T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Abstract

Objective. Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc.Methods. Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D 2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization.Results. Patients with SSc exhibited lower CCR5/ CRTH2 T cell ratios than those exhibited by control subjects (P < 0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P < 0.0001), particularly in patients with active ILD (P < 0.0001) compared with those with stable lung function. Lower CCR5/ CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P < 0.0001). In patients with an estimated right ventricular systolic pressure >35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P ‫؍‬ 0.009), while in those with right ventricular systolic pressure <35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P < 0.0001), as observed for ILD.

Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis

“…Likewise, several studies have shown that T cells from affected sites such as skin21 22 and bronchoalveolar lavage fluid23 24 from patients with SSc have higher Th2-type cytokines. More recently, the existence of a skewed Th2 response in SSc was further substantiated by a study from Boin et al , in which specific T-cell surface markers were analysed displaying a Th2 phenotype 25. The pathways that underlie such a Th2 skewing have thus far not been identified.…”

Treatment of rapidly progressive systemic sclerosis: current and futures perspectives

“…Regardless of the initiating event or trigger, the extensive innate and cellular immune abnormalities in SSc [3–5,62–67] result in exaggerated Th2 response driving the increased expression and production of numerous and potent profibrotic cytokines and growth factors. Besides cellular immunity alterations, abnormal humoral immunity leading to the production of numerous autoantibodies is a nearly universal manifestation of SSc.…”

Vγ9+ γδ T cells in systemic sclerosis patients are numerically and functionally preserved and induce fibroblast apoptosis

“…Activated fibroblasts differentiating to myofibroblasts secrete excessive amounts of hyaluronic acid, fibronectin, proteoglycans and interstitial collagens, that remodel and destroy normal tissue architecture (Wynn 2007). In particular, fibroblast collagen production is enhanced by T helper type 2 lymphocytes (Th2) cytokines, including interleukin (IL)-4 and IL-13 and inhibited by cytokines produced by Th1 cells (e.g., interferon (IFN)-g and tumor necrosis factor (TNF)-a) (Aliprantis et al 2007;Bhogal et al 2005;Lafyatis 2006;Boin et al 2008). gd T cells may also influence the fibrotic process after exposure to chronic inflammatory stimuli, since it has recently been found that: (1) mice lacking the gd T cell subset (T cell receptor (TCR) d À/À ) have enhanced bleomycin-induced lung fibrosis, (2) gd T cell depletion augments pulmonary fibrosis in C57BL/6 mice repetitively exposed to B. subtilis and (3) adriamycin-induced interstitial fibrosis of the kidney is exacerbated in the absence of gd T cells (Braun et al 2008;Simonian et al 2006;Wu et al 2007).…”