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Allergic rhinitis (AR) occupies a leading position among the causes of morbidity throughout the world, to date, it has been diagnosed in 400 million people. In the formation and progression of AR, a significant role is assigned to cytokines associated with the second type of immune response, in particular, IL-4, IL-5, IL-9, IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP). This literature review provides information on the influence of the listed mediators on the structural cells of the nasal cavity and blood immune cells (T- and B-lymphocytes, eosinophils, macrophages, dendritic cells), and discusses their association with the manifestation of AR symptoms and the severity of the disease. The results of studies aimed at establishing the level of IL-4, IL-5, IL-9, IL-13, IL-25, IL-33 and TSLP in biological fluids (blood serum, nasal lavage) and their expression in nasal epithelial cells in patients with AR compared to healthy people are assessed.

The development of pollinosis in children and adolescents is determined by the influence of genetic and environmental factors. The pathogenetic basis of pollinosis in children and adolescents is the differentiation of Th0 to Th2, activation of Th2cells and increasing of the production of IL-4, IL-5, IL-13, sIgE, activation of mast cells, basophils, eosinophils, with following development of IgE-mediated allergic reaction after exposure to pollen allergens and the manifestation of clinical symptoms of pollinosis (allergic rhinitis, allergic conjunctivitis, bronchial asthma). Children and adolescents with pollinosis often develop cross-allergic reactions to plant-based foods. Pathogenetic pharmacotherapy (antihistamines of the second generation, topical corticosteroids, antileukotrienes, decongestants) allows to achieve control over the symptoms of pollinosis. Subcutaneous and sublingual ASIT are high effective, they reduce the severity of symptoms of pollinosis, decrease the risk of developing bronchial asthma and severe clinical forms of pollinosis. The sublingual ASIT is more safe than subcutaneous ASIT.

This article presents the experience of successful use of the drug dupilumab in a patient with severe atopic dermatitis and bronchial asthma. The effectiveness of biological therapy with dupilumab 300 mg subcutaneously for 52 weeks of T-2 associated diseases, including a combination of severe atopic dermatitis and bronchial asthma, uncontrolled course based on the case history of patient Ts., born in 2006 with the diagnosis "Main: atopic dermatitis, common form, severe course. Concomitant diagnosis: bronchial asthma, persistent course, uncontrolled, moderate severity". Dynamic monitoring of the total blood count with the calculation of the absolute number of eosinophils in peripheral blood was performed. The study showed high efficacy and safety of biological therapy with dupilumab 300 mg subcutaneously every 2 weeks for 52 weeks with a combination of severe atopic dermatitis and bronchial asthma, uncontrolled course in patient Ts (Born in 2006). The examination of the ALEX2 allergochip made it possible to establish the molecular components of the primary causal allergens, predict the course of an allergic disease, and carry out successful elimination measures against food allergens, preserving the maximum set of nutrients in the patient's diet. Dupilumab therapy in severe atopic dermatitis and uncontrolled bronchial asthma leads to clinically significant improvement in the course of diseases, control of disease symptoms. Atopic dermatitis shows a decrease in itching of the skin, normalization of sleep, improvement of quality of life. With bronchial asthma, a reduction in exacerbations, normalization of respiratory function indicators, complete control of the disease has been achieved. The targeted biological drug dupilumab has a targeted effect on the key links in the pathogenesis of atopic dermatitis and bronchial asthma and reduces the burden of severe diseases. Therefore, the use of dupilumab in atopic dermatitis and bronchial asthma contributes to achieving disease control and improving the patient's quality of life.

This review presents current data on immunopathogenesis, the role of cytokines in inflammation in atopic dermatitis (AD). The pathogenetic phenotypes of the disease associated with various abnormalities of immune mechanisms and dysfunction of the epidermal barrier are considered. The inflammatory processes in atopic dermatitis were shown to be implemented mainly through Th2-lymphocytes and IL-4 and IL-13 produced by these cells, which play a key role in the allergic cascade. It is the effects of IL-4 and IL-13 cytokines that determine the main pathophysiological mechanisms, such as decreased expression of epidermal barrier proteins and suppression of terminal differentiation of keratinocytes, microbiota disturbances, tissue remodelling, immunoglobulin isotype switching by B-lymphocytes and IgE synthesis, degranulation of mast cells and basophils, trafficking of inflammatory cells into tissues, itching. Moderate and severe forms of AD require administration of systemic therapy, which has been represented until recently by non-selective immunosuppressive drugs with moderate efficacy and pronounced side effects if they are used for a long time. Modern targeted therapy of atopic dermatitis provides for the use of monoclonal antibodies against both pro-inflammatory cytokines and their receptors. Directional action on the key mechanisms and targets of immune inflammation can minimize possible side effects of immunosuppressive therapy. Clinical trials on the efficacy and safety of IL-4 and IL-13 inhibitors in the treatment of atopic dermatitis are described.

The asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), eosinophilic esophagitis and other diseases based on T2-inflammation are a widespread in the world. It has led to the development of genetically engineered drugs aimed at individual and specific components of inflammation. One of the leading positions in the pathogenesis of T2-mediated diseases is occupied by interleukin (IL)-4 and IL-13, which explains the prospects of studying these cytokines for the creation of anti-IL-4/IL-13 monoclonal antibodies. The first immunobiological drug was registered to directe against the α subunit of the IL-4 receptor (IL-4Ra), common to both IL-4 and IL-4/IL-13 receptor complexes is dupilumab which is a fully human monoclonal antibody. Dupilumab targets the IL-4 receptor alpha chain (IL-4Rα), common to both IL-4R complexes: type 1 (IL-4Rα/γc; IL-4 specific) and type 2 (IL-4Rα/IL-13Rα1; IL-4 and IL-13 specific). Because the IL-4/IL-13/STAT6 signaling pathway plays a significant role in T2 inflammation. IL-4 and IL-13 are secreted by several cells and, along with other T2 cytokines, as well as with the participation of IL-33, IL-25 and TSLP can stimulate cells to further secrete pro-inflammatory cytokines, contributing to the maintenance of the inflammatory process. Currently, dupilumab has been studied in at least 3,000 patients with asthma, AD, CRSwNP and eosinophilic esophagitis. The results of investigation show an acceptable safety profile in placebo-controlled studies worldwide. In this article, we have highlighted the results of numerous clinical studies and observations that have proven the effectiveness and safety of the use of dupilumab in asthma, AD, CRSwNP, prurigo, eosinophilic esophagitis and eosinophilic pneumonia.

Atopic dermatitis is one of the most common chronic inflammatory skin diseases caused by both terminal defects in keratinocyte differentiation, and pronounced type 2 immune responses. Atopic dermatitis is a fairly heterogenous disease, depending on the age subtype caused by activation of the Th22, Th17/IL-23 and Th1 cytokine pathway. Clinical studies using classical and targeted therapies have helped to determine contribution of various immune axes to the disease phenotype.We present the modern activation theory mediated by Th2 reactions, due to congenital lymphoid cells of the 2nd group. Correlations between immune response in acute (IL-4, IL-5, IL-13, IL-31, CCL18, IL-22, S100A proteins) and chronic (IFNγ, CXCL9, and CXCL10) manifestations of atopic dermatitis are described. The theory of relationship between clinical manifestations and overexpression of some cytokines (IL-4, IL-13) is discussed. The correlation was shown between peripheral blood phenotype in atopic dermatitis of early childhood and in adult patients and individual production of serum biomarkers. In addition to excess Th17 production, early onset of atopic dermatitis in children correlated with elevated levels of antimicrobial peptides, which may serve as a signaling marker that triggers the disease. The article provides information about relationship between atopic dermatitis and other systemic non-allergic processes and diseases (psoriasis, atherosclerosis, cardiovascular diseases, obesity). Despite different polarity of T cells in atopic dermatitis and psoriasis, and different groups of cytokines produced in these diseases. Psoriasis is most of all due to Th17 associated with activation of IL-17, whereas atopic dermatitis is a consequence of Th2 dominance and associated excessive production of IL-4 and IL-13. The both diseases show activation of Th1 and Th22 with increased production of interferon-γ and IL-22, respectively. The article also concerns an interesting hypothesis on effects of the TWEAK protein upon clinical course of atopic dermatitis and psoriasis. In response to increased TWEAK activity, keratinocytes and skin fibroblasts produce a number of chemoattractant and pro-inflammatory factors commonly found in atopic dermatitis and psoriasis, in particular IL-13 and IL-17. TWEAK is not a single etiological factor for atopic dermatitis or psoriasis, but it causes the production of chemokines that promote chemotaxis of pathogenic inflammatory cells into the skin. With further studies of this pathogenetic factor, it will be possible to synthesize a new targeted drug for the treatment of atopic dermatitis and psoriasis.

The review is devoted to two key Th2 cytokines - IL-4 and IL-13, which are directly involved in the immunopathogenesis of atopic dermatitis. The identification of IL-4 and IL-13 in AD was first reported by Hamid Q. et al. in 1994. Since then, a huge number of studies have appeared confirming the relationship of these Th2 cytokines with disruption of the epidermal barrier of the skin; a decrease in the immune response of the skin due to inhibition of the expression of antimicrobial peptides against Staphylococcus aureus, etc. Studies also convincingly confirm the relationship with IL-4/IL-13 of such clinical manifestations of atopic dermatitis as skin infections, as well as inflammation, lichenification and itching of the skin. The role of IL-4 and IL-13 is also confirmed by clinical studies, which indicate a beneficial effect of drugs inhibiting these cytokines on the relief of skin symptoms of atopic dermatitis (itching, rashes). It turned out that IL-4 and IL-13 connect the JAK/STAT signaling pathway due to the common α-subunit of the IL-4 receptor - IL–4Ra. Another important ability of IL-4, IL-13 and other cytokines (including IL-31) is the activation of sensory neurons, so they are often considered as potent pruritogens. The article also discusses issues related to the role of the JAK/STAT signaling pathway and, in particular, the JAK1 protein in the development of atopic dermatitis. Based on the pathogenetic significance of IL-4 and IL-13, drugs have recently been developed that block their activity and thereby affect important molecular pathways in the development of atopic disease. These drugs are classified as systemic therapy, which includes, among other things: 1). biological therapy (dupilumab, the first monoclonal IgG4 antibody), which blocks IL-4Ra and thereby suppresses the IL-4/IL-13 axis, and 2). Janus kinase (JAK) inhibitors or small molecule (currently, such drugs from the group of Janus kinase inhibitors as abrocitinib, upadacitinib and barocitinib are available in Russia). Studies show that both biological therapy and small molecules have an immunomodulatory effect on the course of atopic dermatitis. The review briefly presents the main data of recent meta-analyses on the comparative characteristics of biological therapy and Janus kinase inhibitors in this disease.

The search for new rational ways to improve the effectiveness of treatment and rehabilitation measures of patients with true eczema continues to be one of the pressing issues in modern clinical dermatology., Objective: The comparative analysis of influence of different variants of SCL: balneotherapy and balneotherapy combined with magnetic laser therapy on the dermatological status, IL-4 and IL-13 level, psycho-emotional state and QOL evaluation in patients with true eczema., Material and Methods: The study involved 112 patients with true eczema undergoing spa treatment (SCR) (54 in the balneotherapy group and 58 in the balneotherapy group combined with magnetic laser therapy. The effectiveness of SCR was assessed using the EASI, HARS and MADRS scales, and the DLQI questionnaire. The dynamics of IL-4 and IL-13 plasma levels were studied. The duration of the study was 6 months and 14 days., Results: After 14 days of SCR, a statistically significant reduction of the EASI index was more pronounced in the balneotherapy group in combination with MLT compared to the balneotherapy group ( p =0.041). Balneotherapy combined with MLT contributed to a statistically significant reduction in the HARS and HDRS scores. The decrease in IL-4 and IL-13 levels was statistically more significant in the balneotherapy group in combination with MLT. The combined use of balneotherapy and MLT in comparison with the balneotherapy group was accompanied by a more pronounced improvement in QOL. The combined use of balneotherapy and MLT in the follow-up phase showed a long-term positive effect: 6 months after completing SCR, the number of patients who had clinical remission was statistically significantly higher than that of the balneotherapy group (87.4% vs 22.5%)., Conclusion: The combined use of balneotherapy and MLT compared with balneotherapy in patients with true eczema on SCR was shown to be advantageous. The complex application of balneotherapy and MLT decreases inflammatory biomarker scores, improves dermatological and psychoemotional status, QOL parameters and is well tolerated.

This article presents the experience of successful use of the drug dupilumab in a patient with severe atopic dermatitis and bronchial asthma. The effectiveness of biological therapy with dupilumab 300 mg subcutaneously for 52 weeks of T-2 associated diseases, including a combination of severe atopic dermatitis and bronchial asthma, uncontrolled course based on the case history of patient Ts., born in 2006 with the diagnosis "Main: atopic dermatitis, common form, severe course. Concomitant diagnosis: bronchial asthma, persistent course, uncontrolled, moderate severity". Dynamic monitoring of the total blood count with the calculation of the absolute number of eosinophils in peripheral blood was performed. The study showed high efficacy and safety of biological therapy with dupilumab 300 mg subcutaneously every 2 weeks for 52 weeks with a combination of severe atopic dermatitis and bronchial asthma, uncontrolled course in patient Ts (Born in 2006). The examination of the ALEX2 allergochip made it possible to establish the molecular components of the primary causal allergens, predict the course of an allergic disease, and carry out successful elimination measures against food allergens, preserving the maximum set of nutrients in the patient's diet. Dupilumab therapy in severe atopic dermatitis and uncontrolled bronchial asthma leads to clinically significant improvement in the course of diseases, control of disease symptoms. Atopic dermatitis shows a decrease in itching of the skin, normalization of sleep, improvement of quality of life. With bronchial asthma, a reduction in exacerbations, normalization of respiratory function indicators, complete control of the disease has been achieved. The targeted biological drug dupilumab has a targeted effect on the key links in the pathogenesis of atopic dermatitis and bronchial asthma and reduces the burden of severe diseases. Therefore, the use of dupilumab in atopic dermatitis and bronchial asthma contributes to achieving disease control and improving the patient's quality of life.