**2. Pathogenesis**

The pathogenesis of SSc is not fully known. Disease-triggering agents are some organic solvents (e.g., silica, vinyl chloride, trichloroethylene, epoxy resins, benzene, carbon tetrachloride), some viral diseases (HSV5, CMV), some medications (bleomycin, pentazocine), and radiotherapy [8].

Basic pathogenicities of the disease are microvascular function disorder (vasculopathy) and immune activation, and the final effect of these events is progressive tissue fibrosis with activation of fibroblasts [9].

Vascular disease is observed earliest in SSc pathogenesis. The disease plays an important role in the occurrence of pulmonary artery hypertension, Raynaud's phenomenon, renal damage, and digital ulcers (DU) [10–13]. Raynaud's phenomenon, a typical clinical characteristic of SSc, is a finding characterized by persistent vasospasm and increased adhesion molecules following ischemia and reperfusion attacks [14]. Increased adhesion molecules trigger platelets and neutrophils that bind to endothelial cells and produce superoxide radicals responsible for endothelial cell damage [15]. In addition, an imbalance between vasoconstrictor agents such as endothelin-1 (ET-1) and vasodilating agents such as nitric oxide was observed in SSc, which plays a role in the change of vascular permeability [16]. Increased ET-1 expression plays a role in vascular fibrosis, inflammation, and increased smooth muscle cell proliferation [12]. An impaired cross talk between endothelial cells and perivascular cells may induce an abnormal expression of endothelial growth factor (VEGF), TGF-β, and platelet-derived growth factor (PDGF) in SSc. This may lead to a disruption of peripheral vascularization, which results in fibrosis of the skin and internal organs [17].

It has been determined that Th2 cytokines such as IL 4, IL 5, and IL 13 are oversecreted in SSc patients. It increases IL 4 collagen synthesis and TGF-β production. With IL 13, however, fibroblast activity and TGF-β stimulation are carried out [18]. Also, B-cells produce antibodies and carry out direct fibroblast stimulation via IL 6 [18].
