Expression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells from patients with systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a rare, chronic, multisystem autoimmune disease clinically characterized by progressive fibrosis of the skin and internal organs. The basic mechanism appears to involve endothelial cell injury, overproduction of extracellular matrix proteins, and aberrant immune activation. So far, there have been a few attempts to find genetic biomarkers for monitoring disease activity or for correlation with certain symptoms. In order to reveal reliable biomarkers, we analyzed the expression of four genes representing three important signaling pathways, TLR7, TLR9, and JAK2-STAT3. Using RT-qPCR technique, we analyzed the expression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells of 50 SSc patients and 13 healthy individuals. We detected significant upregulation of TLR7 gene expression in a group of SSc patients compared to non-SSc group. Receiver operating characteristic (ROC) analysis showed that TLR7 expression efficiently discriminates SSc cases from healthy individuals. High TLR7 expression positively correlated with the late form of disease, active SSc, and the presence of digital ulcers. Decreased levels of TLR9 and JAK2 mRNA were found in the patient's cohort in comparison to non-SSc individuals, but showed no correlation with specific clinical outcomes. The expression level of the STAT3 gene did not differ between the analyzed groups. This is the first study on the expression of TLR7, TLR9, and STAT3 genes in SSc patients. Our results show that TLR7, TLR9, and JAK2 genes are potential biomarkers for SSc. The results obtained in this study could contribute to better classification, monitoring, and outcome prediction of patients with SSc based on genetics.

Variety of endosomal TLRs and Interferons (IFN-α, IFN-β, IFN-γ) expression profiles in patients with SLE, SSc and MCTD

“…In contrast to our study, Vreca et al . [52] showed significant up‐regulation of TLR‐7 expression and significantly lower expression levels of the TLR‐9 in PBMCs of SSc patients. Moreover, they also observed that increased TLR‐7 expression correlated with disease activity, advanced disease and digital ulcers.…”

Nucleic Acid Sensors as Therapeutic Targets for Human Disease

“…TLR8 is also atypically expressed on pDCs from SSc patients, driving IFN induction (Kioon et al, 2018). TLR9 expression is increased on human SSc skin biopsies and drives TGF-b-dependent fibroblast activation (Fang et al, 2016), while TLR7 expression is upregulated in SSc peripheral blood mononuclear cells (PBMCs) and correlates with late-stage disease (Vre ca et al, 2018). In patients with dermatomyositis and polymyositis, upregulation of TLR3, TLR7, and TLR9 contributes to the induction of type I IFNs and autoimmune responses (Kim et al, 2010;Tournadre et al, 2010).…”

Toll-like receptors in mediating pathogenesis in systemic sclerosis

“…In-vitro treatment of normal cutaneous fibroblasts with the TLR-9 ligand unmethylated CpG induced a profibrotic profile, involving autocrine TGF-β production. A recent paper detected a significant up-regulation of TLR7 gene expression in PBMCs of a group of SSc patients compared to a non-SSc group using the reverse transcriptionquantitative polymerase chain reaction (RT-qPCR) technique [41]. It is worth mention that several genes linked to autoimmunity are located on the X chromosome.…”

“…It is worth mention that several genes linked to autoimmunity are located on the X chromosome. Remarkably, among these genes are TLR-8 and TLR-7 [41]. Many autoimmune disorders, SSc included, are markedly sex-biased and studies support a gene-dose effect of the X chromosome loci in systemic lupus erythematosus (SLE) predisposition and, perhaps, establishment [42].…”