Aberrant Expression of Shared Master-Key Genes Contributes to the Immunopathogenesis in Patients with Juvenile Spondyloarthritis

Abstract

Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in the development of the disease. To date, only a few studies have tried to find those associated genes by obtaining expression profiles, but with inconsistent results due to various patient selection criteria and methodology. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in highly homogeneous cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA) according to ILAR criteria. For the purposes of the research, total RNA was isolated from whole blood of 45 children with jSpA and known HLA genotype, 11 children with oligo- and polyarticular forms of JIA, as well as 12 age and sex matched control participants without diagnosis of inflammatory disease. DNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes where analyzed by qRT-PCR in all participants of the study. Microarray results and bioinformatical analysis revealed 745 differentially expressed genes involved in various inflammatory processes, while qRT-PCR analysis of selected genes confirmed data universality and specificity of expression profiles in jSpA patients. The present study indicates that jSpA could be a polygenic disease with a possible malfunction in antigen recognition and activation of immunological response, migration of inflammatory cells and regulation of the immune system. Among genes involved in these processes TLR4, NLRP3, CXCR4 and PTPN12 showed almost consistent expression in study patients diagnosed with jSpA. Those genes and their products could therefore potentially be used as novel biomarkers, possibly predictive of disease prognosis and response to therapy, or even as a target for new therapeutic approaches.

Identification of genes and signaling pathways associated with the pathogenesis of juvenile spondyloarthritis

“…Spondyloarthritis (SpA) includes a group of immune-mediated inflammatory diseases with similar genetic and clinical manifestations, including ankylosing spondylitis (AS), psoriatic arthritis (PsA) and juvenile SpA (JSA) ( 1 , 2 ). In particular, JSA is a group of chronic inflammatory diseases associated with human leukocyte antigen B27, affecting children at ≤16 years of age.…”

Epigenetic Alterations in Juvenile Spondyloarthritis Patients: a Preliminary Study of Selected Genes Promoter Methylation and Silencing

“…Our previous study demonstrated that jSpA patients exhibit complex patterns of gene expression for functions related to inflammatory and defense response, mitogen-activated protein (MAP) kinase and cell cycle, chromatin modulation and transcription, cell death, and apoptosis [10]. NLRP3, a gene closely linked to autoinflammatory diseases was among genes with consistently decreased expression, while TLR4, another gene important for inflammatory response, had persistently increased expression in jSpA patients.…”

“…To date, several expression profiling studies in patients diagnosed with SpA have been conducted, with the majority focused on AS patients, and only a few involving jSpA patients [7][8][9]. Hence, our group recently performed a thorough gene expression analysis in a very homogenous group of jSpA patients diagnosed according to ILAR classification criteria for ErA [10]. The results of the study revealed increased expression of TLR4 and CXCR4, with decreased expression of NLRP3 and PTPN12 genes.…”

Juvenile Spondyloarthritis

“…Additionally, Lamot et al examined gene signatures in JSpA and found evidence to suggest that JSpA is a polygenic disease with involvement of TLR4, NLRP3, CXCR4 and PTPN12 (15).…”