Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95

Objective. Apoptosis of endothelial cells is a key event in the pathogenesi s of systemic sclerosis (SSc), The aim of the present study was to analyze in vitro the mechanism causing endothelial cell apoptosis in SSc, Methods. Human dermal microvascular endothelial cells (HDMEC) or human umbi lical vein endothelial cells (HUVEC) were cultured with native or heat-inac tivated serum from SSc patients or controls with or without interleukin-2-a ctivated natural killer (NK) cells or peripheral blood mononuclear cells. S Sc and control sera were tested for the presence or absence, respectively, of anti-endothelial cell antibodies (AECA) by indirect immunofluorescence, Apoptosis was detected by the TUNEL technique. Results. Native sera alone had no effect. Apoptosis induction was observed on HDMEC, but not on HUVEC, in the presence of AECA-positive SSc sera and a ctivated NK cells, and could be inhibited by an anti-Fas ligand antibody. I nhibition of the perforin/granzyme pathway with concanamycin A had no effec t on apoptosis induction in this in vitro model. Immunofluorescence analysi s of cryosections from SSc skin showed Fas (CD95) expression by endothelial cells, supporting the in vitro findings. Conclusion, The results suggest that endothelial cell apoptosis in SSc is i nduced by antibody-dependent cell-mediated cytotoxicity via the Fas pathway . These data not only provide insight into the pathogenesis of SSc, but als o may open new ways to rational therapy for this disease.