Mice expressing either of the recessive autosomal mutations, lpr or gld, develop autoimmune syndromes associated with massive lymphoid hyperplasia and excessive autoantibody production. Since the range of autoantibody specificities produced by these mice is similar to that of patients afflicted with SLE and other systemic autoimmune diseases, they have been considered a useful model for human disease. The lpr and gld mutations have recently been mapped to the genes that encode the cell surface molecules APO-1/Fas and Fas-ligand, respectively. Fas/Fas-ligand interactions have been shown to be intimately involved in the apoptotic pathways associated with calcium-independent T cell-mediated cytotoxicity and peripheral T cell tolerance mechanisms associated with activation induced cell death. Activated B cells also express the Fas antigen and studies from this lab and others involving chimeric mice have shown that in lpr/lpr B cells are inherently different from normal B cells, however the actual role of Fas/Fas-ligand interactions in conventional B cells responses is unexplored. The current proposal will address the role of Fas/Fas-ligand in the regulation of conventional B cell immunity and attempt to determine why normal B cell survival and function are suppressed in an [lpr + wildtype] chimeric environment. These issues will be addressed through the following specific aims: (1) Investigate how different in vitro activation and cytokine signals regulate Fas and Fas- ligand expression in T and/or B lymphocyte subpopulations and identify the cells and conditions that are responsible for in vivo Fas-ligand expression; (2) Determine the functional consequences of constitutive Fas expression on B cell survival and function in lpr, gld and +/+ host environments by producing and analyzing transgenic mice that inherit a B lineage restricted Fas transgene; (3) Assess the functional properties of lymphocytes from mice incapable of effectively expressing both Fas and Fas-ligand, i.e. double mutant lpr/lpr gld/gld ice; and (4) Compare the germinal center response of normal, lpr, and lpr beta2-microglobulin KO mice with regard to magnitude, kinetics, antibody diversification, and affinity maturation. The better understanding of the etiology of autoimmunity gained from these studies should be directly applicable to the treatment of human disease.
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