• systemic sclerosis
• TGFβ1
• polymorphisms

In this issue, Crilly et al demonstrate polymorphisms of transforming growth factor β1 (TGFβ1) in subjects with systemic sclerosis (SSc) which might have functional significance.¹ Much remains unknown about the pathogenesis of SSc, the generalised form of scleroderma, which comprises prominent autoimmune, vascular/microvascular, and ultimately fibrotic features. This combination substantially reduces both quality of life and life expectancy, depending on the site and a highly variable rate of involvement. Underlying the unregulated deposition of extracellular matrix (ECM) in skin, lung, heart, gut, and kidney, there is a fibroproliferative intimal vascular lesion which extends into the microcirculation, seems to be progressive, and remains poorly understood, despite attempts to isolate abnormalities of platelets, and of endothelial, immune, and vascular wall smooth muscle cells, among others (for example, pericytes and myofibroblasts).

ECM depositions by immune/inflammatory reactions have in common the expression of profibrogenic cytokines, including platelet derived growth factor (PDGF), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), and perhaps the master profibrogenic cytokine, TGFβ, a ligand-receptor system with many family members, which is highly conserved among vertebrates. Biologically, each of three ligands is expressed in inactive form and …