Scleroderma is a major connective tissue disease characterized by fibrosis of the affected organs. Patients with either progressive systemic sclerosis or CREST syndrome develop autoantibodies to intracellular antigens and show altered cellular immunity to Collagen I and II. One hypothesis is that scleroderma is an autoimmune disease. A variety of immunological abnormalities found in scleroderma supports the theory that there may be a fundamental defect in the immune system. Experimental models of human disease, particularly naturally occurring ones, related to a well defined genetic defect are important research tools for the understanding of the pathogenesis of disease. Tight skin mice develop a spontaneous cutaneous hyperplasia and lung emphysema syndrome which exhibit the histopathological picture of human scleroderma. Furthermore, we recently showed that tight skin mice produce anti topoisomerase antibodies, autoantibodies found in scleroderma but not in other human autoimmune disease. One long term goal is to elucidate the cellular and molecular mechanisms involved in the activation of self reactive immune response to study its eventual role in the progression of this collagen disorder in both the experimental model and human disease. Parallel studies aimed to characterize the specificities of autoantibodies produced by hybridomas, the V gene encoding them and the cellular origin of antibodies will allow us to determine the role of genetic factors in the disease. These studies are favored by the fact that the occurrence of the disease in tight skin mice is due to a single mutation located on chromosome 2.
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