Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis

Abstract

Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

“…Treating SSc CD4+ T cells with a DNMT inhibitor not only reduced DNA methylation levels, but also increased FOXP3 expression and number of Tregs. These results contradicted the recent study reported by Almanzar et al, where they showed increased FOXP3 expression and the number of Tregs in SSc patients, with no significant change in DNA methylation in FOXP3 regulatory regions in peripheral blood mononuclear cells (PBMCs) [84]. They reported that Th17-specific transcription factors, RORC1 and 2, were hypermethylated in PBMCs.…”

IL-17 and Th17 cells in systemic sclerosis: a comprehensive review

“…Th17 alongside with Th22 have pulmonary and cutaneous homing [23]. Larger Ssc group flow cytometry studies (135 Ssc patients) confirmed these findings [24], but also described in late Ssc patients an increase in Th2 cells in addition to Th17. As for circulating T reg cells there were no differences from healthy controls.…”

The role of T lymphocytes in the pathogenesis of systemic sclerosis and new therapeutic perspectives

“…For example, in the presence of IL-6, Tregs is converted into Th17-secreting IL-17 cells, which further releases pro-inflammatory and fibrosis-increasing mediators. This passage of Tregs in Th17 under the influence of optimal environmental conditions may explain the reduction of Tregs lymphocytes observed in systemic sclerosis [28][29][30].…”

“…Dla przykładu, w obecności IL-6 dochodzi do konwersji Tregs w komórki Th17 -wydzielające IL-17, co powoduje dalsze uwalnianie prozapalnych oraz nasilających włóknienie mediatorów. To przejście Tregs w Th17 pod wpływem optymalnych warunków środowiska może tłumaczyć obserwowaną w twardzinie układowej redukcję limfocytów Tregs [28,29,30].…”