Etiology and pathogenesis of slercodrema: Effector mechanisms,target cells and molecular basis for fibrosis in an animal model with spontaneous progressive systemic sclerosis

Systemic sclerosis (SSc - scleroderma) belongs to the connective tissue diseases. It is a chronic, inflammatory- fibrotic disease that generally starts in the skin but later spreads to internal organs. In the first acute stage, edema and mononuclear cell perivascular infiltrations are found in the skin. The subsequent subacute stage is characterized by a proliferation of fibroblasts and an increase of extracellular matrix proteins, mainly collagen, in the neighborhood of the infiltrates. In the chronic final stage, these mononuclear infiltrates disappear and the alterations in the skin are characterized by an excessive increase of collagen with a walling in of appendages and severely impaired function. Vascular occlusion, especially in hands and feet, are a hallmark of scleroderma, leading to so called Raynauds syndrome that is associated with cold hypersensitivity, pain and even the development of necrotic lesions. Early in the course of SSc, lesions of the endothelium entailing denudation of the subendothelial space and the development of thrombosis occur. Histological and functional changes of skin and internal organs, including severe fibrosis. The etiology of SSc is so far unknown, but there is general agreement that it is likely to be an autoimmune disease. The involved antigen(s) has (have), however, not yet been identified. Neither is clear whether the cellular and humoral autoimmune reactions found in patients with SSc are of primary or secondary nature. Since SSc is a chronic disease, clinicians are generally not, or only rarely, confronted with the very earliest stage that is, therefore, not accessible to immunopathological studies. During the past years, we were able to show that the University of California at Davis 200 (UCD 200) line of chickens represents an excellent model for human SSc. Chickens of this line spontaneously develop all the symptoms of SSc on a hereditary basis and in a time-lapse fashion. This model is, therefore, optimally suited for investigations on the pathogenesis of SSc and for future development of new diagnostic and therapeutic procedures. Based on our data obtained in previous studies, the present project is aimed at answering the following questions: (1) What are the genetically determined humoral and/or cellular effector mechanisms? (2) Which mechanisms induce the early programmed cell death (apoptiosis) of endothelial cells that we found in both UCD 200 chickens and human SSc? (3) What are the molecular mechanisms responsible for the altered synthesis and regulation of extracellular matrix protein, especially collagen?