Identification of Key Biomarkers and Immune Infiltration in Systemic Juvenile Idiopathic Arthritis by Integrated Bioinformatic Analysis

Abstract

Systemic juvenile idiopathic arthritis (sJIA) is a rare and serious type of JIA characterized by an unknown etiology and atypical manifestations in the early stage, and early diagnosis and effective treatment are needed. We aimed to identify diagnostic biomarkers, immune cells and pathways involved in sJIA pathogenesis as well as potential treatment targets. The GSE17590, GSE80060, and GSE112057 gene expression profiles from the Gene Expression Omnibus (GEO) database were screened to obtain differentially expressed genes (DEGs) between sJIA and healthy controls. Common DEGs were subjected to pathway enrichment analysis; a protein-protein interaction network was constructed, and hub genes were identified. In addition, functional annotation of hub genes was performed with GenCLiP2. Immune infiltration analysis was then conducted with xCell, and correlation analysis between immune cells and the enriched pathways identified from gene set variation analysis was performed. The Connectivity Map database was used to identify candidate molecules for treating sJIA patients. Finally, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out, and the GEO dataset GSE8361 was applied for validation of hub gene expression levels in blood samples from healthy individuals with sJIA. A total of 73 common DEGs were identified, and analysis indicated enrichment of neutrophil and platelet functions and the MAPK pathway in sJIA. Six hub genes were identified, of which three had high diagnostic sensitivity and specificity; ARG1 and PGLYRP1 were validated by qRT-PCR and microarray data of the GSE8361 dataset. We found that increased megakaryocytes and decreased Th1 cells correlated positively and negatively with the MAPK pathway, respectively. Furthermore, MEK inhibitors and some kinase inhibitors of the MAPK family were identified as candidate agents for sJIA treatment. Our results indicate two candidate markers for sJIA diagnosis and reveal the important roles of platelets and the MAPK pathway in the pathogenesis of sJIA, providing a new perspective for exploring potential molecular targets for sJIA treatment.

Exploration of Common Genomic Signatures of Systemic Juvenile Rheumatoid Arthritis and Type 1 Diabetes

“…The pathway has been found to participate in insulin-resistant, hypothalamic signaling associated with diabetes remission, the regulatory mechanism associated with diabetic nephropathy, etc [33][34][35]. On the other hand, MAPK-ERK pathway mediating the abnormal activation of broblast-like synoviocytes is believed to be involved in the joint destruction process in rheumatoid arthritis, and the increasing evidence of MAPK involvement in sJIA is gradually being discovered, but the underline mechanism is still needed to be further explored [36,37]. JAK-STAT is an evolutionarily conserved signaling pathway mediating cellular responses to cytokines and growth factors, mediating cell proliferation, differentiation, migration, apoptosis, and cell survival.…”

Biomarkers in Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome and Their Importance in COVID Era

“…Six hub genes were identified, three of which had high diagnostic sensitivity and specificity; ARG1 and PGLYRP1 were validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and microarray data from the GSE8361 dataset as potential markers for the early diagnosis of JIA, revealing new pathways and molecular targets for sJIA. Further studies with larger sample sizes and in-depth analysis are needed to confirm these results [ 28 ].…”

“…The important roles of platelets and the MAPK pathway in the pathogenesis of sJIA provide a new perspective for exploring potential molecular targets for the treatment of sJIA, as Zhang et al revealed by integrated bioinformatics analysis [ 28 ].…”