Vol 23, No 3 (2020)

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Assessing physical development and immunological parameters in adolescent girls with altered menstrual cycle

Komleva M.O., Smolyagin A.I., Konstantinova O.D., Komleva N.V.


Gynecological morbidity particularly formation of menstrual function poses an important task because menstrual irregularities comprise a lead pathology among adolescent girls and considered as a marker of adverse environmental impact on female body [1, 2, 3]. The territories of the Orenburg Region [4] are known to be coupled to profound environmental and hygienic issues. We acknowledge the influence of anthropogenic stress on physical development and health in childhood by recording deviated physical development most frequently in children living in ecologically unfavorable territories [5]. Previously, we published the data on gynecological morbidity pattern in adolescent girls living in the Orenburg Region in territories with differed 7 year-monitored (from 2010 to 2016) anthropogenic stress [6]. Here we present the data on surveying girls aged 15-17 years with menstrual irregularities (MIs) living in the regions of the Orenburg region with varying anthropogenic stress assessed for their physical development, hormonal and immunological parameters. 2010- 2019 primary gynecological morbidity data were assessed based on available annual reports for various territories of the Orenburg Region. Subjects residing in the Western, Central and Eastern territories of the Orenburg Region were assesed based immune status data such as parameters of cell-mediated immunity, phagocytic indices, serum immunoglobulin class A, M, G as well as circulating immune complex levels. Hormone status was analyzed by assessing serum level of thyroid and sex hormones. It was found that oligomenorrhea in MIs was prevalent that tended to result in leptosomy and pachisomy in physical development. Most changes in adolescent girls were found in relative frequency of peripheral blood CD3+, CD4+ and CD19+ lymphocytes, phagocytic index as well as IgM, estradiol, progesterone, testosterone levels, LH, 17-OH-progesterone and cortisol. Our study demonstrated that adolescent girls living in the West and East of the region were featured with dominant oligomenorrhea in MIs associated with physical development tended to leptosomy and pachisomy. Assessing parameters of physical development in adolescent girls is of great importance and should be performed to diagnose potential menstrual irregularities. Thus, our data underline importance of negative impact of anthropogenic burden on gynecological health in adolescent girls.

Russian Journal of Immunology. 2020;23(3):243-248
pages 243-248 views

Severity of odontogenic phlegmons affects local mucosal immunity

Markelova E.V., Romanchuk A.L., Shumatov V.B., Krasnikov V.E., Demyanenko A.S., Dzhafarov R.N.


Safe methods for examining phlegmon of the maxillofacial area (MFA) have been extensively sought for, and assessing cytokine profile in the patient mixed unstimulated saliva may be used to control its development. There were enrolled 102 patients with maxillofacial phlegmon aged 25 to 75 years as well as age-matched 30 healthy subjects. Concentration of IL-1β, TNFα, TNFβ, IL-17, IFNγ, IL-4, IL-10, IL-22, TGF-β1 и TGF-β2 in mixed unstimulated saliva was measured. We found that patients with MFA inflammation vs. control group had significantly increased level of almost all cytokines except IFNγ. Additionally, we analyzed changes in saliva cytokine profile of patients with maxillofacial phlegmon, subdivided into groups by age, gender, and spread of the disease. It allowed to find that amount of IL-1β, TNFα, IL-17, IL-10, IL-22, TGF-β1 directly correlated with spread of the process, whereas level of IL-4, IFNγ, TGF-β2, on the contrary, was decreased with aggravated disease severity.

Russian Journal of Immunology. 2020;23(3):249-256
pages 249-256 views

A role of single nucleotide polymorphism in TNF, NOS3 and MMP9 genes at the risk of developing neonatal pneumonia

Meremianina E.A., Svitich O.A., Alieva A.I., Sobolev V.V.


Neonatal pneumonia is one of the most common causes of infant mortality. Moreover, the diagnosis of this pathology represents a difficult task and requires to seek for additional solutions in clinical and laboratory practice. One of the current and promising ways to diagnose rerlies on search of predictive markers among the innate and adaptive immunity genes involved in disease pathogenesis. We used bioinformatics analysis to select genes playing essential role developing neonatal pneumonia. Next, cord blood samples collected from 234 newborns were examined by real-time polymerase chain reaction for nine polymorphic markers in the TNF, IL10, IL17A, IL17F, IL6, NOS3, and MMP9 genes. The results of statistical analysis showed that heterozygous genotypes in the MMP9 and TNF genes were associated with the risk of developing early neonatal pneumonia, and also the protective role of homozygotes AA in the MMP9 gene and GG in the TNF gene. A search for associations with a risk of intrauterine pneumonia revealed an unfavorable role for heterozygous genotypes in the NOS3 and MMP9 genes. Thus, due to difficulties in diagnosis or in case of developing neonatal pneumonia, it may be recommended to add genetic analysis for assessing polymorphic markers in the MMP9 (rs17576), TNF (rs1800629) and NOS3 (rs1549758) genes along with standard test assays.

Russian Journal of Immunology. 2020;23(3):257-262
pages 257-262 views

Parameters of interferon system, matrix metalloproteinases and related tissue inhibitors in women with papillomavirus infection during preconceptional preparation

Nevezhkina T.A., Knysh S.V., Chagina E.A., Matushkina L.S., Umerenkova S.A.


Pregravid or preconceptional preparation comprises one of important aspects in planing pregnancy and labor that includes a set of diagnostics as well as vurative and preventive measures aimed at ensuring conception and birth of healthy children. Currently, preconceptional preparation is viewed crucial for successful conception, both provided by a woman as well as a man. Virus-associated infection is one of the main causes resulting in impaired reproductive function. Host immune response in the urinary tract is often manifested as bacterial vaginosis (BV) underlying sufficient enviroinment for developing ascending inflammatory process that accounts for its intensity and duration and lead to reproductive disorders.
Our study provides the data on interferon system, matrix metalloproteinases and related tissue inhibitors in women with STDs and/or papillomavirus infection.
The aim of the study was to assess level of interferons, components of matrix metalloproteinases and related tissue inhibitors in women with papillomavirus infection during preconceptional preparation.
There were examined 73 patients for infection with sexually transmitted diseases (STDs) in accordance with standard protocol. All patients were divided into three groups: Group I (n = 32) – STDs with papillomavirus infection (PVI); Group II (n = 27) – STDs without papillomavirus infection and Group III – Control, consisting of 14 apparently healthy female volunteers. The average age of the patients and control subjects was 26.3±3.2 and 29.5±2.2 years, respectively. Blood serum IFN, MMP and TIMP levels were measured by using specific reagents (R&D Diagnostics Inc., USA) with sandwich ELISA, according to the manufacturer’s instructions, on Multiskan immunoassay analyzer (Finland), presented as pg/ml and ng/ml. SPSS v. 20 software was used for the statistical analysis with non-parametric method.
Disturbances in type 1, 2 and 3 interferons were found in women with papillomavirus infection. An increased amount of MMP-2,8,9 and related tissue inhibitors TIMP-1 and TIMP-3 in women with PVI was revealed. Long-term HPV persistence leads to developing chronic systemic inflammatory response manifested as immune-inflammatory syndrome accounting for tissue morphological changes making impossible onset of pregnancy.

Russian Journal of Immunology. 2020;23(3):263-270
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IL-1β and TNFα measured in supernatants of peripheral blood cell cultures from children with autoimmune and infectious pathology

Pashnina I.A., Krivolapova I.M., Chereshneva M.V.


Cytokines are small-molecular weight proteins involved in regulating inflammation, proliferation and differentiation of immunocompetent cells, as well as effector functions. IL-1β and TNFα are among the most powerful inducers of the inflammatory response. Production of proinflammatory cytokines comprises normal response to infection and represents an arm of various autoimmune disease pathogenesis. It is worth comparing cytokine production in autoimmune and infectious diseases to determine features of cytokine profile. The aim of the study was to evaluate proinflammatory cytokines IL-1β and TNFα produced by blood cells in children with autoimmune and infectious diseases.
194 children, aged 2-17 years, were examined: 99 patients with juvenile idiopathic arthritis; 26 patients with unspecified reactive arthropathy; 14 children with systemic lupus erythematosus; 24 children with chronic viral hepatitis C; 33 healthy children. Heparinized blood samples were diluted with a glutamine-containing culture medium RPMI-1640, samples with/without phytohemagglutinin stimulation were prepared as well. Samples of diluted blood were incubated for 24 hours (37 °C, 5% CO2). The concentrations of IL-1β and TNFα in the cell culture supernatants were determined by ELISA.
It was found that groups of patients with rheumatic diseases (systemic lupus erythematosus, juvenile idiopathic arthritis and unspecified reactive arthropathy) were featured with spontaneous production of IL-1β and TNFα at higher level than in control, and the stimulated synthesis of IL-1β was lower. In patients with chronic viral hepatitis C, the spontaneous concentration IL-1β and TNFα and the stimulated concentration of IL-1β did not differ those ones found in healthy children. Stimulated TNFα production in patients with juvenile idiopathic arthritis, unspecified reactive arthropathy, and hepatitis C was significantly higher than in control group. More intensive spontaneous production IL-1β and TNFα in groups of patients with rheumatic diseases indicates previous activation of immunocompetent cells. Decreased stimulated IL-1β production in groups with various diseases points at exhaustion of immunocompetent cell functional reserve due to chronic activation.

Russian Journal of Immunology. 2020;23(3):271-278
pages 271-278 views

Assessment of the role of WIF-1 in the genesis of ischemic heart disease

Plotnikova M.O., Snimshchikova I.A., Afoninа I.A., Kulakova A.S.


Coronary heart disease poses one of the most serious threats to human health resulting in enormous physical and economic losses worldwide. WNT signaling pathways play an important role in cardiogenesis both in embryogenesis and cardiac repair after previous ischemic attacks that motivated to conduct this study.
The aim of the study was to examine features of WIF-1 production in patients with coronary heart disease. There were enrolled 60 patients with a clinically verified and diagnosed coronary artery disease. WIF-1 serum concentration was measured by using enzyme-linked immunosorbent assay presenting data as absolute numbers (n, %) or medians, 1 and 3 quartiles – Me (Q0.25-Q0.75). Analyzing study data showed that WIF-1 serum concentration in patients with myocardial infarction was 2890 (1700-3337.5) pg/ml being by 7.97-fold higher than that one in healthy individuals (p <0.001), in agreement with previous studies. Moreover, in patients with angina pectoris WIF-1 serum level comprised 2170 (1493-2650) pg/ml, exceeding that one in healthy individuals by 6.14-fold (p < 0.001). Thus, the data obtained regarding changes in serum WNT-inhibiting factor-1 concentration in patients with coronary heart disease expand our understanding about an impact from affected WNT-signaling pathway components in pathogenesis of inflammatory process during hypoxic injuries.

Russian Journal of Immunology. 2020;23(3):279-284
pages 279-284 views

Interleukin 17A gene polymorphism in patients with rheumatoid arthritis

Stashkevich D.S., Devald I.V., Khromova E.B., Evdokimov A.V., Suslova T.A.


Interleukin 17 plays a key role in the immunopathogenesis of rheumatoid arthritis (RA) and serves as a link between activation of innate and adaptive immune cells, whereas its increased expression may represent one of the causes for uncontrolled inflammation and formation of immunopathological reactions. Among members of the interleukin 17 family, most studied is IL-17A, which is characterized by peak biological activity. IL-17A is one of the important immune mediators able to induce production of other pro-inflammatory cytokines and chemokines and promote recruitment of inflammatory cells, such as monocytes and neutrophils, into inflamed organs. IL17A gene contains a number of polymorphic sites, wherein single-nucleotide substitutions particularly at position the -197G/A may affect its expression level. Here in case-control study we retrospectively examined contribution of genetic polymorphism at the -197G/A position within the IL17A gene. Allele-specific PCR was used to iderntify the -197G/A polymorphism in IL17A gene in groups of patients with rheumatoid arthritis and healthy donors of the Russian ethnic group. Our study was made within a framework on assessing immunogenetic component for rheumatoid arthritis in ethnic Russian subjects in the Chelyabinsk Region. Prevalence of IL17A gene alleles and genotypes obtained in the work is in agreement with the Hardy– Weinberg equilibrium, and is characterized by rather high frequency of allele replacement (40%), which is typical for Caucasoid populations. Thus, it was found that interpopulation differences are characteristic of such gene polymorphism shown not to be associated with predisposition to rheumatoid arthritis in ethnic Russian subjects in the Chelyabinsk Region. Women with RA in our study were found to display certain changfes in frequencies of alleles and genotypes formed due to single-nucleotide substitution in IL17A gene at position -197G/A. However, in women such features cannot be considered as additional risk factors for developing RA. Allele -197*G, homozygous genotype -197G/G may be considered as markers of late-onset for the first RA attack in women. Analysis on distribution of SNP -197G/A alleles and genotypes within the IL17A gene showed that such polymorphism is of low value predictor likely being more associated with some RA clinical variants, but not with predisposition to RA development.

Russian Journal of Immunology. 2020;23(3):285-290
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Association between peripheral blood lymphocyte subsets, insulin resistance and endothelial dysfunction in males with abdominal obesity and metabolic syndrome

Sumerkina V.A., Telesheva L.F., Golovneva E.S., Tumanov S.V.


The components of the metabolic syndrome are associated with endothelial dysfunction and immune disorders, but the features of cell immunity in abdominal obesity and metabolic syndrome remain ambiguous, and no unified concept regarding a mechanism for developing immune disorders has been proposed. Here we examined peripheral blood lymphocyte subset composition in males with abdominal obesity and metabolic syndrome as well as their relationship with insulin resistance, visceral adipose tissue dysfunction and endothelial dysfunction. There were enrolled 124 males aged 18-45 years. Patients were divided into 4 groups: 1 group – males without abdominal obesity and metabolic syndrome components; 2 group – males with abdominal obesity; 3 group – males with abdominal obesity and one metabolic syndrome component; 4 group – males with metabolic syndrome. The level of serum leptin, adiponectin, TFPI, PAI-I, uric acid, homocysteine, angiotensin II, and endothelin (1-21) was measured followed by calculating HOMA-IR, Tg/HDL, TyG, and VAI. Lymphocyte subset frequency was determined by flow cytometry (Beckman Coulter, USA). Group 2 vs Group 1 patients showed no significant differences in study parameters. In Group 3, count of CD3+CD25+ and CD3+HLA-DR+T lymphocytes was increased, whereas the TyG index was associated with percentage of T helper cells. In Group 4, males were found to have decreased percentage of lymphocytes as well as increased frequency of activated CD3+HLA-DR+ lymphocytes as compared to Group 1. A relationship between serum leptin level percentage of lymphocytes was found. Tg/HDL, TyG and VAI in metabolic syndrome were associated with count of CD3+CD4+ lymphocytes. Arterial hypertension co-found in patients with metabolic syndrome correlated with count of NK cells.

Russian Journal of Immunology. 2020;23(3):291-298
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Food and inhaled allergen sensitization range in children with atopyrelated gastrointestinal manifestations

Feizer А.А., Barilo A.A., Smirnova S.V.


The gastrointestinal tract is a barrier to the penetration of allergens into the organism and can be one of the shock organs of the development of allergic inflammation. The diagnosis of gastrointestinal manifestations of allergies is not given due attention, since their clinical symptoms are not pathognomonic, but are identical to diseases of the gastrointestinal tract of various genesis. The aim: to study the features of the structural and functional state of the gastrointestinal tract and the spectrum of sensitization to food and inhalation allergens of children with gastrointestinal manifestations of atopy. The analysis of medical histories of children with gastrointestinal manifestations of allergies aged from 1 to 18 years (n = 28), who were treated at the Regional children's allergological center in Krasnoyarsk, was performed. All patients underwent a specific allergological examination (allergological history, determination of the concentration of total IgE, specific IgE to food and inhalation allergens). The assessment of the state of the gastrointestinal tract was carried out taking into account complaints, anamnesis, objective examination and the results of esophagogastroduodenoscopy. It is established that gastrointestinal manifestations of atopy were most often combined with dermatorespiratory manifestations of allergy in the form of allergic rhinitis, atopic bronchial asthma and atopic dermatitis. Among the lesions of the gastrointestinal tract with the highest frequency of occurrence, changes in the nature of the stool (diarrhea, constipation) and the presence of symptoms of inflammation of the gastrointestinal tract-gastroesophageal reflux, gastritis, bulbitis, duodenitis, were determined. According to the results of esophagogastroduodenoscopy, gastritis and cardia insufficiency were most often determined. According to the results of the analysis of the concentration of total IgE in the blood serum, the increased level was determined in 42,8% of cases, the average value of total IgE in the blood serum in patients with atopic genesis of allergies was 140,9 IU/ml. These data evidence that the immunopathological basis for triggering allergic inflammation of the gastrointestinal tract may be based not only on atopic mechanisms. Based on the analysis of specific IgE concentrations, the characteristics of the spectrum of sensitization to food and inhalant allergens of children with gastrointestinal manifestations of atopy were determined. The most significant allergens were: food – flour mix; pollen – mixed of trees; domestic – perennial mixed. Thus, when conducting a specific allergological examination of children with atopy, it is necessary to take into account the systemic nature of the process and pay special attention to assessing the state of the gastrointestinal tract, as one of the shock organs in the development of allergic inflammation.

Russian Journal of Immunology. 2020;23(3):299-302
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Chronic inflammation and stress-hormones: a common pathway of cognitive disorders in ageing

Filippova Y.Y., Burmistrova A.L.


Here we present the data on examining inter-connections cytokine network and stress hormones in senile vascular dementia by assessing systemic cytokine levels for IL-1β, IL-6, IL-10, TNFα, IFNγ as well as hormones cortisol, adrenocorticotropic hormone (ACTH), epinephrine, norepinephrine and dopamine in 23 subjects with vascular dementia and 40 individuals without overt cognitive impairment. It was found, that the concentrations of IL-6, TNFα, epinephrine and dopamine were significantly increased, whereas those for IL-1β, IL-10, ACTH and norepinephrine were decreased in elderly people with dementia compared to healthy aging. In addition, virtually no inter-connection between cytokine, sympathoadrenal and hypothalamicpituitary (HPA-axis) axis was observed in vascular dementia highlighted by no significant correlation within the cytokine network. However, a single positive intrahormonal link for cortisol-ACTH and two positive links between IFNγ and cortisol/adrenaline level were detected. In general, vascular dementia was featured by marked inflammatory reaction, excessive activation of stress hormone production and disconnection of cytokine network, HPA-axis and the sympathoadrenal medullary system.

Russian Journal of Immunology. 2020;23(3):303-308
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Features of immune regulation and specific sensitization in children of the Northern Siberia

Chelakova Y.A.


This paper highlights the features of immune regulation and specific hypersensitivity in children residing in the Northern Siberia being exposed to the extreme climatic and exogenous chemical risk factors. An immunological diagnostic examination of 255 children permanently residing in the region of exogenous hapten exposure was conducted. The control group consisted of 130 children residing on the territory not being exposed to exogenous chemical factors. Level of serum class G, A, M immunoglobulins was assessed by using a Mancini radial immunodiffusion reaction. Amount of total serum IgE, neuron-specific enolase, and VEGF was measured by using the ELISA. Changes in level of IgG specific to phenol and copper as well as IgE specific to nickel and benz(a)pyrene were measured by using enzyme-linked allergosorbent test. Peripheral blood lymphocyte subsets were analyzed by using membrane-bound immunofluorescence with a panel of labeled specific monoclonal antibodies. High-quality statistical data analysis was performed by using Microsoft® Office Excel 2003 software as well as Statistica 6.0 application software package (StatSoft, USA). Statistical significance was determined by using Student’s t-test. Relation between signs was estimated by using correlation and regression analysis as well as Fisher’s test. Immunological study demonstrated that immunogram parameters were significantly changed in the observation group by containing increased percentage of CD16+ effector cells absolute and relative CD19+ cell count (p ≤ 0.05), relative and absolute count of CD25+ lymphocytes (p ≤ 0.05) as well as CD95+T cells as compared to the reference values and control group (p ≤ 0.05). Moreover, level of neuron-specific enolase and VEGF (vascular endothelial growth factor) was increased compared to control group (p ≤ 0.05). It points that regulatory mediators potentially mapped to the glia and vascular intima in children from the observation group were extremely activated. The level of both total (total IgE) and specific sensitization was significantly increased by assessing immunoglobulin G specific to phenol as well as immunoglobulin E specific to nickel and benz(a)pyrene (p < 0.05). Parameters of programmed cell death were significantly altered that was paralleled with simultaneous activation of general and specific sensitization highlighting features of the immunological status in children examined distinguished by excessive stress of immune regulatory arms in case of combined exposure to climate-geographic as well as exogenous chemical risk factors.

Russian Journal of Immunology. 2020;23(3):309-314
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Role of antisperm antibodies in the formation of infertility in varicocele and infertility

Chereshnev V.A., Pichugova S.V., Rybina I.V., Beikin Y.B.


An effect of ASA on reproductive function may be accomplished via several ways. At the present stage, despite the large number of available studies, there is no unequivocal understanding regarding prevalence of the immunological infertility in infertile males and adolescents with varicocele, who have a high risk of future infertility. Hence, it is necessary not only determining the serum and ejaculate level of antisperm antibodies (ASA) as one of prognostic infertility criteria, but also assessing their dynamic concentration depending on the degree of varicocele, after surgical correction. Objective of the study – to evaluate a role of ASA in developing infertility in infertile males of active reproductive age as well as adolescents with varicocele, to assess dynamics in serum ASA level in various age groups of adolescents, depending on the degree of varicocele, after surgical correction. For adolescents with left-sided varicocele and without varicocele, serum ASA level was measured annually at within age of subjects from 14 to 17 years, whereas ASA titer in seminal fluid was estimated at the age of 17 years. Dynamic levels of serum ACA were measured in the main vs. comparison group, between the groups based on degree of varicocele, between the groups before and after surgical correction of varicocele. 100 infertile and 30 fertile males were examined underwent a single measurement of serum and ejaculate ASA level. Anti-sperm autoimmune reactions are not the lead cause of male infertility, as none of the examined groups with reproductive pathology were highlighted by increased level of serum ASA found to be higher than the permissible normal limit. Detection of ASA in blood serum within the reference interval indicates that the hematotesticular barrier is not completely impenetrable, thereby contributing to developing immunological gamete tolerance. The degree of varicocele and surgical correction do not provoke development of autoimmune reactions against spermatozoa. Similar serum ASA levels in infertile patients and patients with varicocele without a tendency to decrease in the latter; the presence of ASA in seminal fluid requires further monitoring of such patients for timely diagnostics of developing immunological form of infertility.

Russian Journal of Immunology. 2020;23(3):315-322
pages 315-322 views

Dynamics of the level of cytokines in the isolated femoral fracture under conditions of system ozone therapy

Abramov K.S., Davydova E.V., Osikov M.V.


A close link between processes of immune-based and osteogenesis, influence of immune system on reparative processes after a traumatic femur fracture, as well as state of increased afferent signals emitted by intraosseous receptors and hyperstimulation of immune cells during trauma accounts for feasibility of using efferent multimodal therapy interventions, which may be accomplished by medical ozone. The aim of the study was to assess dynamic changes in pain syndrome and level of pro- and anti-inflammatory cytokines in isolated femur fracture treated with systemic ozone therapy.
The study group coprised 32 male patients with isolated femur fracture, average age 44.2±2.4 years. Starting from day 2 after surgical treatment, all patients received standard anticoagulant treatment and antibiotic therapy, 16 patients additionally received ozone therapy applied as small autohemotherapy (MAGT) at ozone therapeutic unit by using ozone destructor UOTA-60-01 “Medozon” manufactured by Medozon LLC, Moscow. Ozone concentration in ozone-oxygen mixture was 20 mg/l, per 10 ml-volume, applied as 7-9 injections course every other day. Patient-provided assessment of pain level in all groups was investigated by using a visual analogue pain scale. Concentrations of IL-6 and IL-4 cytokines were measured by using standard test systems (pruchased from Vector-Best JSC, Novosibirsk). Statistical data processing was carried out by using software package Statistica 10.0. The subjective pain level prior to the onset of the course ozone therapy and 2 days after surgical treatment was higher than average level after the end of MAGT course, pain level decreased to low level and significantly differed from that one before surgery, which indicates developed analgesic effect after systemic ozone therapy, likely associated with oxidative modification of inflammatory mediators. The level of pro-inflammatory cytokine IL-6 in patients with IPPK during systemic ozone therapy significantly decreased, which indicates some normalizing effect induced by ozone therapy on parameters of immunocyte secretory activity and prevents ovgert effects triggered by “cytokine storm”. Concentration of IL-4 vs after traumatic femur damage did not significantly differ among patient groups, except for differences with control group. Spearman correlation analysis revealed high degree of dependence between pain intensity and level of pro-inflammatory cytokines, whereas ozone therapy led to decreased pain intensity in lesion site and directly correlated with decreased IL-6 concentration. Thus, use of ozone at therapeutic concentrations limits excessive reactions of innate immunity that can lead to massive tissue damage in early stages of the posttraumatic process.

Russian Journal of Immunology. 2020;23(3):323-328
pages 323-328 views

State of hyperglycemic and immunomodulator-treated peripheral blood lymphocytes

Gette I.F., Danilova I.G.


A level of peripheral blood lymphocytes, their functional activity and particularly produced range of secreted cytokines underlie severity of autoimmune process in diabetes mellitus (DM) against islet β-cells and other body cells. Because cytokine production is coordinated by macrophages and may also depend on accessibility lymphocyte nucleic acids, we aimed at examining level of nucleic acids in blood lymphocytes as well as cytokine production in rats with alloxan-induced diabetes treated with immunomodulatory 3-aminophthalhydrazide (3-APH).
Type 1 DM was modeled in male WISTAR rats by intraperitoneally administered alloxan at a dose of 300 mg/kg followed by inoculating 3-APH (2 mg/kg, in total 20 intramuscular injections). It was found that modeled diabetes was accompanied by increased number of peripheral blood lymphocytes and their bone marrow precursors, coupled to higher DNA amount in blood lymphocytes and associated with increased IL-6 and TNFα production. Administration of 3-APH to diabetic rats contributed to decreased number of peripheral blood lymphocytes and related DNA level likely resulting in decreased level of pro-inflammatory cytokine IL-6 in the blood serum and contributing to corrected hyperglycemia.

Russian Journal of Immunology. 2020;23(3):329-334
pages 329-334 views

Gamma-glutamyl hydrolase gene polymorphisms – another way to predict methotrexate efficacy in rheumatoid arthritis

Devald I.V., Khodus E.A., Khromova E.B., Myslivtsova K.Y., Burmistrova A.L.


The current treatment strategy for rheumatoid arthritis has been formulated within the framework of the European League Against Rheumatism (EULAR) concept “Treatment to achieve the goal”. Methotrexate prescribed as soon as possible after verifying rheumatoid arthritis is recognized as a first-line drug that allows to achieve disease remission and prevent destructive changes in the joints. Long-term clinical experience of using methotrexate allowed to conclude that almost 30% patients with rheumatoid arthritis turn out to be resistant to such treatment, enforcing to change the basal anti-inflammatory therapy, shift to using targeted or genetically engineered biological drugs, so that timeframe to prevent disease progression can be irreversibly lost. In the last decade, genetic testing for drug therapy effectiveness has been gaining momentum based on individual features in functioning of enzyme systems which regulate various stages of drug biotransformation. To date, a personalized approach to treatment of rheumatoid arthritis may be implemented after examining more than a dozen of single nucleotide polymorphisms (SNPs) within the folate cycle genes responsible for metabolizing methotrexate as well as its mechanism of action. In our work, we attempted to test a relationship between therapeutic response (efficacy and resistance) to methotrexate and -401C>T (rs 3758149) SNP in the GGH (gamma-glutamyl hydrolase) gene, which coordinates the processes of extracellular methotrexate transport. A groups patients consisted of 85 basic anti-inflammatory therapy-naïve patients diagnosed with rheumatoid arthritis, who were initially treated with methotrexate at a dose of 10 to 17.5 mg per week, with subsequently assessed therapeutic efficacy 6 months after the treatment onset based on dynamics in DAS28 index that allowed to identify groups of “responders” and “non-responders”. Next, all patients from select groups underwent molecular genetic typing for GGH-401C>T SNP by using real-time polymerase chain reaction. Our study allowed to find that prevalence of the TT homozygous genotype (OR = 5.09; 95% CI 1.11- 23.3; p = 0.037) dominated in “methotrexate non-responders”, whereas “methotrexate responders” tended to have higher C allele frequency (OR = 0.54; 95% CI 0.27-1.01; p = 0.087), which allowed to identify them by genetic predictors of methotrexate therapeutic response in rheumatoid arthritis.

Russian Journal of Immunology. 2020;23(3):335-340
pages 335-340 views

Role of neuroinflammation in pathogenesis of cognitive disorders after aortocoronary bypass grafting

Zenina A.A., Levman R.A., Silaev A.A., Shumatov V.B., Markelova E.V.


Here we present the study aimed to identify dynamic quantitative changes in NSE, NGF, IL-1β, IL-10, IL-6 in patients with postoperative cognitive dysfunction after coronary artery bypass grafting. There were enrolled 44 patients aged 62 to 75 years after coronary artery bypass grafting. MoСA test data allowed to subdivide patients into two groups: group I – 22 patients with MoСA test data changed by less than 3b score before surgery and on day 7 after surgery, no postoperative cognitive dysfunction; Group II – 22 patients with deteriorated MoСA test score by more than 3b, with postoperative cognitive dysfunction. Level of NSE, NGF, IL-1β, IL-10, IL-6 was measured by using enzyme-linked immunosorbent assay (R&D Systems, USA) at four time points: before surgery, after surgery, 24 hours and 7t day after surgery. Mean values were compared by using non-parametric Mann–Whitney test. Significance level was set at p < 0.05. It was found that patients with postoperative cognitive disorders contained higher level of serum NSE before surgery, immediately postsurgery and 24 hours after surgery, evidences about a role for neuron-specific enolase in the pathogenesis of early postoperative cognitive complications. A pronouncedly increased level of serum nerve growth factor in patients from group II was revealed 24 hours after surgery and elevated concentration on day 7 after surgery, which may be related to compensatory processes in response to damaging factors. Patients from group II were noted to have more marked and prolonged pro-inflammatory response confirmed by dynamic changes in IL-6 level paralleled with elevated amount of serum IL-10. It might be linked to some IL-10-mediated pro-inflammatory properties or more extensive reaction to pronounced pro-inflammatory response. The association between increased NSE and IL-10 levels was revealed. Of interest, the level of IL-1β smoothly declined at all stages in group II patients potentially reflecting impaired anti-inflammatory response, despite the fact that IL-1β is a pro-inflammatory interleukin, or its lack contributes to developing postoperative cognitive disorders, due to disturbed neural plasticity and hippocampus functioning.

Russian Journal of Immunology. 2020;23(3):341-346
pages 341-346 views

Effect of ultrasonic cavitation on pro-inflammatory cytokine profile in complex therapy of patients with acute rhinosinusitis and exacerbation of chronic suppurative otitis media

Korkmazov M.Y., Korkmazov A.M., Dubinets I.D., Smirnov A.A., Kornova N.V.


Patients with exacerbated chronic suppurative otitis media occurring in subjects with acute rhinosinusitis often consulted by ENT spacialists. A literature review has shown that much attention is paid to improving conservative therapy for such patients, and non-drug techniques remain applied rarely. In this context, based on a detailed study of biophysical characteristics, an opportunity of using low-frequency ultrasonic cavitation in combination therapy to increase local immunological resistance of mucous membranes in ENT organ cavities is justified. The aim of the study was to increase clinical therapeutic effectiveness of acute rhinosinusitis and exacerbated chronic suppurative otitis media based on examining timeframe necessary for normalization of pro-inflammatory cytokine profile after using low-frequency ultrasonic cavitation in combination therapy. 63 patients were enrolled to the study. The control group (n = 15) consisted of healthy volunteers, whereas main group had 48 patients with acute rhinosinusitis and exacerbated chronic suppurative otitis media, subdivided into 2 subgroups: subgroup 1 (n = 20) – patients receiving conventional treatment methods (elimination, unloading, local and systemic antibacterial therapy, puncture and anti-inflammatory treatment), subgroup 2 (n = 28) – patients underwent low-frequency ultrasonic cavitation (frequency 29 kHz, amplitude 25 μm) in combination therapy. Washouts from the surface mucous membranes of nasal cavity and nasopharynx were examined for level of IL-1β, IL-2, IL-8, IL-10, TNFα, IFNγ levels before treatment, at day 2, 7, 10 days and in one month after treatment.
Application of low-frequency ultrasonic cavitation in combination therapy in patients with acute rhinosinusitis associated with exacerbated chronic suppurative otitis media is accompanied by early recovery of balance in pro-inflammatory cytokines comparewd with conventional treatment methods. Data analysis showed that positive and satisfactory treatment result was achieved in 11 (56.2%) and 22 (78.2%) as well as 7 (36.2%) and 6 (21.8%) patients from subgroup 1 and 2, respectively. In two patients from subgroup 1 the result was noted as unsatisfactory.
Early recovery in balance of pro-inflammatory cytokines, improvement of clinical results and shortened treatment duration were observed after using low-frequency ultrasonic cavitation in combination therapy of patients with acute rhinosinusitis and exacerbated chronic purulent otitis. The data obtained may serve to justify introduction of low-frequency ultrasonic cavitation into combination conservative therapy of infected nasal and middle ear cavities as an effective and non-invasive approach.

Russian Journal of Immunology. 2020;23(3):347-352
pages 347-352 views

Human placenta hydrolyzate affects neutrophils of systemic immunity during cosmetic procedures

Kudrevich Y.V., Kuznetsova E.K., Shchipacheva O.V., Dolgushin I.I., Ziganshin O.R.


In cosmetology, various types of procedures acting via varying mechanisms are used, including those based on rather aggressive mode of action. Few evidences have been collected so far regarding an effect of such procedures on human skin and entire body. Aim: to determine response of neutrophil arm of systemic immunity to injected placental hydrolyzate, compare effectiveness and safety of cosmetic methods affecting quality of skin layers. There were enrolled 75 healthy women subdivided into three groups with 25 subjects in each group. Patients in Group 1 underwent a course of intramuscular injections with human placental hydrolysate; Group 2 – fractional photothermolysis of facial skin layers with erbium laser; Group 3 – fractional photothermolysis procedure pretreated with course of intramuscular injected human placental hydrolyzate. Samples of peripheral blood were collected from all patients for assessing baseline state of the immune system before interventions and on day 8, 14 and 24 after the onset. It was shown that level of neutrophil phagocytosis and neutrophil NBT-assay were most markedly changed after interventions. It was found that level of neutrophil phagocytosis and neutrophil NBT-assay were virtually decreased by 2-fold after fractional photothermolysis, but not in patients pre-treated with injected placental hydrolysate followed by fractional photothermolysis. Neutrophil phagocytosis and spontaneous neutrophil NBT-assay data in treated vs. baseline patients did not change, whereas level of induced NBT-assay was decreased, but to much lower extent compared to control group solely treated with fractional photothermolysis. Conclusions: introduction of placental hydrolyzate contributes to accelerated rehabilitation period after applying aggressive medical interventions, and prevents development of adverse events.

Russian Journal of Immunology. 2020;23(3):353-358
pages 353-358 views

Chronic immune activation reduces CD4+T cell susceptibility to IL-7 in HIV-infected patients that poorly respond to antiretroviral therapy

Saidakova E.V., Korolevskaya L.B., Shmagel K.V.


Approximately 30 % of HIV-infected patients with viral load being suppressed during the course of antiretroviral therapy do not recover their peripheral CD4+T-lymphocyte counts. The reason for this phenomenon, named immunological non-response to treatment, remains unknown. In HIV-positive subjects receiving treatment, interleukin 7 plays a key role in increasing the number and supporting the viability of CD4+T-lymphocytes. We hypothesized that chronic immune activation, which develops in response to immunological failure during the therapy course, may reduce the susceptibility of CD4+T-cells to interleukin 7 in HIV-positive subjects. We examined 38 HIV-infected immunological non-responders to therapy; 42 HIVpositive patients with a standard response to treatment; 19 uninfected volunteers. The content of CD4+, CD4+CD127+ and activated HLA-DR+CD38+T-lymphocytes was determined in the peripheral blood of the examined individuals; the concentration of interleukin 7 was established. As a result, it was shown that interleukin 7 concentrations in the blood plasma of HIV positive immunological non-responders to treatment does not differ from the corresponding values of patients who gave a standard response to antiretroviral therapy. At the same time, immunological non-responders to treatment compared with subjects of both control groups were characterized by a deficiency of absolute and relative CD4+CD127+T-cell counts capable of responding to interleukin 7. Moreover, the interleukin 7 receptor expression level was reduced on CD4+T-lymphocytes of immunological non-responders. The higher was the frequency of activated CD4+T-lymphocytes; the lower was the CD127+ expression density. It should be noted that after excluding the data obtained from patients coinfected with HIV and hepatitis C virus, which are known to have significantly higher levels of chronic immune activation and systemic inflammation, we found no differences in CD127 expression between HIVpositive patients with distinct effectiveness of the immunological response to treatment. Thus, in the present study, we showed that in HIV-infection, poor immunologic response to antiretroviral therapy is associated with a decrease in the CD4+CD127+T-cell counts. Moreover, an increase in the level of chronic immune activation is associated with a decrease in CD127 expression density on CD4+T-lymphocytes.

Russian Journal of Immunology. 2020;23(3):359-364
pages 359-364 views

Efficiency of Polyoxidonium as a protector in acute toxic damage of the organism

Tуumentseva N.V., Khramtsova Y.S., Artashyan O.S., Yushkov B.G.


Insufficient effectiveness of therapeutic interventions used to treat toxic liver lesions leads to numerous complications. Liver damage is just one manifestation of multiple organ failure. Objective: to evaluate the possibility of using the Polyoxidonium as a protector in the acute period of poisoning with a toxic chemical agent.The studies were performed on 25 rats weighing 200-300 g. Acute toxic poisoning was modeled with hepatotoxic poison polyhexamethylene guanidine hydrochloride (PHMG). Polyoxidonium was injected once in a dose of 0,1 mg/kg intramuscularly through 2 days after the injection of PHMG. The animals were euthanized by diethyl ether overdose after 1 or 3 days to study the liver and peripheral blood. Through 1 day after the injection of PHMG acute polyorganic failure with predominant damage of the liver is developed in rats. An increase in AST levels with a decrease in alkaline phosphatase indicates hepatic cell failure. Granular dystrophy of hepatocytes is observed under the organ capsule. The number of liver cells increases per unit area (1 mm2). The cell size decreases due to cytoplasm. This phenomenon may be associated with the release of various substances from the cells due to damage to their membranes. Pancreatic dysfunction manifests itself in an increase in blood levels of glucose and amylase. An increase in the de Ritis coefficient indicates damage to the heart muscle. An increase in urea without a significant change in creatinine indicates kidney damage. An increase in the number of granulocytes in peripheral blood and ESR indicates the development of the inflammatory process in damaged tissues. Polyoxidonium has a protective effect on most organs examined. This is manifested in a decrease of degenerative changes in the liver and heart, a weakening of the inflammatory reaction and functional disorders of the pancreas. Polyoxidonium can be considered as a drug for detoxification therapy.

Russian Journal of Immunology. 2020;23(3):365-372
pages 365-372 views

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