The Pronounced Th17 Profile in Systemic Sclerosis (SSc) Together with Intracellular Expression of TGFβ and IFNγ Distinguishes SSc Phenotypes

Abstract

BackgroundSystemic sclerosis (SSc) is an autoimmune disease where controversy on Th1/Th2 balance dominates. We investigated whether the recently discovered Th17 pattern was present in SSc.Methodology and Principal FindingsPatients were subdivided as having limited cutaneous SSc (lcSSc, n = 12) or diffuse cutaneous SSc (dcSSc, n = 24). A further arbitrary subdivision was made between early dcSSc (n = 11) and late dcSSc (n = 13) based upon the duration of disease. As a comparator group 14 healthy controls were studied. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, CD45Ro, CD45Ra, IL-23, GITR, CD69 and intracellular expression of IL-17, TGFβ and IFNγ using flow cytometry. Levels of IL-17, IL-6, IL-1α and IL-23 were measured using Bioplex assays. SSc patients had more and more activated CD4+ cells. In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well. In contrast, IFNγ and TGFβ were selectively up regulated in SSc subsets. In line with these observation, circulating levels of IL-17 inducing cytokines IL-6, IL-23 and IL-1α were increased in all or subsets of SSc patients.Conclusion and SignificanceThe combination of IL-17, IFNγ and TGFβ levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc. Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc.

Comparison of Serum IL-23 and IL-17 Levels in Patients with Systemic Sclerosis and Healthy Subjects

“…In the study by Komura et al, involving 63 SSc, 15 SLE patients and 31 healthy controls, IL-23 levels were found to be significantly higher in SSc patients compared to SLE patients and healthy controls [13]. In contrast to our study, in a study by Radstake et al, along with increased IL-17 levels in the patient group, had also found IL-23 level and IL-23 receptor expression on CD4+ cells to be higher comparing to the control group was shown in a study by Radstake et al, [14]. In contrast, in a study by Gourh et al on 444 SSc and 216 healthy controls, IL17 and IL23 levels were found to be lower while IL-6, IL-13 ve TNF alpha levels were higher in the SSc group [15].…”

“…Komura K et al, found higher IL-23 levels in SSc patients [13]. In another study by Radstake TR et al, found both higher IL-17 and IL-23 levels in SSc patients [14]. However, IL-17 and IL-23 levels were determined higher in healthy controls compared to SSc patients in some studies [15].…”

Biological Therapy in Systemic Sclerosis

“…Furthermore, IL-17 overproduction significantly correlated with an early disease stage and an enhanced proliferation of fibroblasts and IL-1 production in SSc patients [39]. Altered IL-17 expression in SSc has also been reported elsewhere, with studies documenting a decrease in regulatory T-cell (Treg) levels, as well as a functional deficiency, accompanied by an increase in CD4+CD25+FoxP3+ T-cells and IL-17 levels, potentially causing an immune imbalance between Treg and Th17 cells [40,41].…”

Cytokines in Systemic Sclerosis: Focus on IL-17

“…More recently, Radstake et al described increase levels of activated CD4 + cells in SSc patients compared to healthy controls and CD4 + lymphocytes (activated or not) highly expressed the IL23R, which was associated with a higher IL-17 expression. They also observed increased levels of IL-6, IL-23 and IL-1 cytokines in SSc patients, which all induced IL-17 production (Radstake et al 2009). Furthermore, IL-21 cytokine, which is mainly produced by Th17 and NK cells, potentiates Th17 inflammatory response via stimulation of IL-23 receptor expression and Treg inhibition.…”