The cause of systemic lupus erythematosus (SLE) remains unknown. Current evidence suggests that SLE develops when a person with the appropriate genetic makeup is exposed to certain environmental agents, but how environmental agents interact with the immune system to produce lupus is not clear. Some drugs, like procainamide (Pca), can cause a lupus-like disease, as can CD4+ T cells in the chronic graft-versus-host disease model. However, how drugs and CD4+ T cells produce lupus-like diseases is again uncertain. Determining the mechanisms is important, because the results may pertain to the pathogenesis of SLE. Our group has identified one mechanism by which some drugs can interact with CD4+ T cells to cause a lupus-like disease. We reported that 5- azacytidine (5-azaC) and Pca inhibit DNA methylation, modify gene expression and induce autoreactivity in human and murine CD4+ T cells. Adoptive transfer of 5-azaC orPca treated murine T cells into unirradiated syngeneic recipients induces an immune complex glomerulonephritis, lupus band test and anti-DNA and anti-histone antibodies. These studies demonstrate that gene expression in CD4+ T cells can be modified by some """"""""environmental"""""""" agents, and the modified T cells can induce a lupuslike disease. This represents a new concept in the pathogenesis of autoimmunity. Similar changes in T cell DNA methylation, gene expression and autoreactivity were found in patients with active lupus, implying that similar mechanisms are involved. However, the mechanisms by which these DNA methylation inhibitors modify T cells to induce autoreactivity, and by which the autoreactive cells induce autoimmunity, are unknown. This new murine model provides a unique opportunity to examine these questions, and to apply the results to patients with lupus. The studies described in this grant will: 1. Further characterize the disease induced by 5-azaC and Pca treated CD4+ T cells, 2. Characterize T cell effector mechanisms important to the development of autoimmunity, 3. Test whether T cells treated with other agents associated with triggering lupus can also induce autoimmunity, 4. Determine if altered expression of specific cell surface gene products contributes to autoreactivity and disease development, and 5. Test whether the model is relevant to human disease, by searching for similar cells in patients with active lupus. These experiments will characterize mechanisms by which some environmental agents can induce a lupus-like disease, and will provide new insights into the pathogenesis and treatment of idiopathic lupus.
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