Mice deficient in Fas antigen as a consequence of inheriting the lpr mutation fail to initiate apoptosis and eliminate autoreactive lymphocytes. The interaction of lpr with the MRL background genes causes autoimmune skin destruction. By comparison, lpr on non-autoimmune backgrounds does not induce skin injury. Therefore the absence of Fas accelerates the tempo and severity of skin disease in the MRL background. Macrophage growth factors and beta chemokines are notable in tissues undergoing autoimmune injury. We have established that macrophage growth factors(CSF-l and GM-CSF) can incite autoimmune kidney destruction in strains with lpr using an ex-vivo gene transfer approach. This gene transfer system is ideally suited to determine which molecules target the skin for autoimmune destruction. The skin lesions in MRL-lpr mice consist of infiltrating macrophage and T cells. Since macrophage growth factors and beta chemokines(MCP-1 and RANTES) attract and foster the accumulation of macrophage and T cells, we propose to test the hypothesis that macrophage growth factors and beta chemokines incite autoimmune skin destruction in strains with the lpr mutation. Therefore, the aims are to determine whether macrophage growth factors and beta chemokines incite skin destruction. We will examine whether using an ex-vivo gene transfer strategy to introduce these molecules into the skin of MRL-lpr mice initiates progressive skin destruction. We will investigate the expression of macrophage growth factors and beta chemokines in MRL-lpr spontaneous skin disease. We pian to establish the requirement for the lpr mutation by examining MRL-lpr and C3H-lpr strains and the congenic counterparts. Finally, we will determine whether macrophage growth factors and beta chemokines are required for skin disease in MRL-lpr mice by creating MRL- lpr strains deficient in each of these molecules. We will evaluate the impact on the skin disease in each deficient strain. The consequence of eliminating expression of each macrophage growth factor and beta chemokine on the skin lesions will be compared with the kidney disease to determine the contribution of systemic and local factors. By identifying the molecules that target the skin for autoimmune tissue injury, we will be able to design novel therapeutic approaches to abort tissue destruction.
Showing the most recent 10 out of 113 publications
