of the respiratory system and ENT – organs. Revealed NG dysfunctions in children with CCLP of various age groups indicate their inability to implement adequate anti-infective protection, which can lead to atypically occurring viral – bacterial infections and the occurrence of various, including purulent complications in the postoperative period, which requires the development of targeted immunotherapy, included in the program of comprehensive rehabilitation in children with CCLP and aimed at restoring impaired NG functions.

External genital endometriosis is an inflammatory, estrogen-dependent disease that develops predominantly in women of reproductive age and is characterized by the presence of pain syndrome and infertility. Today, endometriosis is one of the most common gynecological diseases in women of reproductive age, however, the etiology and pathogenesis of it are not completely clear. Violations of systemic immunity are most important in the pathogenesis of endometriosis. The literature data on the features of the immune response in endometriosis in combination with genital infection are few and contradictory. Purpose – to study the features of systemic immunity in women with external genital endometriosis and pathogens of genital infection.

A total of 159 women with external genital endometriosis were examined. The main lymphocyte subpopulations, the functional activity of neutrophils and peripheral blood monocytes, and the content of cytokines in the blood serum were studied. A study of systemic immunity was performed in women with 1-2 and 3-4 stages of endometriosis, as well as depending on the presence of pathogens of genital infection. The presence of Chlamydia trachomatis, Ureaplasma spp., Mycoplasma genitalium, HSV1, 2/CMV, HPV in the endometrium, peritoneal fluid, and endometrioid heterotopies was determined. Statistical processing was performed using the IBM SPSS Statistics Version 22.2 statistical analysis software package.

According to the results of the study, it was found that women with endometriosis of stages 1-2 show signs of systemic inflammation with a predominance of the Th2 type of immune response and inhibition of cellular immunity. A particular feature of HPV was an increase in T-NK lymphocytes, a decrease in IL-2 and neutrophil functional activity. The presence of Ureaplasma spp./Mycoplasma genitalium was characterized by a decrease in cellular immunity and an increase in T-NK cells. Only with HPV and Ureaplasma spp./Mycoplasma genitalium decreased synthesis of IL-2, IL-6. With 3-4 stages, the most significant changes in immunity were found in groups of women with genital infection. When HPV – a high level of IgA, increased IgM, IL-8. With Ureaplasma spp./Mycoplasma genitalium – inhibition of cellular immunity, high levels of IgA, reduction of neutrophil phagocytic activity.

Thus, in women with endometriosis in the presence of pathogens of genital infection revealed features that may contribute to the development and progression of the disease.

Tuberculosis is a granulomatous disease caused by Mycobacterium tuberculosis, being characterized by the development of caseous granulomas in various organs, mainly in lungs. M. tuberculosis is known to be a trigger for autoimmune inflammation, due to the possible mimicry of bacterial proteins as autoantigens. Recently, a significance of mesenchymal vimentin as an autoantigen in mycobacterial infections has been actively discussed. The aim of the present study was to determine autoantibodies for various vimentin modifications in the patients with tuberculosis.

The study was performed in 2014-2017 and included 28 patients with pulmonary tuberculosis (group I), 30 patients with nonspecific lung diseases (group II): 15 with granulomatous polyangiitis, and 15 with different alveolites. Control group consisted of healthy subjects (n = 40). Concentration of antibodies to mutated citrullinated vimentin (anti-MCV) was measured using ELISA (ORGENTEC, Germany). The patients with elevated anti-MCV levels were tested for antibodies to cyclic citrullinated peptide (anti-CCP) using ELISA technique (EUROIMMUN, Germany). Statistical analysis was carried out using GraphPad Prism 6 (GraphPad Software, USA), Statistica 10 (Statsoft, USA) using nonparametric analysis of samples with Mann-Whitney and Chi-square criteria, and Spearman method for correlation analysis. The differences were considered statistically significant at p < 0.05.

The anti-MCV concentrations were significantly higher in patients with tuberculosis (group I, 60.7% of cases, 17/28) than in group II, and control group (23.6 and 25.0% of cases, respectively). No statistically significant differences were revealed between the results of anti-MVC and anti-CCP levels in comparison group with the control group (p = 0.18).

High levels of anti-MCV antibodies in the patients with pulmonary tuberculosis reflect an opportunity of developing autoimmune process in the disease pathogenesis. Measurement of plasma anti-MCV antibody concentrations may be important for correction of the therapy, especially upon administration of immunosuppressive and hormonal corticosteroid drugs. It has been shown that anti-CCP are not characteristic to the lung diseases.

Aspergillus fumigatus colonization in the patients with cystic fibrosis (CF) may cause sensitization against A. fumigatus and/or allergic bronchopulmonary aspergillosis (ABPA), which significantly worsens the course of underlying disease. At the present time, new diagnostic tests are searched for detection of fungal sensitization in these patients. The aim of this work was to evaluate an opportunity of application of basophile activation test with A. fumigatus allergen in vitro using flow cytometry, aiming for identification of fungal sensitization in the CF patients. The study included 190 patients with CF aged 1 to 37 years. All the patients underwent common allergy screening (skin tests with fungal allergens, determination of serum levels of total IgE and specific IgE for the fungal allergens), and mycological examination (microscopy and culture of respiratory substrates). Computed tomography of the chest was performed upon clinical indications. The basophil activation test with the A. fumigatus allergen was performed in 10 CF patients with ABPA, and 10 CF patients without ABPA, in addition to the standard allergological examination. Frequency of sensitization to A. fumigatus in the patients with cystic fibrosis was 27%, the incidence of allergic bronchopulmonary aspergillosis was 5.7%. The number of eosinophils, total IgE and specific IgE levels in CF patients with ABPA were significantly higher than in CF patients without ABPA. In blood of the ABPA patients we have identified 68.5 (52.5-81.5%) of basophilic leukocytes activated by A. fumigatus allergen, with a stimulation index of 17.07 (10.30-27.70). In appropriate comparison group, the stimulation index did not exceed 1.5 (p = 0.000). Direct positive correlation between the levels of specific IgE to A. fumigatus and the number of basophils activated by A. fumigatus allergens was revealed (r = 0.77; р < 0.05). FVC values and the body mass index in CF patients with ABPA were significantly lower when compared with the patients without fungal sensitization. Introduction of the basophil activation test, along with standard techniques, may enable a more differentiated assessment of ABPA development in CF patients. Timely detection of associations between A. fumigatus sensitization and clinical status of CF patients will facilitate early and effective administration of specific therapy.

High occurence of liver diseases (toxic, viral hepatitis, liver failure, cirrhosis) requires urgent search of new methods for management of the hepatobiliary diseases. At the present time, the role of immune mechanisms in pathogenesis of diffuse toxic liver damage is not finally clarified. The model of toxic hepatitis induced by carbon tetrachloride (CCl₄) is widely known, but this approach allows us to perform complex evaluation and develop the methods for adequate correction of liver disorders in experimental model, which is not always feasible in clinical setting.

To design a model of diffuse toxic liver damage, the CCl₄ oil solution was used, having been administered intraperitoneally to experimental animals, at a single dose of 50 mg per 100 g body mass. Aiming for correction of toxic liver damage, the injections of aminophthalhydrazide (APH) to experimental animals were carried out intramuscularly at the dose of 2 mg/kg over the terms of experiment. An evaluation of the role of sinusoidal cells (SC) and cytokine production at the local and systemic level were carried out in the model of toxic liver damage caused by CCl₄ and its correction by APH treatment. In the course of developing diffuse toxic liver damage induced by CCl₄, the production of proinflammatory cytokines TNFα, IL-1α and IL-18 was enhanced at the local level, whereas an increase in TNFα concentration was observed in blood plasma. Following aminophthalhydrazide (APH) administration, the concentrations of proinflammatory cytokines (TNFα and IL-18) decreased at system level, along with locally decreased levels of IL-6 and IFNγ.

Changes in the functional state of immunocompetent cells, which include sinusoidal cells (SC), have a significant impact on the development of pathological processes in the liver. The results of our study presume that, over the early periods of toxic impact upon liver tissue, the number of SCs increases both due to influx of blood monocytes and mature macrophages from the peritoneal cavity that enter the injury site directly via mesothelial layer. The SCs provide phagocytosis of damaged hepatocytes and contribute to resolution of the inflammatory process.

Modulation of the macrophage activities by APH contributes to increased amounts of SCs at the early stages, and stabilizes their quantities after 2 weeks of APH injections. Change in the numbers of liver SCs during toxic damage affects the production of cytokines. A direct effect of APH upon the SCs may change the production of regulatory factors and compensate the insufficient rate of recovery processes after the toxic damage.

Food allergy against cow milk and its components is highly prevalent among infants and children of pre-school and young school age being a sufficient factor influencing health condition of children during the maturation period. Clinical signs of the milk allergy are non-specific, and they may be pronounced or expressed in mild form, thus enabling hypodiagnistics of this disorder. Moreover, a variety of milk antigens determines different clinical course of this allergic condition and brings additional difficulties to its diagnostics and treatment. Meanwhile, a sensibilization for the cow milk proteins may sometimes trigger a generalized atopy and bronchial asthma, being a factor delayed growth and other health disorders. At the present time, there are no distinct risk criteria for milk allergy. Therefore, its successful prophylaxis and treatment largely depends on the competence of clinical allergologist and informativity of the diagnostic techniques used. So far, however, we have no generally approved laboratory algorithms for diagnostics and monitoring of treatment efficiency in the cow milk allergy and its compomemts.

We have performed a laboratory study of 187 children at the age of 3 months to 10 years. An immunochemoluminescent assay of specific IgE antibody levels to the cow milk using IMMULITE 2000/XPi analyzer has revealed its good informative value at different approaches to prediction and evaluation of food allergy treatment, both oriented for a critical cutoff value of 3 МU/L, and by monitoring a decrease in antibody levels. The authors consider rational an extended indefinity principle during the patient-oriented interpretation of IgE assay results if clinical decision is based on critical value of the index. In cases of clinical monitoring, the limit of interim reproducibility should be taken into account. The prevalence of specific cow milk antibodies among the boys was higher than among girls, however, with lesser frequency of moderate/high reactivity among the males. Moreover. the cases were detected with higher levels of anti-beta-lactalbumin IgG than those against whole milk. This finding should be considered during the screening studies.

On the basis of literature analysis and own results, the authors propose an extensive study of specific IgE antibodies against cow milk and its components in blood serum of infants and children form the pre-school and junior school age groups.

Non-alcoholic fatty liver disease (NAFLD) is a group of conditions closely associated with obesity that are among the most common and socially significant liver diseases in the modern Western world. The emergence and progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis with the subsequent development of fibrosis are the leading factors in the pathogenesis of a significant proportion of the most severe liver pathologies, such as cirrhosis and hepatocellular carcinoma, as well as extrahepatic metabolic complications of NAFLD, such as insulin resistance and type 2 diabetes mellitus. The inflammatory component is one of the most important factors in the pathogenesis of NAFLD, particularly in the context of the progression of simple steatosis to non-alcoholic steatohepatitis. At the same time, the role of the most important mediators of the inflammatory response, innate immunity receptors and the Toll-like receptors in particular, in the pathogenesis of NAFLD has been poorly studied. In the present work, we first used the bioinformatics analysis of the publicly available gene expression databases to demonstrate that only TLR1, TLR2, TLR3 and TLR4 were significantly expressed in the healthy human liver. We then used the reverse transcription PCR to measure the mRNA expression levels of TLR2, TLR3, and TLR4, as well as those of the important pro-inflammatory mediators tumor necrosis factor (TNF) and interleukin-6 (IL-6), in the liver biopsy specimens obtained from 20 patients with NAFLD (simple steatosis, n = 10; non-alcoholic steatohepatitis, n = 10), as well as from 4 obese patients with clinical suspicion for NAFLD but no histological signs of NAFLD in their liver biopsies. We found a significant increase in the expression of TLR2, TLR3 and TLR4 mRNA in liver biopsy samples obtained from patients with non-alcoholic steatohepatitis as compared to those obtained from controls without histological signs of NAFLD. We were also able to demonstrate the association between the hepatic levels of TLR2, TLR3 and TLR4 mRNAs with the histological degree of liver damage as evidenced by the degree of steatosis and balloon dystrophy of hepatocytes, as well as with the plasma levels of uric acid, the important endogenous stimulator of innate immunity. Our data indicate the possible involvement of innate immunity, particularly the Toll-like receptors, in the pathogenesis of NAFLD.

Osteomyelitis of the lower jaw is one of the urgent problems of modern medicine. There are many reasons for the evolvement of purulent necrotic processes of the jaw bones, including the role of disorders in the systems of innate and adaptive immunity. The aim of the study was to determine the content of TNFα, IL-17, IL-4 in serum and mixed saliva in patients with uncomplicated mandibular fractures and posttraumatic osteomyelitis to determine the possibility of using these indicators for early diagnosis of posttraumatic complications. The article presents the results of a study of tumor necrosis factor α (TNFα), interleukin-17 (IL-17) and interleukin-4 (IL-4) cytokines in serum and mixed saliva in patients with uncomplicated mandibular fracture and post-traumatic osteomyelitis at the first and tenth days of observation. By means of single-layer neural networks, binary classifiers were built, allowing patients to be stratified by the clinical form of the disease and to predict its course. The probability of uncomplicated mandibular fracture is described by the ratio P = 1/(1+e^-z), where the index z is determined by the level of TNFα, IL-17, and IL-4 at the first and tenth day of observation. The simulation confirmed high prognostic significance of serum TNFα and IL-17 for early verification of posttraumatic osteomyelitis, which was confirmed by the OTC and ROC indices, which varied from 87 to 100% in different models. Models 4 and 5, where TNFα recorded on the tenth day of the study was used as predictors, and a combination of TNFα and IL-17 obtained on the first day of hospitalization, were the most accurate. Modeling the results of the study of immunological indicators in the mixed saliva showed that the predictive properties have only IL-4 and IL-17, was on the tenth day of hospitalization that distinguishes these binary classifiers from similar indexes, derive from the levels of cytokines in blood serum. The results of the study indicate the important role of disorders in the system of рro- and anti-inflammatory cytokines in pathogenesis of post-traumatic osteomyelitis.

Stress factors, infections, tumor transformation of the cells of organism induce the expression of MICA protein, which is a ligand for the NKG2D receptor of NK and T cells. The interaction of the NKG2D receptor on the surface of the cells of the immune system with MICA results in activation of lymphocytes and elimination of the ligand carrier. The MICA gene has a high level of polymorphism. To date, 87 alleles have been described; their products differ in ability to activate cytotoxic lymphocytes, that can affect the progression of a number of diseases, such as cancer, viral infections, autoimmune diseases. The distribution of MICA alleles in different ethnic groups varies considerably. The analysis of MICA polymorphism in a current ethnos is necessary for revealing the relationships between certain MICA alleles and different diseases. Goal. This work is aimed at studying of the distribution of MICA alleles in Russian population. Materials and methods. Polymorphism of MICA was analyzed according to the procedure proposed by Yizhou Zoe and Peter Stastny. The procedure included: 1) isolation of genomic DNA from whole blood; 2) PCR for amplification of a fragment of the MICA gene; 3) sequencing of the resulting PCR fragments. Analysis of the results of sequencing was carried out using the programs Vector NTI and Chromas Lite. Results. The genotype of the MICA alleles of 119 donors has been determined. Of the 87 MICA alleles described in the literature, 15 were found among the samples studied. The frequencies of MICA alleles were the following: *002 – 19.3%, *004 – 6.7%, *007 – 3.0%, *008 – 35.7%, *009 – 10.1%, *010 – 5.0%, *011 – 3.8%, *012 – 2.1%, *016 – 2.5%, *017 – 3.4% *018 – 5.5%, *019 – 0.4%, *027 – 1.3%, *053 – 0.8%, *068 – 0.4%. The distribution of MICA alleles in Russia was found to be similar to that of European countries. When comparing literary data for different countries of the world, it was found that the differences in the distribution of MICA alleles are expressed mainly between races, and not nations. Conclusions. In this paper, the distribution of MICA alleles in Russian population has been analyzed. It turned out to be very similar to those of other European countries and has a number of significant differences from the ethnoses of the Mongoloid race (Japan, China, Korea). The analysis of the distribution of MICA alleles in the Russian population may be useful for identifying the predisposition of individuals to certain diseases.

The article presents a study on the distribution of gene polymorphisms in the histocompatibility antigens among the patients diagnosed with AML, and healthy donors in the Republic of Kazakhstan, as well as features of the HLA-A*, *B, Cw*, DRB1*, DQB1* distribution among the patients with acute myeloid leukemia (AML). HLA typing and data processing were performed at the Research and Production Center of Transfusiology, Nur-Sultan. A total of 3808 people were examined, including 3621 healthy blood donors and 187 patients diagnosed with AML. Genomic DNA for HLA typing was isolated from peripheral blood leukocytes by proteinase method using columns with silica membrane and using a set of reagents PROTRANS DNA BOX (Protrans, Germany). Typing of HLA-A, B, C, DRB1, DQB1 in the patients and blood donors was performed by polymerase chain reaction using commercial reagent kits from Protrans (PROTRANS HLA- A*/B*/DRB1* Cyclerplate System, PROTRANS HLA-C* Cyclerplate System, PROTRANS HLA-DQB1* Cyclerplate System).

HLA-A*31 (OR = 1.8; CI 1.16-2.79; p < 0.01) proved to be more common in the group of patients compared to the control group, which suggesting an association between AML and presence of this antigen. The control group showed an increased frequency of HLA-A*02 antigen (OR = 0.55; CI 0.41-0.75; p < 0.01). This antigen may be, therefore, exert a protective effect in AML development.

The studies of major histocompatibility complex which include HLA genes, did significantly expanded the understanding of HLA antigens which may have strong associative links with distinct diseases, and moderately or poorly expressed links in other disorders. Analysis of the literature data showed that myeloid leukemia is characterized by decreased frequency of HLA-B13, B14, B40 antigens, most often determined by antigens B16, Bw 22, B27. In this study, HLA-A*31, B*37 were associated with AML. Phenotypes with antigens HLA-A*02, B*27, C*02, DRB1*01, *04, DQB1*06 have a probable protective effect on the development of this pathology.

The study has determined some features of histocompatibility gene distribution in AML patients, detection of HLA-markers that determine the risk or resistance to the occurrence of this disease. We have established characteristic specific markers of HLA system among AML patients in Kazakhstan, which may be associated with higher risk of the disease.

Occurrence of coronary artery disease in combination with anxiety-depressive disorders is common in clinical practice. In such patients, affective disorders significantly may cause progression of atherosclerotic processes, thus complicating the course of cardiac pathology and prognosis. Distinct markers of immune inflammation, first of all, cytokines are of particular importance for the pro-atherogenic effects in atherosclerotic foci. Endogenous opiate peptides are considered the main regulators of these processes at the neuroimmune level. Their role for stabilization of cytokine levels in evolving inflammation in atherosclerotic plaque, and during adaptation of heart muscle to stressful effects was previously shown. Despite reliable data on the role of immune inflammatory markers in atherogenesis, the validity of the regulatory role of opiate peptides in this process, questions still exist about the effects of affective disorders upon neuropeptide-cytokine status of the immune system in the patients with chronic ischemic heart disease (IHD). Another issue concerns the ranges of these changes in painful and painless forms of myocardial ischemia.

Therefore, the purpose of our study was to assess the impact of severity of anxiety-depressive disorders upon the neuropeptide-cytokine status of immune system in patients with various clinical variants of chronic IHD, as well as comparisons of these changes expressed in painlul and painless myocardial ischemia.

Appropriate groups were formed, then being divided into subgroups, according to the percentage of painful and painless episodes of angina pectoris: Group 1 (n = 36) included patients with chronic coronary artery disease occurring and moderate-grade anxiety/depression; Group 2 (n = 34) consisted of patients with chronic coronary artery disease and mild anxiety-depressive disorders; Group 3 (n = 20) included patients with chronic coronary artery disease without anxiety and depressive disorders; Group 4 (n = 22) represented controls (healthy persons). As based on presence of painful and painless episodes of stenocardia, the following subgroups were specified: in the 1 st group of patients, painful form of IHD was detected in 44% of cases (n = 17); painless form of IHD was detected in 56% of patients (n = 19); in the 2 nd group of patients, painful form of IHD is in 52% of the examined persons (n = 18), painless form of IHD was revealed in 48% of cases (n = 16); in the 3 rd group, the painful form of IHD was confirmed in 37% of patients (n = 8), painless form of IHD was observed in 63% of patients (n = 12). In all these groups, the following parameters were evaluated: the state of psychophysiological status determined by psychological testing, the levels of vegetative regulation (β-endorphin), the function of cardiovascular system (SMECG), and the levels of peripheral blood TNFα, IL-1β, IL-6 and IL-4, IL-10 were also measured.

As based on the data of clinical and laboratory examination, we have suggested that, in the patients with chronic IHD, anxiety and depressive disorders exert a direct pathological effect on the neuropeptide-cytokine status of immune system expressed as suppression of β-endorphin, increased level of pro-inflammatory cytokines and a decrease in anti-inflammatory factors. Meanwhile, these changes are especially pronounced in the patients with painless myocardial ischemia.

The article aims for description of glandular/lymphoid interactions within digestive tract over the postnatal ontogenesis which is of special importance for clinical immunology. We have examined lingual salivary glands obtained from 299 autopsies, using macroscopic and histological techniques. Their age ranged from newborns to senile individuals; both males and females were included. The biological material was sampled at the local pathology departments at the Moscow Bureau for Forensic and Medical Expertise, according to approval by Russian federal law (No. 323, art. 47, 4180-1, 355н). The cases with pathological changes of digestive system revealed upon autopsies were excluded from evaluation. The transverse tissue sections were stained with H&E and picro fuchsin by van Gieson technique.

The minor salivary lingual and pharyngeal glands, being located in the depth of tongue and pharyngeal walls, perform an important endocrine function, i.e they participate in oral immunity responses. A lot of publications concerns regenerative changes of oral mucosa caused by secretory IgA which plays a main role in regulation of local immunity. The article describes important age-dependent changes of both lingual and pharyngeal minor salivary glands. Typical scarcity of the glands in childhood may be caused by the uniform nutrition at this age, whereas decreased secretory IgA production, is generally leading to development of common inflammatory events in the oropharyngeal area. With increasing age, the glandular apertures become wider and more numerous, thus leading to increased local immunity in oral cavity and oropharynx. Sufficient involutional changes are observed in old and senile age cohorts, accompanied by diminished secretory IgA production, and, respectively, by decreased indexes of local and humoral immunity. These results are entirely reflecting topographical interrelations between the glands and lymphoid cells, and appropriate data are quite important for clinical immunology.

Anti-idiotypic antibodies (Ab2), according to the network theory of Jerne, are second-generation immunoglobulins that are produced against the idiotype of an antibody to a specific antigen. Despite the large number of works devoted to the study of the properties of these proteins, their role in the regulation of the immune system is not fully known. It may consist in maintaining or blocking a minimal immune response to the antigen. The study of Ab2 is of great practical and scientific importance. The special properties of Ab2, namely, the ability to partially reproduce the structure of the primary antigen and, upon immunization, induce the appearance of tertiary antibodies, which, like first-generation antibodies, can bind to the antigen, have found application in the development of Ab2-based vaccines, in particular, for the treatment of tumors. In view of the presence of a number of limitations on research related to psychoactive substances, the development of Ab2- based vaccines against drug addiction also seems promising. To example, anti-idiotypic antibodies obtained for this purpose possessing a cocaine-like structure are described in the literature. In this work, murine monoclonal anti-idiotypic antibodies (mAb2) mimicking the structure of various morphine derivatives were obtained. Rabbit polyclonal antibodies to the 6-hemisuccinyl derivative of morphine conjugated with bovine serum albumin isolated by affinity chromatography were used as primary antibodies for immunization. Four hybridoma clones were obtained as a result of the fusion of immunized mice lymphocytes with mouse Sp2/0 mouse myeloma cells by the Milstein-Köhler method. After growth in animals, mAb2 produced by hybridoma cells were affinity purified. We investigated the physicochemical and antigenic properties of the isolated antibodies. It was shown that the obtained mAb2 differ in immunological specificity, competing in different degree with morphine derivatives for binding to first-generation antibodies. We tested the possibility of using the obtained mAb2 as antigen analogues in the solid-phase enzyme-linked immunosorbent assay to determine the titer of primary antibodies against morphine in the blood serum of laboratory animals immunized with morphine derivatives. Based on the obtained anti-idiotypic antibodies, it is proposed to develop test systems to determine the serum opiate-specific antibodies in people after specific vaccination for therapeutic or prophylactic purposes to avoid the use of drugs as antigens immobilized on the solid phase in the analysis.

Allergen-specific diagnostics is carried out on the basis of the data collection from the patient’s family and personal history, skin test results, provocative tests and laboratory research methods. Methods for determining specific IgE antibodies (sIgE) play a key role in confirming the diagnosis and identifying the pathogenetic mechanism of an immediate-type hypersensitivity to an allergen. The purpose of the study was to evaluate the results of determining sIgE for allergens of cat epithelium, house dust mite D. farinae and birch pollen in the blood serum of patients suffering from respiratory allergy, by comparing two methods of ImmunoCAP Phadia and 3gAllergy Immulite, as well as determining whether the results of these test systems are in concordance with the results of skin tests in the patients. The serum samples were obtained from patients of St. Petersburg adult outpatient clinics, who suffered from respiratory allergies (n = 50). The samples were analyzed in parallel in two laboratories, with each of the laboratories using single test systems. The retrospective skin test results were obtained from twenty six of the fifty selected patients. The inter-method comparison was conducted by determining the concordance of positive and negative results, correlation and regression analysis of sIgE results for each allergen and ROC-analysis to compare the diagnostic specificity and sensitivity of test systems in relation to the results of skin tests. This study showed that, in terms of agreement and contingency of the results, the Immulite test system had a close relationship with the Phadia test system. Both analysis of classes and quantitative sIgE analysis showed a good positive correlation from 0.79 to 0.99 (p < 0.0001) between the two test systems for all three allergens. High accuracy of coincidence in terms of sensitivity, area under the ROC curves (AUC) and cut-off threshold in both test systems was obtained for the D. farinae allergen. For allergens of cat epithelium and birch pollen, some differences between test systems were observed, i.e., sensitivity and AUC values were significantly higher in Immulite than in Phadia assay for both allergens.

Thus, the inter-method comparison gave almost equivalent binary and quantitative results of the determination of sIgE antibodies to cat, tick and birch allergens. Comparison of in vitro test results, and their correlation with skin tests showed that the cat and birch in vitro antibody testing with Immulite assay was more closely connected with skin test results, than Phadia assay system.