Furthermore, Arason outlined a deficiency of complement-dependent prevention of immune precipitation in SSc and Sprott et al. documented presence of the C5b-9 complex and C5a receptor in microvessels of SSc skin sections both in early and in late phases of the disease. It is conceivable that activation of complement system in SSc might be due to immune complexes, but inadequate protection of the EC surface might also be involved. In fact, ECs located at the interface between blood and tissues are natural targets of complement attack. The classical functions of complement, such as opsonization, recruitment of inflammatory cells, target cell lysis, immune complex clearance, and its capability to influence many other pathways, such as coagulation cascade and angiogenesis, seem to be pivotal for the integrity of ECs. In normal conditions, complement attack is tightly regulated by fluid-phase and surface-bound regulatory proteins which allow adequate immune surveillance while CT99021 GSK-3 inhibitor ensuring protection of host cells. In different vascular diseases, overtly activated or poorly controlled complement activation not only promotes EC damage and apoptosis, but also enhances the expression of vascular cell adhesion molecules and amplifies the local immune response. Factor H is the main fluid-phase regulator of the alternative complement pathway. It acts on C3, the central component of the complement cascade by accelerating decay of C3 convertase and acting as a cofactor of factor I in the inactivation of C3b. This plasma regulator also contributes to human tissue protection allowing complement activation only to foreign targets or altered self cells. In our previous study, we documented high FH levels in sera of SSc and Sclerodermatous Graft Versus Host Disease patients, but only in SSc subjects we found a defective capacity of FH to protect cellular surface from complement mediated damage in in vitro experiments. On human ECs, other complement regulators participate in cell protection from activation of both AP and classical complement pathway. The group of membrane-bound complement regulators include the membrane cofactor protein, which is a cofactor of FI in the proteolytic inactivation of C3b and C4b, and the decay accelerating factor, which accelerates the breakdown of C3- and C5-convertases. Recently, Venneker et al. demonstrated an impaired expression of MCP and DAF in endothelium of the lesional and non-lesional skin of SSc patients and in the skin of patients with morphea, in comparison to healthy controls and subjects affected by other autoimmune diseases, suggesting that a defective endothelial protection might be mediated by reduced expression of the complement regulatory proteins. Since the mechanisms involved in SSc pathogenesis are still under investigation, we focused our attention on local complement activation and regulation, using skin biopsies as an observational window of the EC damage related to SSc. Here, we propose the endothelium-bound membrane attack complex of complement as a promising marker of active vascular damage in SSc.