The Vascular Perspective of Systemic Sclerosis: Of Chickens, Mice and Men

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Abstract
Systemic sclerosis (SSc), or scleroderma, is an autoimmune connective tissue disease characterized by structural and functional vascular abnormalities, perivascular mononuclear cell infiltration, and increased deposition of extracellular matrix in skin and internal organs. The initial stages of SSc are generally not accessible for analysis in man, therefore, the availability of appropriate animal models is of great importance for the elucidation of the pathogenesis of this disease. UCD–200 chickens show the entire clinical, histopathological and serological spectrum of SSc, whereas tight skin (Tsk)1/+ and Tsk2/+ mice, other animal models of scleroderma, lack the vascular injury. A parallel comparative study of skin biopsies of UCD–200 chickens and human SSc patients revealed that endothelial cell apoptosis, induced by anti–endothelial cell antibody (AECA)– dependent cellular cytotoxicity, is a primary event in the pathogenesis of SSc. This review focuses on recently established data on endothelial cell injury in animals with spontaneous disease and humans, AECA, adhesion molecules and cytokine profiles that support a vascular pathogenesis in scleroderma.