Expression in transgenic mice of dominant interfering Fas mutations: A model for human autoimmune lymphoproliferative syndrome

Most humans with autoimmune lymphoproliferative syndrome (ALPS) carry heter ozygous dominant mutations in one allele of the gene encoding Fas/APO-1/ CD 95. ALPS patients, like Fas-deficient MRL lpr/lpr mice, have lymphoprolifer ation, autoimmunity, increased CD4(-)/CD8(-) T lymphocytes, and apoptosis d efects. Consistent with the phenotypic variability of lpr/lpr mice of diffe rent background strains, human genetic studies indicate that a Fas mutation is insufficient to induce ALPS in all mutation carriers, To investigate th e dominant function of human Fas mutations and the additional genetic facto r(s) involved in the development of ALPS, we generated transgenic mice expr essing, in addition to endogenous Fas, mouse Fas molecules bearing mutation s in the intracellular death domain corresponding to mutations identified i n ALPS patients. Transgenic mice developed mild features of ALPS, including hepatosplenomegaly, elevated proportions of lymphocytes in spleen and lymp h nodes, apoptotic defects, and hepatic lymphocytic infiltrates. Therefore defective murine Fas proteins act in a dominant manner to impair apoptosis of activated lymphocytes and disrupt lymphocyte homeostasis, The influence of genetic background on phenotype was studied by comparing transgenic mice on FVB/N and (FVB/N x MRL) backgrounds with syngenetic control mice and wi th MRL and MRL lpr/lpr mice. While expression of transgenic mutant Fas cont ributed mainly to hepatosplenomegaly and accumulation of lymphocytes, MRL b ackground genes played a major role in the production of autoantibodies and elevated serum immunoglobulin levels. Moreover, compared to FVB/N (+/+) mi ce, a substantial Fas-specific apoptotic defect was found in MRL (+/+) mice , suggesting a mechanism for the known tendency of this strain to develop a utoimmunity. (C) 1999 Academic Press.