ASSOCIATION BETWEEN POLYMORPHIC MARKERS OF THE IL4 (с-590Т) AND IL10 (с-597А) GENES AND PSORIATIC ARTHRITIS

Psoriatic arthritis is a chronic progressive disease of joints developing along with psoriasis. Likewise arthritis and psoriasis alone, it represents the systemic multifactorial disease of unknown etiology; therefore prevention of the disease is inefficient. Genetic predisposition to psoriatic arthritis development is proposed with essential role of genes coding for cytokines, the main mediators of immune response. A study of the prevalence of polymorphisms of the genes of anti-inflammatory cytokines IL4 (C-590T) and IL10 (C-597A) in patients with psoriasis, psoriatic arthritis and healthy donors was carried out. The prevalence of the polymorphisms in the European population of Krasnoyarsk was obtained. An association of the C-590T polymorphic marker of the promoter region of the IL4 gene with psoriatic arthritis was established. The obtained results suggest that the C-590 allele is a contributing factor to heavier course of psoriasis and the development of bone system pathology

Prevalence of the polymorphic H-ficolin (FCN3) genes and mannosebinding lectin-associated serine protease-2 (MASP2) in indigenous populations from the Russian Arctic regions

Lectins, being the main proteins of the lectin pathway activating the complement system, are encoded by polymorphic genes, wherein point mutations cause the protein conformation and expression to change, which turns out to have an effect on the functionality and ability to respond to the pathogen. In the current study, largescale data on the population genotype distribution of the genes for H-ficolin FCN3 rs28357092 and mannose-binding lectin-associated serine protease MASP2 rs72550870 among the indigenous peoples of the Russian Arctic regions (Nenets, Dolgans and Nganasans, a mixed population and Russians: a total sample was about 1000 newborns) have been obtained for the first time. Genotyping was carried out using RT-PCR. The frequency of the homozygous variant del/del FCN3 rs28357092 associated with the total absence of the most powerful activator of the lectin complement pathway, N-ficolin, was revealed; 0 % in the Nenets, 0.8 % in the Dolgans and Nganasans, and 3.5 % among the Russians ( p < 0.01). Analysis of the prevalence of the MASP2 genotypes has shown the predominance of the homozygous variant AA in all studied populations, which agrees with the available world data. The heterozygous genotype AG rs72550870 associated with a reduced level of protease was found to occur rarely in the Nenets, Dolgans and Nganasans compared to newborns of Caucasoid origin from Krasnoyarsk: 0.5 % versus 3.3 %, respectively. Moreover, among 323 examined Nenets, one AG carrier was identified, whereas in Russians, 16 out of 242 examined newborns were found to be AG carriers ( p < 0.001). A homozygous variant (GG) in total absence of protease with impaired binding of both MBL and ficolins was not detected in any of the 980 examined newborns. An additional analysis of infectious morbidity in Arctic populations allows one to find phenotypic characteristics related to a high functional activity of the lectin pathway of complement activation as an most important factor for the first-line of anti-infectious defense, including such new viral diseases as COVID-19

Congenitally impaired pattern-recognition receptors in pathogenesis of pediatric invasive and recurrent pneumococcal infection

Here we review currently available data showing that innate immune signs predisposing to recurrent and invasive pneumococcal infections were identified in children. Streptococcus pneumoniae (pneumococcus) belongs to Grampositive bacteria being the major cause of morbidity and mortality in infants, especially in developing countries and in communities with low socioeconomic status. Due to the lack of anti-pneumococcal vaccination, the significant proportion of pneumococcus carriers develop non-invasive (pneumonia, otitis media, sinusitis) and severe invasive (bacteremia/septicemia, meningitis) pneumococcal infection. A great deal of diverse factors related to pneumococcus biological features (virulence factors) as well individualized host-specific immunity are implicated in efficient bacterial penetration across the mucous membranes. The TLR signaling system plays a crucial role in the human nonspecific defense upon the first encounter with the pathogen. Various TLRs comprise the first pattern recognition receptor fami ly ever described which sense ligands derived from the outer bacterial wall. The complement system is the ancient innate immunity component mainly involved in intravascular elimination of bacterial agents. In addition, the complement proteins serve as a bridge between innate and adaptive immunity, ensuring optimal conditions for B- and T-cell maturation and differentiation. Because pneumococcus secretes the IgA protease, a local protective effects related to IgA antibodies might not be so prominent. Therefore, B-cell immunodeficiency and impaired complement system hold a lead place among congenital causes resulting in severe and recurrent pneumococcal infections in children. Thus, based on available data, we concluded that impaired B-cell function, the complement components deficiency as well as receptor-recognition receptors (TLR-2, -9, -4, MYD88 adapter protein, TLR cascade enzymes: IRAK4, NEMO, NOD-like receptors: NOD2, NLRP3; C-type lectins: MBL, Dextin-2, and, possibly, ficoline) play the most important role among congenital immunodeficiencies predisposing to invasive and recurrent pneumococcal infections play the most important role among congenital immunodeficiencies predisposing to invasive and recurrent pneumococcal infections, and should be used as a rationale for immunological surveillance and organizing immunogenetics screening in these patients

Polymorphism of the mannose-binding lectin gene in the Arctic indigenous populations of the Russian Federation

Mannose-binding lectin (MBL) is a pattern recognizing acute-phase protein of the innate immunity system actively involved in the elimination of a wide range of pathogenic microorganisms by activating the lectin pathway of the complement system. A significant part of the human population has a congenitally low production level and/or low MBL activity due to the carriage of various MBL2 variants, which can modify the course of a wide range of infectious diseases. The genotype and haplotype frequencies of the MBL2 polymorphisms have significant population differences. So far, data on the prevalence of the MBL2 genotypes in indigenous populations of the Russian Arctic regions have not been available. The aim of the study was to analyze the frequency and ethnic specificity of the distribution of allelic variants of the MBL2 polymorphisms rs11003125, rs7096206, rs7095891, rs5030737, rs1800450 and rs1800451 and their haplotypes in the populations of the Taimyr Dolgans-Nenets region of the Krasnoyarsk territory (Nenets, Dolgans-Nganasans, Russians). Data on the genotype and haplotype frequencies of the MBL2 gene among indigenous peoples of the Russian Arctic territories was first obtained in the study. The HYPA haplotype prevalence associated with a high concentration of MBL amounted to 35.4 % for Russian newborns in Eastern Siberia, corresponding to the one for European populations (27–33 %). In newborns of the Arctic populations, the prevalence of HYPA haplotype was significantly higher than in Russians and amounted to 64 % for Nenets and 56 % for the DolgansNganasans, which is close to the one detected for the Eskimos and North American Indians (64–81 %). Populations of Nenets and Dolgans-Nganasans demonstrated a significantly lower prevalence of MBL-deficient haplotypes compared with Caucasians of Eastern Siberia (3.9, 6.4 and 21.3 % respectively). Isolated Arctic populations were suggested to experience some intracellular infections (tuberculosis, leprosy) historically later and, unlike Caucasoid populations, to retain the high activity of the lectin complement activation pathway formed in the early stages of human evolution

THE MORPHOLOGY FEATURES OF THE APPENDIX AND IMMUNOPATOGENESIS OF ACUTE APPENDICITIS AT PATIENTS WITH ALLERGY

Appendix as one their major part of immune system., not only carries out immunological supervision in an organism of the person, but also can serve as "shock" body of development of an allergic inflammation. Morphological changes observed in the inflamed shoot, reveal a number of the features inherent on the one hand in the form of disease, from other side — genesis of inflammation. In the review changes of a functional condition of immune system and morphological features appendix at patients with acute appendicitis, testifying in favor of allergic genesis inflammation are specified

The frequency of distribution of the genotypes of the IL4 polymorphism (rs 2243250) in psoriasis and psoriatic arthritis

Psoriasis (PS) and psoriatic arthritis (PsA) are multifactorial diseases determined by the result of complex combined interaction of genetic and environmental factors. The study of genetic polymorphism of PS and PsA will allow identification of common diagnostic criteria for the progression of pathology. The aim was to analyze the frequency of distribution of genotypes of the promoter region of the C-590T (rs2243250) gene IL4 in patients with psoriasis and psoriatic. The study included patients with psoriasis (n = 49) and psoriatic arthritis (n = 48), which, taking into account the carriage of certain genotypes, are divided into groups: 1, PS, carriers of the C/С genotype (n = 31); 2, PS, carriers of the C/T and T/T genotype (n = 18); 3, PsA, carriers of the C/С genotype (n = 30); and 4, PsA, carriers of the C/T and T/T genotype (n = 18). DNA extraction from whole venous blood was performed using a standard kit with a sorbent. Genotyping allelic variants was carried out by the method of restriction analysis of amplification products (RFLP-analysis) of specific regions of the genome. In PS carriers of the C/С IL4 (rs2243250), the value of the PASI index is statistically significantly lower relative to the carriers of the C/T and T/T genotypes. A possible association of the carriage of the C/T and T/T genotypes in PsA with nail psoriasis was noted in comparison with the C/C genotype. When studying intergroup differences, it was determined that the carriage of the C/C genotype in PsA can influence the clinical course of the psoriatic process with frequent exacerbations and involvement of more than 30 % of the hairy part in the pathological process. The carriage of the C/T and T/T genotypes in PsA may be associated with the Koebner phenomenon and the metabolic disorders in comparison with PS. Differences in the carriage of the C/C genotypes relative to C/T and T/T IL4 (rs2243250) in psoriasis and psoriatic arthritis were determined. Given the extremely low number of patient groups, the results should be considered as preliminary and require further testing on much larger samples

AGE-DEPENDENT INDEXES OF IMMUNITY IN THE PATIENTS WITH PSORIATIC ARTHRITIS

Psoriatic arthritis is a chronic progressive systemic inflammatory disease of joints and spine, which leads to the development of erosive arthritis, bone resorbtion, multiple enthesitis and spondylitis. Severe clinical course, resistance to therapy, high prevalence of disability, increased mortality of patients determine a need for further study of the disease. Psoriatic arthritis is a multifactorial disease including immune pathogenic factors representing a complex process of interaction between cellular and humoral components of immune system. The most important way of activating epidermal cells and synovial membrane proliferation in psoriatic arthritis is an imbalance of proinflammatory and anti-inflammatory cytokines. It is noted that the features of clinical course in psoriasis are age-dependent. The study of immune response indices in different age groups allows to reveal distinct progression features of the psoriatic pathology.The purpose of this study was to compare concentrations of proinflammatory and anti-inflammatory cytokines, cellular and humoral immunity, and to conduct a comparative analysis in young and adult patients with psoriatic arthritis.The study included a group of patients with psoriatic arthritis (n = 101) who were divided by their age: group 1, from 18 to 44 years (n = 43); group 2, over 44 years (n = 58). The control groups (3 and 4) included virtually healthy people (n = 103) matched for sex and age with the patients. Populational and subpopulation profiling of blood lymphocytes was performed by flow-cytometry using monoclonal antibodies to CD3, CD4, CD8, CD16, CD19 (LLC “Sorbent”, Moscow, Russia). Phagocytic activity of peripheral blood neutrophils was assessed microscopically by uptake of latex particles. Concentrations of IgA, IgM, and IgG immunoglobulins, circulating immune complexes, cytokines (IL-4, IL-6, IL-10, TNFα) in blood serum was determined by enzyme-linked immunosorbent assay. Statistical evaluation of the results obtained was performed using applied “Statistica 6.0” software.In all the age subgroups of patients with psoriatic arthritis, we have revealedstatistically significant differences against controls, i.e., increased relative and absolute number of CD3-CD16+ lymphocytes in peripheral blood, higher concentration of CIC-C1q, with decreased concentrations of IgA, IgM, IgG in blood serum. The analysis of the main cellular and humoral indicators of immunity in psoriatic arthritis patients revealed a statistically significant differences for psoriatic arthritis in young and adulthood. E.g., the serum concentration of IL- 10 was statistically significantly lower in psoriatic arthritis at a young age in comparison with adult psoriatic arthritis. Phagocytic number and IgG concentration in serum were statistically significantly lower in adults with psoriatic arthritis adulthood than in young patients.In conclusion, The revealed changes in immunological indices in psoriatic arthritis in young and adult patients indicate to differences against healthy controls, as well as intergroup differences. Previous studies have not revealed statistically any significant differences in immunological parameters between young and adult patients with psoriatic arthritis in, thus suggesting a presence of immune disorders associated with psoriatic pathology, but not with the age of patients. However, changes of immunological reactivity are observed with increasing age of patients with psoriatic arthritis and development of severe clinical forms, and they can be considered as markers of psoriatic disease progression, such as increased concentrations of IL-10 and lower IgG amounts in blood serum, a decreased phagocytic number

Genetic markers of children asthma: predisposition to disease course variants

Asthma is a heterogeneous and often difficult to treat condition that results in a disproportionate cost to healthcare systems. Children with severe asthma are at increased risk for adverse outcomes including medication-related side effects, life-threatening exacerbations, and impaired quality of life. An important therapeutic focus is to achieve disease control, which is supposed to involve a personalized approach to treatment of asthma of any severity. Asthma is a multifactorial disease with a significant genetic determinant, however, the inheritance of asthma has not been fully elucidated. Polymorphic genes of inflammatory mediators, including cytokines, play an important role in developing various disease forms. In the current study, large-scale original data on the prevalence of cytokine gene genotypes (IL2, IL4, IL5, IL6, IL10, IL12, IL13, IL17A, IL31, IL33, IFNG, TNFA) among Russian children with asthma in Krasnoyarsk region have been obtained. Genotyping was carried out using real-time PCR. We identified markers predisposing to the development of different variants of the course of childhood asthma: the CT genotype and T allele of IL4 rs2243250 are associated with asthma (p < 0.05), especially in mild asthma and in controlled asthma. The TT genotype and allele T of IL13 rs1800925 are associated with severe and uncontrolled asthma (p < 0.05). The AA genotype of IL17A rs2275913, the TT genotype of IFNG rs2069705 and allelic A variants of TNFA rs1800629 are associated with mild asthma, and the TT genotype of IFNG rs2069705 is additionally associated with controlled asthma. The results obtained will supplement information on the prevalence of polymorphic variants of the cytokine genes in the Russian population and in asthma patients with different disease courses, which is likely to be used in order to shape a plan for Public Health Authority to prevent the development of severe uncontrolled asthma and to optimize personalized therapy

PLASMA Th1/Th2/Th17 CYTOKINE PROFILE AND CYTOKINE GENE POLYMORPHISMS (IL12B, IL13, IL31, IL33) IN ASTHMATIC CHILDREN: A MAGNETIC MULTIPLEX ASSAY

The study of the bronchial asthma pathogenesis is an urgent problem due to its high prevalence and often developing uncontrolled severe ashma, including in childhood. The first signs of asthma development tend to occur in childhood, which causes deterioration in the patient’s quality of life and early disability. Since BA is a genetically mediated process, the severity of the disease is assumed to depend on the presence of a specific allelic variant in the mediator (e.g. cytokines) genes involved in the BA pathogenesis. The aim of this study was to search for immunogenetic markers of severe asthma in Slavs children living in Krasnoyarsk city. The quantitative indicators of the Th1/Th2/Th17-cytokine profile in children with bronchial asthma (BA) with varying disease severity, depending on the polymorphism of cytokine genes, using the method of multiplex analysis (xMAP), were first determined. Changes in the cytokine background in BA patients fit into the concept that a percentage of neutrophilic endotype, which performs its functions through Th1 and Th17-lymphocytes in severe asthma, increases. In addition, the cytokine profile data depending on concomitant acute respiratory infections were obtained. There was an imbalance when analyzing the cytokine plasma level, with a tendency to maintain the protective functions of the immune system among patients in remission. Distribution of cytokine genes was obtained: allelic variants of IL12B rs321220*G, IL13 rs1800925*C, IL31 rs7977932*C and IL33 rs7044343*T are the most common in the population sampling from Krasnoyarsk. The probability of the genotype association of cytokine genes (IL12B, IL13, IL31, IL33) with the state of the immune system in bronchial asthma with varying disease severity in children was studied: a significant association of the TT genotype IL12B rs3212220 with a low concentration of IL-12B was presented. Our data obtained can be used along with the previously obtained immunogenetic markers of severe and uncontrolled asthma in children for patient-specific prognosis of the disease nature

Search for genetic markers of predisposition to psoriasis and psoriatic arthritis

Psoriasis (PS) and psoriatic arthritis (PsA) are interrelated diseases that occur in approximately 30% of patients and are characterized by the presence of a systemic inflammatory reaction that occurs as a result of a violation of the functional state of the immune system. With the advent of new technologies, several new pro-inflammatory cytokines, such as IL-23, IL-31, and IL-33, which play an important role in the pathogenesis of the psoriatic process, have been discovered and characterized. It was determined that single nucleotide polymorphisms (SNPs) in the promoter regions of the IL23, IL31 and IL33 genes play an important role in controlling the expression of relevant cytokines involved in the immunopathogenesis of psoriatic disease. The purpose of the study: to analyze the distribution of genotypes and allelic variants of polymorphisms of the IL23A (rs2066808), IL23R (rs2201841), IL31 (rs7977932) and IL33 (rs7044343), in order to search for genetic markers of predisposition to psoriasis and psoriatic arthritis. Materials and methods. The genotyping of the patients was conducted: psoriasis (PS, n = 77), median age 31.0 years (27.0-43.0), psoriatic arthritis (PsA, n = 99), median age 49.0 years (39.0-56.0) and practically healthy residents of Krasnoyarsk (n = 103), a median age of 32.0 years (24.0-38.0). DNA was isolated from whole venous blood using a standard sorbent kit. Genotyping of single nucleotide polymorphisms IL23A (rs2066808), IL23R (rs2201841), IL31 (rs7977932), IL33 (rs7044343) was carried out using real-time PCR using specific oligonucleotide primers and fluorescentlylabeled probes. Results and discussion. The frequencies of allelic variants of the studied cytokine genes in the control group obtained during the study correspond to their distribution in Caucasoid populations – the alleles IL23A * T, IL23R * T, IL31 * C, IL33 * C prevail. When comparing the distribution frequency of allelic variants of the IL23A, IL23R, IL31, IL33 genes, we did not obtain statistically significant differences between patients and the control group. Conclusions. Despite the fact that when comparing the distribution frequency of allelic variants of the IL23A, IL23R, IL31, IL33 genes, we did not obtain statistically significant differences between the patients and the control group, there are results worthy of attention. So, in patients with PS, the frequency of the C * IL23A allelic variant (rs2066808) is lower than in the population sample, which may indicate its specific role in relation to the development of the disease. All this dictates the need to continue research with the assessment of other SNPs and increase the sample of patients in search of potential genetic markers of psoriatic disease