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

Background: Systemic 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 Findings: Patients 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, TGFb and IFNc using flow cytometry. Levels of IL-17, IL-6, IL-1a 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, IFNc and TGFb 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-1a were increased in all or subsets of SSc patients. Conclusion and Significance: The combination of IL-17, IFNc and TGFb 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. Citation: Radstake TRDJ, van Bon L, Broen J, Hussiani A, Hesselstrand R, et al. (2009) The Pronounced Th17 Profile in Systemic Sclerosis (SSc) Together with Intracellular Expression of TGFb and IFNc Distinguishes SSc Phenotypes. PLoS ONE 4(6): e5903. doi:10.1371/journal.pone.0005903 Editor: Derya Unutmaz, New York University School of Medicine, United States of America Received March 13, 2009; Accepted May 13, 2009; Published June 17, 2009 Copyright: 2009 Radstake et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The Post-doctoral program (T.R.) was funded by the Niels-Stensen Foundation from The Netherlands. The work presented here was partly funded by the VIDI laureate (T.R) from the Dutch Organization of Research (NWO). Support was also provided by grants to R.L. from the National Institutes of Health, (NIAMS U01AR055063) and an unrestricted grant from the American Society for Scleroderma Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work.