However, it is well established that tissue fibrosis (promoted by aberrant TGF-β signaling) and immune dysregulation are key components involved in the systemic effects of the disease in later phases (i.e. presence of proliferative vasculopathy with intimal proliferation in peripheral, pulmonary, coronary, and renal arteries in the absence of inflammation is a hallmark feature of SSc). This evidence concerns the gene TGFB1 and systemic sclerosis.