Global Journal of Science Frontier Research, G: Bio-Tech & Genetics, Volume 22 Issue 2

In 19.3 % of children, there were variation changes in the nucleotide sequence in the NOD2 gene, which mutations are classically associated with Crohn's disease, Blau syndrome signs of which were not detected in our patients. A significant difference in the frequency of NOD2 mutations in our patients with JIA compared to the population indicates the significance of this genetic variation in onset initiation of juvenile arthritis, the mechanisms of which have not yet been fully determined [ExAC Database; Negroni A., 2018]. The NOD2 gene encodes a protein that plays an important role in the activities of cells of both the innate and adaptive immune system (including monocytes, macrophages, and dendritic cells). It happens through the regulation of cytokines, chemokines, and antimicrobial peptides that take part in the antibacterial and antiviral response. NOD2 protein is also active in certain types of epithelial cells, including Paneth cells, in the intestinal mucosa; it is also involved in the recognition of bacteria and modulates the protective function of the immune system of the mucous membranes. NOD2 protein takes part in such processes as autophagy, apoptosis and proteolysis, determines innate inflammatory responses to bacteria and viruses through the activation of NF-KB and caspase-1 pathways, which leads to increased expression of pro inflammatory factors, including IL-1 β , TNF- α , IL-6, IL- 12p40, IL-8, chemokine ligands, antimicrobial factors. In addition to its main role in the innate immunity, NOD2 is able to activate the adaptive immune system. It is a key regulator of T-helper 2 cells, which leads to the expression of IL-4 and IL-5. Several studies have shown that joint stimulation by NOD2 agonists and TLR receptors (TLR) causes synergistic production of Th1-associated cytokines in various cell types, although the mechanisms of such reactions are unknown. NOD2 activation, in addition, contributes to the formation of Th17 cells and the production of IL-17A, IL-17F, IL-21 and IL-22 [Brembilla NC, 2018]. The involvement of NOD2 in the pathogenesis of various genetic diseases indicates that this protein is a key regulator of immune and inflammatory responses and plays a crucial role in maintaining the balance between bacteria, epithelium, and the innate immune response of the organism. This protective function is absent in case of NOD2 mutation, which leads to an exacerbation of inflammation and the clinical manifestation of various diseases. Many questions remain unanswered, including the relationship between NOD2 mutations and the microbiota as well as understanding the processes through which mutations in NOD2 can be associated with susceptibility to inflammation and the development of diseases. Recent studies indicate that the NOD2 gene can be activated in idiopathic arthritis with increased production of TNFa, IL-8, and IL-1 β by peripheral blood mononuclear cells, while decreased NOD2 regulation reduced the level of proinflammatory cytokines, NF-kB, TRAF6, and IKK [Franca RFO, 2015]. NOD2 protein is expressed in fibroblasts and synovial fluid of patients with RA [Gupta V, 2018]. It is supposed that the NOD2 regulatory pathway is functional, since stimulation of peripheral blood mononuclear cells with muramyl dipeptide (MDP) has induced the production of larger amount of tumor necrosis factor (TNF- α ), interleukins (IL-8 and IL-1 β ) compared to osteoarthritis. Synovial fluid obtained from patients with RA is able to activate the NF-kB signaling pathway [Kim HW, 2017]. Therefore, activation of NOD2-associated auto inflammatory mechanisms can lead to modification and transformation of autoimmunity, which should be taken into account for treatment of juvenile arthritis. Elucidating the mechanisms of regulation and function of NOD2 in juvenile arthritis may lead to the development of an effective therapeutic strategy for inflammation. The change in the nucleotide sequence in the ADA2 gene in a child with idiopathic arthritis calls attention to itself too. To date, more than 60 mutations of this gene have been identified; they cause changes in the adenosine deaminase 2 enzyme, the deficiency or activity loss of which is characterized by abnormal inflammation of organs and tissues with various clinical phenotypes, including vasculopathy, stroke, hematological and multisystemic disorders that can occur along with arthritis. An enzyme deficiency is assumed to be able to disrupt the balance between proinflammatory and anti-inflammatory macrophages in tissues and lead to the accumulation of proinflammatory macrophages resulting in abnormal inflammation [Lee PY, 2020]. ADA is considered a probable candidate gene for susceptibility to common immune-mediated diseases. ADA polymorphism in the clinical modification of RA and response to methotrexate treatment has been less studied [Lee PY, 2020]. The mutation found in the child in our study does not correspond to an autoinflammatory disease, which requires further research for the possibility of new prospects for the treatment of this category of patients. Frequency data for this variant in population databases is considered unreliable, and the ExAC database indicates poor data quality in this position. The variant was registered in a person with Behcet's disease [Burillo-Sanz S., 2017]. ClinVar contains an entry for this variant (option ID: 375246). The protein, which is encoded by NLRP12, inhibits the activation of nuclear transcription factor NF- kB, which regulates the expression of proinflammatory cytokine genes, activates caspase 1. Inadequate functional activity of NLRP12 can lead to the development of cryopyrin-associated periodic syndrome (CAPS) [Gupta V., 2018]. In our patient, who has changes in the nucleotide sequence in this gene, the clinical picture does not correspond to CASP, but © 2022 Global Journals 1 Year 2022 90 Global Journal of Science Frontier Research Volume XXII Issue ersion I VII ( G ) Autoinflammation Candidate Genes in Juvenile Idiopathic Arthritis