Russian Journal of Immunology

The review concerns the history of the evolution of views on the interrelations between the immune, nervous, and endocrine systems. The article presents arguments justifying the concept that they are components of a single regulatory system, since their structures are tightly integrated into each other and they use the same biologically active substances as signaling molecules. At the same time, the similar molecules may be categorized as either neurotransmitters, hormones, or cytokines, depending on the producing cells. E.g., the cytokine receptors have been found on peripheral neurons and vagal nerve endings, and IL-4 regulates synaptic transmission. The function of immune system cells to produce hormones and neuropeptides has been proven. Catecholamines may originate from cells of the immune system. Hypothalamic neurosecretory cells express IL-1, and astrocytic glial cells express interferon. In the functional regulation, they always act together, complementing or replacing each other, having a common coordinating center. Thus, the anterior lobe of pituitary gland, by producing growth hormone, affects the synthesis and secretion of thymulin by epithelial thymic cells. Hence, the hypothalamic-pituitary-thymic axis is formed. Neuroimmunoendocrinology has emerged as a novel science. Disturbances in either of these systems invariably lead to significant changes in other compartments. There are no types of pathology that would not involve all three parts of entire system. The unity of all components of the system clearly manifests in stress, traumatic shock, and cytokine storm.  Of particular interest is the cross-usage of drugs applied in therapy of disorders affecting either of three systems. The use of immunotropic drugs has found application in the treatment of psychiatric disorders. Methods of pharmacological action on macrophages are being developed for treatment of endocrine disorders. Thus, sufficient evidence has been accumulated to consider the immune, nervous and endocrine systems as a common system of physiological regulation, which seems to be based on transmission and processing of information.

Schnitzler's syndrome is a rare but usually underdiagnosed autoinflammatory disease, characterized by monoclonal IgM gammopathy, persistent urticaria, intermittent fever, bone pain, and arthralgia or arthritis. Although first reported by Dr. Liliane Schnitzler in 1972, the syndrome continues to pose challenges in diagnosis, and it usually takes more than five years before it is properly identified. Disorders show up in a form of urticaria, arthritis, organomegaly, fever, lymphadenopathy, high ESR, leukocytosis, and bone pain. Central to its pathogenesis are immunologic perturbations and activation of the inflammasome. It is typically diagnosed through clinical exam with history and important feature identification such as monoclonal gammopathy and acute or relapsing urticarial rash. Therapeutically synthetic agents include anakinra, canakinumab, rilonacept, and anti-IL-6 have been used with variable success. Recent research also demonstrated how natural treatments such as Terminalia chebula, Emblica offcinalis, Schinus terebinthifolia, tulsi, asafoetida, and Wedelia plants have the potential for controlling the symptoms and changing inflammatory paths. Promising medicinal possibilities for these plants, according to in-silico investigations, point to further research into their clinical uses. With new therapy paths that promise better patient outcomes, Schnitzler's illness is overall a therapeutic challenge.

Accurate diagnosis and classification of leukemia are essential for effective treatment planning. Traditional cytochemistry relies on enzyme-based staining for morphological evaluation, while flow cytometry (FCM) employs monoclonal antibodies to detect multiple surface and intracellular markers. This systematic review and meta-analysis compared the diagnostic accuracy of cytochemistry and FCM in leukemia immunophenotyping. Methods: A systematic search of PubMed and Google Scholar was conducted according to PRISMA guidelines. Studies evaluating sensitivity, specificity, and accuracy of cytochemistry and FCM in diagnosing acute and chronic leukemia were included. Data extraction covered study characteristics, diagnostic markers, and performance outcomes. Meta-analysis was performed to compare diagnostic values across methods. Results: Eleven eligible studies comprising pediatric and adult leukemia cases were analyzed. Cytochemical stains such as Myeloperoxidase (MPO) and Sudan Black B (SBB) showed high specificity (91–100%) and moderate-to-high sensitivity (60–97%), while Periodic Acid–Schiff (PAS) and Nonspecific Esterase (NSE) had lower reliability. FCM demonstrated superior diagnostic performance with average sensitivity of 87.7% and specificity of 85.6%, achieving >95% accuracy in several studies. Marker panels including CD3, CD45, CD79a, and MPO enabled precise subtype differentiation and minimal residual disease (MRD) detection. Conclusion: Cytochemistry remains useful as an affordable screening tool in resource-limited settings, but FCM provides greater sensitivity, specificity, and comprehensive immunophenotypic data, making it the preferred method for leukemia diagnosis and monitoring. Combining both approaches can enhance diagnostic performance across diverse clinical contexts.

Reactive erythemas represent a group of dermatoses with complex immunogenesis as in a number of autoinflammatory disorders, with probable involvement of γδ T cell subpopulations. Despite important role of IL-17, its excessive synthesis, e.g., by γδ T cells, may induce autoinflammation. On the contrary, IL-10 plays a key role in the control of innate immune responses by suppressing the function of monocytes/macrophages and reducing production of pro-inflammatory cytokines by these cells. Our aim was to assess the content of IL-17 and IL-10 in cell culture supernatants from γδ T cells expanded by in vitro cultivation of blood lymphocytes from the patients with erythema. The cultures were supplied by zoledronate, IL-2 and IL-15. Materials and methods: Peripheral blood mononuclear cells (PBMC) were isolated from 8 patients with reactive erythema (5 patients with erythema multiforme, 1 patient with ring–shaped centrifugal erythema, 2 patients with erythema migrans, an early form of Lyme disease) and two healthy donors aged 23 to 70 years. A modified van Ackeretal method (2016) was used to culture γδ T lymphocytes. Spontaneous and induced cytokine secretion was determined by solid-phase ELISA using Human IL-17 ELISA Kit (RK00397, ABclonal BiotechnologyCo., China) and Interleukin-10-ELISA-BEST (Vector Best, Russia) according to the manufacturers' instructions. Results and Conclusion. In patients with reactive erythema, 3.1% to 62.8% of cells with γδ TCR expression of were obtained by 7 days of cultivation with zoledronate, IL-2 and IL-15. The lowest percentage of these cells was observed in blood cell culture from patients with continuously recurrent erythema multiforme and ring-shaped centrifugal erythema. In the group of patients studied, high levels of induced IL-17 production may suggest the presence of autoimmune component in pathogenesis of the disease and/or to reflect the severity of its course. The effectiveness of therapy in the examined patients correlated with ability of blood cells to in vitro synthesis and release of IL-10. It has been shown that high values of spontaneous and induced IL-10 production are associated with good response to therapy (significant clinical improvement, long-term clinical remission). Meanwhile, suboptimal therapeutic effect (rapid development of relapses after the end of the course of therapy) was detected in cases of low spontaneous and induced IL-10 production. The data obtained indicate the probable prognostic significance of these analytes as biomarkers. In future, the determination of these factors in MLPC culture in patients with studied pathologies may improve assessment of therapeutic efficiency and predict the course of the disease. However, further research is required in this area, including studies of other disorders.

Desminopathies represent rare, or so-called “orphan” diseases. Little is known about the sensitivity of these patients to allergens and physical factors. The study aimed for evaluation of allergic status in a patient with desminopathy T341P in a heterozygous state. Materials and methods: The retrospective study concerned a case of familial desminopathy diagnosed in South-Western Siberia. Quantitative analysis of total and specific immunoglobulins in blood and coprofiltrate of the proband was carried out by turbidimetric and chemiluminescence immunoassay, enzyme allergosorbent testing, as well as enzyme immunoassay. Results. The subject with desminopathy also revealed a polyvalent allergy to plant-, food- and infectious allergens. Specific IgE antibodies to pollen of early-blooming meadow grasses and Secale cereale, as well as cow’s milk, Mucor racemosus and Fusarium moniliforme fungi, were found in blood samples. Coprofiltrate contained specific IgE to pollen of early-blooming meadow grasses and trees, as well as chicken eggs and casein. At the onset of clinical manifestations of desminopathy, the levels of total IgE in blood of the proband showed a two-fold increase over the reference values, being decreased by 5.5 times over the past 10 years. Over the past two years, the total concentration and average level of specific IgG4 antibodies to food allergens in the blood increased by 15%. Provocation tests for cold- and cholinergic urticaria proved to be positive. Conclusion. A respiratory allergy, which had emerged by the age of 20, seems to be the sign of desminopathy T341P. By this age, the proband developed ventricular extrasystole, as well as a minor decrease in physical strength. Later, since the age of 30, a progressive weakness of the skeletal muscles and a noticeable decrease in physical strength have been developed, with full-scale manifestations of the disease, since the age of 40. In combination with excessive bacterial growth of intestinal and oral microbiota, and increased endotoxin levels, the polyvalent allergies with a high concentration of specific IgG4 antibodies and other (sub)classes may participate in clinical etiology and pathogenesis of desminopathy T341P.

The worldwide prevalence of metabolic syndrome is 20-40%. Due to the high incidence of metabolic syndrome, its early detection is of great importance for the timely initiation of prevention of complications. Researchers still do not have a consensus on the ethology, diagnosis and treatment of metabolic syndrome. At the moment, it has only been shown that there are risk factors for the development of metabolic syndrome such as genetic factors, lifestyle and disorder of the normal qualitative and quantitative composition of the microbiota. In our opinion, chronic sluggish inflammation and microbiological intestinal dysbiosis play an important role in the development of metabolic disorders, and the key predictor of their development is the state of food hyperreactivity. The aim of the work was to assess the role of food hyperreactivity in the development of chronic inflammation, metabolic disorders, intestinal dysbiosis and the relationship of microbiota with inflammation indicators and metabolic disorders. To achieve the goal, specific IgG antibodies to 111 food antigens were determined using the immunohealth methodology (RZN 2020/9970), biochemical indicators of lipid and carbohydrate metabolism, proinflammatory cytokines (IL-6, IL-17), complete blood counts, and 33 indices of intestinal microbiota using PCR (Colonoflor-16, premium) were determined. The study included 60 patients with an increased body mass index and 20 volunteers with a normal body mass index. The study material included venous blood samples and fecal samples. The concentrations of cytokines, insulin, and biochemical indicators were determined in the blood serum. Fecal samples were used to assess the qualitative and quantitative composition of the colon microbiota. We obtained data suggesting a role of food hyperreactivity in the development of chronic inflammation and metabolic disorders. We also showed the role of individual representatives of the intestinal microbiota and their relationship with inflammation and development of metabolic disorders. Thus, we demonstrated an integral relationship between food hyperreactivity, intestinal microbiological dysbiosis, inflammation indicators and markers of metabolic disorders. These data can form the basis for new ways of preventing and correcting metabolic syndrome, as well as for further studies in the field of microbiota in various conditions.

Abnormal uterine bleeding (AUB) is frequently observed during menopausal hormone therapy (MHT), significantly impairing the quality of life of postmenopausal women and reducing their adherence to treatment. In most cases, AUB associated with MHT is not linked to pathological changes in the endometrium. A potential role of uterine natural killer (uNK) cells in this process remains unexplored.  Our objective was to evaluate the role of uNK cells in the pathogenesis of AUB in women receiving MHT.  Materials and methods: A randomized controlled trial was conducted at the N.I. Pirogov City Clinical Hospital from November 2022 to October 2024, involving 75 postmenopausal women. The participants were divided into three groups: women receiving MHT with AUB (n=27); women receiving MHT without AUB (n=25); and postmenopausal women not receiving MHT (n=23). For immunohistochemical analysis and flow cytometry, endometrial samples obtained via pipelle biopsy were analyzed in the control group (not receiving MHT) and in the study group before MHT initiation, after 6 months of MHT, and during AUB episodes.  Results. The women with AUB during MHT exhibited a statistically significant increase in uNK cells in endometrial samples if compared to those without AUB (CD3-/CD16+/CD56+: 1.7[1.46–1.85] vs. 0.66 [0.5–0.79], p<0.001). Immunohistochemical analysis revealed increased amounts of CD56+ cells in endometrial stroma of patients with AUB during MHT.  Conclusion. The study findings suggest the role of uNK cells in pathogenesis of AUB in women receiving MHT. Further research may contribute to development of new approaches to prevention and treatment of AUB via modulation of uNK cell activity. 

Macrophages are actively involved in recognition, capture, and destruction of pathogens as well as removal of cellular debris. The most important role of macrophages is to initiate and regulate the inflammatory response: they synthesize and secrete a wide range of proinflammatory cytokines that activate other immune cells and promote inflammation. Functional state of macrophages directly depends on the work of mitochondria that serve not only as energy source, but also as key participants in signaling pathways associated with production of reactive oxygen species and regulation of the inflammasome. Mitochondrial dysfunction may lead to excessive macrophage activation and chronic inflammation, which is typical to common diseases like atherosclerosis and metabolic disorders. Damaged mitochondria release components such as mtDNA and cardiolipin, potentially triggering autoimmune responses. To prevent it, the cells utilize mitophagy, a selective autophagy process that removes dysfunctional mitochondria via lysosomal pathway. Polyunsaturated fatty acids are known to influence inflammation and mitochondrial function, including mitophagy. Arachidonic acid, a precursor of prostaglandins and leukotrienes, modulates immune responses, but its role in mitophagy remains unclear. The aim of this study was to investigate whether arachidonic acid affects mitophagy and proinflammatory response of human macrophages. Primary monocytes were isolated from whole blood of healthy donors and differentiated into macrophages over 5 days. The cells were treated with 20 μM arachidonic acid for 24 hours, followed by 1 μg/ml LPS stimulation for another 24 hours. Cytokine secretion (TNF, IL6, IL8, CCL2) was measured by ELISA technique. Mitophagy was assessed using confocal microscopy by evaluating colocalization of mitochondrial and lysosomal dyes. The results showed that arachidonic acid enhanced mitophagy and reduced secretion of TNF, IL6, and CCL2 in response to LPS. These findings suggest that activation of mitophagy may contribute to anti-inflammatory effects of arachidonic acid in macrophages.

Professional activity and terms of exposure to factors associated with profession and work experience contribute to modulation of both physiological and psychological functions of human body. Ecological and climatic features at high latitudes, characterized by almost year-round low temperatures, reduced UV index and photoperiodism, lead to an aggravated impact of professional activities. The complex of professional and environmental factors causes stress on adaptive capabilities, including immune functions. The aim of the present study was to specify the influence of work experience on the state of immune homeostasis in hydrographers of the Northern Fleet of Russian Federation. A total of 64 practically healthy men working under the conditions of the Northern seas were examined, depending on the length of their service: (1) 2.3 ± 0.4 years; (2) 9.0 ± 0.5 years; (3) 15.9 ± 0.6 years; (4) 28.9 ± 1.0 years. The number of lymphocytes (CD5+, CD10+, CD95+, CD71+) and the ratio of their concentrations (CD10+/CD95+ and CD71+/CD95+) were determined in peripheral blood using the indirect immunoperoxidase reaction method with monoclonal antibodies on dried drop lymphocyte preparations with a peroxidase conjugate and staining with a chromogenic solution. The results of study showed that the number of lymphocytes with the CD5+ marker decreases in individuals with up to 9.0±0.5 years of work experience. The ratio of CD10+/CD95+ to CD71+/CD95+  cell subpopulations were within optimal balanced values ​​​​(0.94-1.06) compared to the normal levels (1±0.05) without any significant difference depending on the length of service. We suggest that the putative mechanism of immune adaptation in hydrographers is implemented in two ways: in young hydrographers (with short and medium work experience), it proceeds by maintenance of the lymphoproliferation-to-apoptosis ratio (CD10+/CD95+), accompanied by a decreased level of CD5+ marker expression. In older hydrographers (with significant and long-term work experience), the adaptation events include restoration of CD5+ marker expression, along with expanding distribution of CD10+/CD95+ ratio, and maintenance of (CD71+/CD95+) ratio within narrow limits. The obtained results emphasize the need for individual medical and biological monitoring aiming for correction of immune homeostasis among the working population of high latitudes.

Acute respiratory viral infection (ARVI) is a common cause of global morbidity. Arterial hypertension (AH) is the most common chronic non-infectious disease, which may be complicated by ARVI. The aim of our study was to investigate the clinical features of ARVI of various etiologies (COVID-19, influenza, and unspecified) in patients with arterial hypertension. Patients and methods: A retrospective, comparative study included 536 patients divided into three groups: unspecified ARVI (group 1), 249 people; COVID-19 (group 2), 250 patients; influenza (group 3), 36 cases. Each cohort was divided in two subgroups: A, only ARVI (unspecified, COVID-19, influenza); B, ARVI (unspecified, COVID-19, influenza) in presence of AH condition. Statistical data evaluation was carried out with STATISTICA 10.0 software packages. Results and discussion: Clinical manifestations of intoxication and catarrhal syndrome were observed in patients of 1A and 1B groups, but their severity was different. In respondents with ARVI + AH (group 1B), the course of ARVI differed in the following parameters: rhinorrhea (χ2=4.3; p=0.040), sore throat (χ2=4.3; p=0.037), fever to febrile body temperature (χ =24.5; p=0.000). Clinical pattern in patients with COVID-19+ AH differed from patients with COVID-19 without hypertension in more common loss of sense of smell (χ2=3.84; p=0.050), headaches (χ2=3.84; p=0.050), myalgia (χ2=4.38; p=0.036), sleep disorders (χ2=4.11; p=0.043), cough (χ2=4.18; p=0.041), prolonged febrile fever (U = 2.01; p=0.044) (χ2 =5.74; p=0.017). Patients with influenza and AH were more likely to report nasal congestion (χ2=9.93; p=0.002), cough (χ2=4.11; p=0.043), and durable fever (χ2=11.25; p=0.000), for up to 8.5 days (U=2.59; p=0.023). Conclusion: Among all cohorts, regardless of ARVI etiology, the patients with AH exhibited more common and longer febrile period. In patients with influenza+AH, the symptoms of intoxication and catarrhal syndrome are characterized by complaints for nasal congestion, cough and sleep disorders. In COVID-19, loss of smell, headache, myalgia, sleep disorders are more common in AH patients. Awareness of these clinical ARVI features among patients with AH will allow for timely correction of therapies for both ARVI and AH at the early stages.