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Epigenetic alterations leading to specific expression patterns of immune response regulating gene might be responsible for distinctive microbiota composition and disease development in juvenile spondyloarthritis patients.

Background: Juvenile spondyloarthritis (jSpA) is a diverse group of related syndromes with shared symptoms and pathogenic mechanisms in which both extrinsic environmental factors and intrinsic genetic background perpetuate inflammatory response through immune system alterations. Recently obtained gene signatures in jSpA patients revealed TLR4 and CXCR4 gene had increased, while NLRP3 and PTPN12 had decreased expression.1 Although gene expression is regulated by various mechanisms, the increasing numbers of studies is showing the importance of epigenetic mechanisms in this fundamental biological process. Objectives: To investigate the possible mechanistic role of DNA promoter region methylation and several non-coding micro RNA (miR-150, miR-146a, miR-181a, miR-223) in jSpA patients regarding the expression of genes with previously observed alterations. Methods: The expression of specific microRNAs was analysed in 8 jSpA patients and 5 matched controls using RT-PCR with predeveloped microRNA assays. Methylated DNA Immunoprecipitation (MeDIP) was performed in 19 patients and 7 controls. Enrichment in MeDIP fraction was determined by qRT-PCR using the AriaMx. Results: The difference in fold enrichment of immunoprecipitated DNA was significant only for NLRP3 promotor site (p=0.0220). Expression analysis of selected miRs showed no significant difference in fold change between jSpA patients and healthy controls. Conclusions: Our study indicated epigenetic modifications are probably responsible for some of the expression alterations in jSpA patients in the initial phase of the disease. Since NLRP3 has a crucial role in inflammasome assembly and inflammasomes have been shown to shape microbiota, it is reasonable to assume dysbiosis in jSpA patients can at least partially be explained by reduced NLRP3 expression due to hypermethylation, stressing for the first time the epigenetic contribution to jSpA pathophysiology. While it is still not clear if these epigenetic alterations are caused by genetic mutations in epigenetic factors or exposure to certain environmental factors that mediate the occurrence of aberrant epigenetic profiles, the disocvery of DNA methylation-based signature of the NLRP3 gene could have important implications in addressing extrinsic and intrinsic contribution to jSpA pathophysiology, whereas the possibility of reverting epigenetic modifications opens whole new prospects for therapeutic treatment of this complex disease.

juvenile spondyloarthritis ; enthesitis related arthritis ; epigenetics ; methylation ; microRNA

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