Vasculopathy, activation of the cellular immune system, and tissue fibrosis are hallmarks in the pathogenesis of systemic sclerosis (SSc). Variable expression of each of the 3 key pathologic features may reflect the heterogeneity of the disease. Although certain genetic polymorphisms can increase susceptibility to SSc, the etiology of the disease remains unknown (1, 2). Vascular injury and endothelial cell apoptosis are among the earliest events in the pathogenesis of SSc (3). Histopathologic evidence of vascular disease often precedes fibrosis, and patients with SSc exhibit early clinical signs of vasculopathy. Vascular damage leads to a progressive loss of capillaries, because repair of existing vessels and formation of new vessels are severely disturbed (4–7). Early in the disease, nailfold capillaroscopy demonstrates specific changes, with capillary dilatation and loss of capillaries followed by vascular malformations, including sac-like, giant and bushy capillaries, which might reflect futile attempts to form new blood vessels (8). Apart from small-vessel vasculopathy, remodeling of medium-sized vessels such as the pulmonary and peripheral arteries frequently occurs in patients with SSc but may result from other disease mechanisms (9). In patients with recent disease onset, perivascular infiltrates of T lymphocytes and B lymphocytes, macrophages, and mast cells occur in dermal lesions (10–14). Perivascular leukocytes release profibrotic mediators and stimulate fibroblasts to secrete extracellular matrix (ECM) proteins. In this context, many studies show an imbalanced cytokine expression profile with preferential secretion of Th2 cell cytokines, including the profibrotic interleukin-4 (IL-4) and IL-13 (15). Moreover, B cell–driven autoimmunity may contribute to disease progression. Autoantibodies against endothelial cells can induce endothelial cell apoptosis, while stimulatory autoantibodies of the platelet-derived growth factor receptor (PDGFR) may increase ECM synthesis in fibroblasts (16, 17).

Fibrosis arises from extracellular accumulation of ECM components. Fibroblasts, which are key effectors of fibrogenesis, produce and release ECM proteins such as collagens (18, 19). Explanted from lesional tissue, SSc fibroblasts display an abnormal activated phenotype that is signal independent and persists for several passages in vitro (18). Incubation of normal fibroblasts with transforming growth factor ß (TGFß) in vitro induces many characteristics specific for SSc fibroblasts. Thus, the