Supported by the discovery of interferon (IFN) α, tumor necrosis factor (TNF) α, TLRs, transforming growth factor (TGF) β, platelet derived growth factor (PDGF), genes signatures in SSc, we hypothesized that both Th1 and Th2 activation signals could derive from different damaged tissues, determining the development of circulating mixed M1/M2 cells. Here, TNF is linked to systemic sclerosis.