Abstract
ObjectivesThe aim of our study was to determine whether there is a correlation between transcription factors expression and Th17/Treg ratio, cytokine profile in the RA phenotype as well as to identify transcription factors that could be a potential biomarker for RA.MethodsThe study was conducted on 45 patients with RA, 27 patients with OA and 46 healthy controls (HCs). Th17 and Treg frequency was determined by flow cytometry (15 patients with RA/OA and 15 subjects of HC). Gene expression was estimated by qPCR, and the serum cytokine levels were determined by ELISA.ResultsThe percentage of Treg (CD4+CD25highCD127-) cells in RA patients was lower than in OA patients or HCs. Proportions of Th17 (CD4+CCR6+CXCR3-) cells were higher in RA and OA in comparison to HCs. STAT5 showed a very high expression in the blood of RA patients compared to healthy subjects. The expression of STAT5 and HELIOS was not detected in Th17 cells. A positive correlation between SMAD3 and STAT3 in RA patients was observed. Negative correlations between HIF-1A and SMAD2 in RA Treg cells and DAS-28 score were observed. The range of serum of IL-17 and IL-21 were higher in RA patients than in OA patients. Concentrations of serum IL-2 and IFN-γ were higher in RA and OA patients than in healthy subjects. Based on the ROC analysis, the diagnostic potential of the combination of HIF1A, SMAD3 and STAT3, was determined at AUC 0.95 for distinguishing RA patients from HCs. For distinguishing RA patients from OA patients the diagnostic potential of the combination of SMAD2, SMAD3, SMAD4 and STAT3, was determined at AUC 0.95.ConclusionBased on our study, we conclude that SMAD3 and STAT3 could be potential diagnostic biomarkers for RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease of multifactorial origin [1]
Based on our study, we conclude that Sma- and Mad-related protein 3 (SMAD3) and signal transducers and activators of transcription (STAT3) could be potential diagnostic biomarkers for RA
We observed that the expression of CD25 on Treg obtained from both RA and OA patients were statistically significantly higher than in healthy controls (HCs) persons (Figure 1B)
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease of multifactorial origin [1]. The connection of the Th17/Treg cells imbalance with pro-/anti-inflammatory cytokines production is relevant for the development and/or progression of the disease, which is in turn associated with the autoimmunity, chronic inflammation and articular destruction in the joints of RA patients [4, 5]. Th17 and Treg cells are characterized by the selective expression of distinct transcriptional factors. Activation of the IL-2–STAT5 pathway by transcriptional factor HELIOS (Ikaros family zinc-finger protein 2; IKZF2) ensures Treg survival and stability [13, 14]. Th17/Treg balance is modulated by hypoxia-inducible factor 1a (HIF-1A) and suppressor of cytokine signaling (SOCS) proteins. HIF-1A promotes Th17 differentiation by induction of RORc2 and in consequence, activates Th17 signature genes, but on the other hand, it inhibits Treg differentiation by FOXP3 protein degradation.
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