FOXP3, IL2R, CD8A and RORγ gene expression in peripheral blood leukocytes of healthy people and patients with arterial hypertension

Impaired balance of T regulatory and T effector lymphocytes has recently been considered as an important pathogenetic link in arterial hypertension (AH). There are, however, contradictory literature data about contents of these cells in the patients with hypertension, or obtained in experimental animal models of induced hypertension. Most results about changed patterns of immune cells in cardiovascular diseases were obtained by means of flow cytometry. There are also some works on expression of genes encoding surface and cytoplasmic differentiation antigens of immune cells in the patients with cardiovascular pathologies. These results coincide with the data obtained with flow cytometric techniques. Purpose of the present study was to analyze of the levels of gene transcripts encoding differentiation markers of regulatory (FOXP3, IL2R) T cells, effector T subpopulations (T helpers 17 (RORγ), and CD8 lymphocytes (CD8A) in healthy subjects and the patients with arterial hypertension (stages I-II). We examined healthy individuals (40 people, 20 men and 20 women), 27 patients with hypertension who did not receive antihypertensive therapy (14 men and 13 women), 26 hypertensive patients taking β-adrenergic receptor blockers (metoprolol or bisoprolol), including 12 men and 14 women. The relative levels of transcripts in peripheral blood leukocytes were assessed by real-time RT-PCR. It was shown that the transcriptional activity of FOXP3, IL2R, RORγ, and CD8A genes in peripheral blood leukocytes of the diseased people was significantly higher than in healthy individuals (p < 0.01). This finding may indicate an increased number of circulating T regulatory lymphocytes, CD8+ cells and T helpers 17 in hypertensive patients, and activation of T cell immunity in these patients. There were no statistically significant gender differences in FOXP3, IL2R, RORγ and CD8A gene expression in leukocytes, both in the group of healthy people and in hypertensive patients. The patients receiving cardioselective β-adrenergic receptor blockers (metoprolol and bisoprolol) exhibited lower expression of these genes, thus, probably, indicating antiinflammatory and immunomodulatory properties of these drugs

The relationship of the carriership of allelic variations in rs2228145 (A > C) of the<i>IL6R</i> gene with the levels of <i>VCAM1</i> and <i>ICAM1</i> gene transcripts in patients with essential hypertension

The levels of plasma interleukin 6 and its soluble receptors were found to be elevated in subjects with cardiovascular diseases, which points to amplification of the IL-6-mediated trans-signaling pathway in cells and the development of chronic inflammation. The allelic variation in the rs2228145 IL6R gene is associated with a change in the contents of the soluble and membrane-bound receptor forms mediating the biological activity of IL-6. Cytokine IL-6 is involved in the development of endothelial dysfunction by regulating the expression of the VCAM1 and ICAM1 genes, encoding intercellular adhesion molecules. Prior to this work, no data on the association of essential arterial hypertension (EAH) with rs2228145 allelic variations of the IL6R gene have been reported. The aim of our work was to study the relationship of the carriership of rs2228145 (A &gt; C) allelic variations with the development of EAH and the VCAM1 and ICAM1 transcript levels. We analyzed samples of DNA isolated from the whole blood of 148 healthy donors and 152 patients with EAH (stages I-II). The genotyp-ing was performed by PCR-RFLP. The level of transcripts in peripheral blood leukocytes (PBL) was assessed by real-time PCR. Differences in the frequency distributions of rs2228145 (A &gt; C) genotypes between the control group and the group of patients with EAH (χ2 = 9.303) were found. The frequency of the CC genotype in EAH patients was higher than in healthy people (0.191 and 0.095, respectively). The risk of EAH (I-II stages) development was shown to be 2.3 times higher in CC genotype carriers as compared to individuals with other genotypes (OR = 2.257, 95 % confidence interval 1.100-4.468). The levels of VCAM1 and ICAM1 gene transcripts in PBL of patients with EAH were significantly higher than in healthy people. The level of ICAM1 gene transcripts was almost 4 times higher in patients with CC genotype. The Kruskal-Wallis analysis of variance revealed an effect of rs2228145 (A &gt; C) genotype on the transcriptional activity of ICAM1, which argues for its role in the pathogenesis of endothelial dysfunction and essential hypertension

Immunological predictors of type 1 diabetes mellitus (literature review)

Background: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by insulin deficiency due β-cell destruction and following hyperglycaemia. Specific markers of T1DM are pancreatic islet-targeting autoantibodies that are found months to years before symptom onset, and can be used to identify individuals who are at risk of developing T1DM.Aim: The study is aimed at the review of current knowledge of diabetes-related autoantibodies as biomarkers of T1DM.Materials and methods: Foreign and national clinical studies on this topic were included. PubMed, Medline and ­eLibrary were searched.Results: Modern ideas about known diabetes-specific autoantibodies as markers of autoimmune inflammation of β-cells of the pancreas were discussed. The analysis of their independent diagnostic value in predicting the occurrence of T1DM were carried out.Conclusion: There is no unified concept in the literature on this issue. Current data on autoantibodies in T1DM show a ­significant individual variability in the timing, dynamic changes and autoantibody composition in T1DM progression

SYNOPSIS AND PROSPECTS OF AUTOIMMUNOLOGY DEVELOPMENT WORLDWIDE (AFTER THE MATERIALS OF THE 11th INTERNATIONAL CONGRESS IN LISBON, MAY 16-20, 2018). PROCEEDING I: FIRST ACADEMY OF AUTOIMMUNITY

A review article is an aftermath of the 11th International Congress on Autoimmunity and First Academy of Autoimmunity, happened 14th to 20th May, 2018 in Lisbon. The first part of paper discusses the formation, main problems and prospects for the development of Autoimmunology as a new integral branch of fundamental and clinical Medicine engaged in the research, diagnosis, treatment and prevention of autoimmune diseases of various organs and systems, totally circa 90 of them. A summary of all lectures conducted during the Academy of Autoimmunity is given, including a discussion of the newest and controversial aspects of the development of the modern concepts of the immune system, autoimmunity and autoimmune pathology. Article reviews data on the current problems of Immunology associated with the use of large databases of clinical and laboratory findings and extrapolation of animal experimentation data to humans. The newest ideas about congenital immunity, including the populations of innate lymphoid cells, on the role of various groups of receptors of the innate immunity system, on the participation of the mechanisms of innate immunity in pathogenesis of autoimmune disorders are highlighted. Modern concepts of antigen presentation are offered, including classification of dendritic cells, alternative pathways of macrophage activation, as well as on costimulatory and inhibitory interactions of ligands and receptors of lymphocytes and antigen-presenting cells. The latest data about the subpopulations of T lymphocytes and their role, including the functions of Tfh cells and the relationships of these subpopulations with various immune responses are highlighted. Influence of microbiota on T cell subpopulations is discussed. The main regularities of the phenomenon of immunological memory are formulated. The questions of antibody production and B lymphocyte functions are considered taking into account recently discovered mechanisms of intracellular penetration of immunoglobulins and details of affinity maturation of lymphoid clones. The new therapeutic approaches in the treatment of autoimmune diseases associated with influences on B and T lymphocytes are described. Mechanisms of central and peripheral autotolerance have been highlighted, taking into account data on the function of the AIRE gene and T regulators. The role of T regulators in placentation is considered. The role of interleukin-2 and its recombinant analogues in immune interactions is interpreted in a new way, taking into account not only their immunostimulating, but, under certain conditions, immunosuppressive potential also. Considerable attention has been paid to the inhibitory receptors of T lymphocytes and to immuno-biotherapeutic effects on them. The history and current status of Oncoimmunology and the use of blockers of inhibitory T lymphocyte receptors in Oncology, including the side effects of treatment with check-point inhibitors, are briefly discussed. Information was given on the held on 21-23 September 2018 2nd Academy of Autoimmunity in St. Petersburg

Potential risk factors for diabetes mellitus type 1

Diabetes mellitus type 1 (T1D) develops as a result of the interaction of genetic and environmental factors. Genetic predisposition to T1D turns into clinical reality only in half of hereditary cases, which indirectly indicates the importance of external factors, the significance of which is periodically reviewed. Retrospective and prospective clinical foreign and national studies were included. PubMed, Medline and eLibrary were searched. Modern ideas about the possible impact of the main prenatal and postnatal environmental factors on the development of autoimmune response against insulin-producing islet cells and T1D were discussed. The risk of developing type 1 diabetes is determined by the complex interaction of environmental factors and genetic predisposition. The mechanisms of their influence remain rather unknown. Further research is needed to determine strategies of primary and secondary prevention of T1D

INFLUENCE OF HLA-DRB1* ALLELIC SETS ON THE DEVELOPMENT OF TUBERCULOSIS IN CHILDREN

According to the WHO data, tuberculosis still represents a serious public health problem worldwide. Deterioration of socio-economic conditions in the population complicates epidemic situation for tuberculosis inRussia, thus leading to increase in acute progressive and complicated forms of tuberculosis in children and, consequently, to worsening structure of its clinical forms. Objectives: to determine associations between certain HLA-DRB1 alleles and risk of tuberculosis development in children. We examined 188 children aged from 3 to 14 years with various manifestations of tuberculous infection. Along with thorough examination of the patients, including multi-spiral CT scans of chest, we undertook genotyping of HLA-DRB1 alleles. Activity of tuberculous infection was determined by a set of immunological tests, i.e., tuberculin skin test, DIASKINTEST® (recombinant allergen of tuberculosis DIASKINTEST®). X ray diagnostics was performed with multi-spiral «Aquilion-32» computed tomograph (Toshiba), according to standard procedures. Molecular genetic typing of HLA-DRB1 alleles was performed by polymerase chain reaction (PCR-SSP), using standard commercial kits PROTRANS Ceclerplate System Protrans HLA-DRB1*. The children were divided into two groups: I group, 90 healthy children, II group, 98 children with tuberculosis. A comparisons group consisted of healthy donors (n = 346). Statistical processing of genetic material included evauation and analysis of the following parameters: frequency distribution of the antigen (F), χ2 criterion for significance (chi-square), the relative risk ratio (RR), etiologic fraction (EF), preventive fraction (PF). Children of the II group had significantly higher *04 allele HLADRB1*, as compared with control group (36.7% vs. 21.1%, χ2 = 10.08; р &lt; 0.01). This finding may suppose a predisposal of these allele carriers to development of tuberculosis. At the same time, the rates of *07 (14.3% vs. 27.5%, χ2 = 7.15, р &lt; 0.01) and *15 (18.4% vs. 28.3%, χ2 = 3.92; р &lt; 0.01) HLA-DRB1* alleles were significantly lower, thus suggesting a protective effect of this allele. *04 allele seems to be a predisposing factor, whereas *07 and *15 alleles are protective for development of tuberculosis in children

Comparative assessment of modern parameters of glycemic control in children with type 1 diabetes after switching to fast-acting insulin aspart using Flash Glucose Monitoring in real clinical practice

BACKGROUND: Postprandial hyperglycaemia contributes significantly to the lack of glycaemic control in patients with type 1 diabetes mellitus (DM1). At least a quarter of patients forget to inject insulin before meals once a week, and more than 40% of them inject bolus insulin immediately before meals, which does not correspond to the pharmacokinetic effects of ultrashort insulins and determines the need to use insulins with better imitations of physiological insulin secretion.AIM: To assess the effect of fast acting insulin aspart (FIAsp) on the current parameters of glycaemic control in children with DM1 after switching from insulin Asp (iAsp) using continuous glucose monitoring.MATERIALS AND METHODS: A multicenter observational 12-week prospective open-label uncontrolled comparative study was initiated. A group of insufficiently controlled patients were identified (n = 48) including a group on multiple insulin injections therapy (MII) (insulin degludec and IAsp) and a group on continuous subcutaneous insulin infusion (CSII) of iAsp. Three 14-day flash glucose monitoring (FMG) were performed: before transferring patients to FiAsp and after 2 and 12 weeks of the transfer. Key endpoints: HbA1c after 2 and 12 weeks on FiAsp relative to baseline, analysis of 5 FMG target glucose ranges, presented as an ambulatory glycemic profile. Additional indicators: dynamics of insulin daily dose, frequency of glucose self- monitoring, the number of severe hypoglycemia, adverse events that occurred during treatment.RESULTS: 2 weeks after the transfer from IAsp to FIAsp, TIR increased in the entire group of patients: from 53% [44.3; 66.5] to 57% [47.4; 71.0] (p-value = 0.010) and TAR decreased from 38% [24.8; 50.2] to 30.5% [22.0; 45, 0] (p-value = 0.0124). Maintaining and increase time spent in the target glucose ranges during a 12-week observation period, in parallel with a significant decrease in hypoglycemic episodes &lt;3.9 mmol / L per week, on FIAsp therapy naturally leads to an improvement in diabetes control: a decrease in HbA1c from 8.15% up to 7.75% (p-value = 0.0224), more pronounced in the group of patients on CSII — from 7.9% to 7.5% (p-value = 0.028).CONCLUSION: Switching from IAsp to BDIAsp in routine clinical practice in the MII and CSII regimen in children and adolescents with type 1 diabetes allows achieving better glycemic control compared to the previous generation prandial insulin analog Iasp. The better diabetes control is associated with an increase or a trend towards an increase in TIR and a decrease or a trend towards a decrease in TAR and TBR, as well as a significant decrease in episodes of hypoglycemia

Features of COVID-19 course in patients with obesity and dysglycemia

Aim. To study the features of coronavirus disease 2019 (COVID-19) in patients with different severity of carbohydrate metabolism disorders (CMDs), taking into account the possible role of obesity in the acceleration of clinical and laboratory disorders.Material and methods. There were 137 consecutive patients admitted to the infectious disease hospital for COVID-19patients. Three 3 groups were formed: group 1 — 42 patients with concomitant type 2 diabetes (T2D); group 2 — 13 patients with concomitant prediabetes; group 3 — 82 patients without concomitant CMDs.Results. Patients with T2D tended to have a more severe disease course according to the SMRT-CO algorithm (p=0,089), which was associated with the longest hospital stay (p=0,038), the most pronounced (p=0,011) and prolonged (p=0,0001) decrease in oxygen saturation, the maximum percentage of lung injury at the beginning (p=0,094) and at the end (p=0,007) of hospitalization, the greater need for intensive care unit (p=0,050), as well as the highest increase in C-reactive protein and fibrinogen (hypercoagulability and systemic inflammation were noted in all groups). Patients with prediabetes in terms of COVID-19 severity occupied an intermediate position between those with T2D and without CMDs; at the same time, they most often needed the prescription of biological preparations (p=0,001). In the first and second groups, there were larger, compared with the control, proportions of obese people (61,9%, 53,8% and 30,5%, respectively, p=0,003). Prediabetes group had a strong correlation between the severity of viral pneumonitis according to SMRT-CO and the presence of obesity (R=0,69, p=0,009).Conclusion. In patients with impaired carbohydrate metabolism of any severity, COVID-19 is more severe. At the same time, persons with overt T2D are prone to the most severe COVID-19 course, while patients with prediabetes in terms of disease severity occupy an intermediate position between them and those without CMDs. Obesity is a strong risk factor for severe COVID-19 among patients with initial CMDs (prediabetes), which is partly mediated by prior liver dysfunction associated with the metabolic syndrome. The increase in proinflammatory changes and hypercoagulability is associated with COVID-19 severity in patients with and without CMDs. These disorders had the greatest severity and persistence in patients with T2D

Reduction Operators of Linear Second-Order Parabolic Equations

The reduction operators, i.e., the operators of nonclassical (conditional) symmetry, of (1+1)-dimensional second order linear parabolic partial differential equations and all the possible reductions of these equations to ordinary differential ones are exhaustively described. This problem proves to be equivalent, in some sense, to solving the initial equations. The ``no-go'' result is extended to the investigation of point transformations (admissible transformations, equivalence transformations, Lie symmetries) and Lie reductions of the determining equations for the nonclassical symmetries. Transformations linearizing the determining equations are obtained in the general case and under different additional constraints. A nontrivial example illustrating applications of reduction operators to finding exact solutions of equations from the class under consideration is presented. An observed connection between reduction operators and Darboux transformations is discussed.Comment: 31 pages, minor misprints are correcte

Pharmacogenetic testing of patients with atrial fibrillation who required warfarin therapy

66 patients with atrial fibrillation from Smolensk region who needed warfarin therapy were recruited into the study. The significant variants of CYP2C9 and VK0RC1 genes (CYP2C9*2, CYP2C9‘ 3, VK0RC1 *2) were detected by real-time PCR. Among the study population the prevalence of warfarin sensitivity genotypes were widespread.Обследовано 66 пациентов с фибрилляцией предсердий, проживающих на территории Смоленской области и нуждающихся в назначении варфарина. У пациентов определялось наличие клинически значимых вариантов генов CYP2C9 и VK0RC1: CYP2C9*2, CYP2C9*3, VK0RC1 *2 методом ПЦР в режиме реального времени. Среди обследованной популяции выявлено широкое распространение полиморфизмов, определяющих повышенную индивидуальную чувствительность к варфарину