University of California (UCD) line 200 (L200) chickens develop an inherited auto-immune fibrotic disease associated with autoantibodies and features similar to human progressive systemic sclerosis. Early in life L200 chickens develop T cell infiltrates in the skin, followed by severe dermal fibrosis and vascular occlusions. In birds that survive this initial episode of disease, a chronic course follows with the development of fibrosis, mononuclear cell infiltration and vascular alterations in the esophagus, small intestine, lungs, kidneys, heart, and testes. We have, during the current period of the grant, demonstrated that L200 chickens have a major developmental defect in type I thymic epithelium recognized by our monoclonal antibody MUI 70. The antigen recognized by MUI 70 is absent in L200 type I thymic epithelium but is found in all other normal chicken strains examined. Furthermore, MUI 70 is also expressed in the epidermis of normal chickens but is absent in L200 animals. We now propose to investigate in detail the relationship between the presence (or absence) of MUI 70+ stromal element and T cell differentiation, by its expression during T cell development in ovo in embryonic thymic organ cultures, and by doing embryonic thymic transplants. We also postulate that MUI 70, a conserved antigen, recognizes a cytoskeletal component of a distinct subset of epithelial cells. Its generalized function may be in restricted cell-cell interactions or adhesions and in the thymus, in particular, it may mediate one of the earliest interactions between incoming precursors (located near type I epithelium) and thymic stroma. To explain the dermal pathology observed in L200 birds, we have demonstrated that fibroblast cultures derived from fibrotic skin of diseased L200 chickens display an activated phenotype producing elevated quantities of collagen, non-collagenous protein, and glycosaminoglycans (GAG). Moreover, supernatants constitutively generated by culturing mononuclear cells isolated from fibrotic skin lesions of L200 chickens contain a 24 kD cytokine that stimulates fibroblast collagen synthesis and a 28 kD cytokine that stimulates fibroblast GAG synthesis. We will characterize these cytokines and concurrently study the alterations in L200 cultured vascular smooth muscle cells and vascular endothelial cells. Hence, we propose that L200 chickens have a developmental defect in type I thymic epithelium which induces abnormal thymocyte differentiation and maturation, thereby predisposing them to autoimmune disease with resultant fibrotic and vascular pathology in the dermis and other organs.
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