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Expression in Transgenic Mice of Dominant Interfering Fas Mutations: A Model for Human Autoimmune Lymphoproliferative Syndrome

Authors :
Amy Chen
Jennifer M. Puck
David E. Kleiner
Jan Erikson
Venktesh R. Ramnath
Karen L. Simon-Stoos
Youngnim Choi
Ashlyn Eaton
Source :
Clinical Immunology. 93:34-45
Publication Year :
1999
Publisher :
Elsevier BV, 1999.

Abstract

Most humans with autoimmune lymphoproliferative syndrome (ALPS) carry heterozygous dominant mutations in one allele of the gene encoding Fas/APO-1/CD95. ALPS patients, like Fas-deficient MRL lpr/lpr mice, have lymphoproliferation, autoimmunity, increased CD4(-)/CD8(-) T lymphocytes, and apoptosis defects. Consistent with the phenotypic variability of lpr/lpr mice of different background strains, human genetic studies indicate that a Fas mutation is insufficient to induce ALPS in all mutation carriers. To investigate the dominant function of human Fas mutations and the additional genetic factor(s) involved in the development of ALPS, we generated transgenic mice expressing, in addition to endogenous Fas, mouse Fas molecules bearing mutations in the intracellular death domain corresponding to mutations identified in ALPS patients. Transgenic mice developed mild features of ALPS, including hepatosplenomegaly, elevated proportions of lymphocytes in spleen and lymph 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 with MRL and MRL lpr/lpr mice. While expression of transgenic mutant Fas contributed mainly to hepatosplenomegaly and accumulation of lymphocytes, MRL background genes played a major role in the production of autoantibodies and elevated serum immunoglobulin levels. Moreover, compared to FVB/N (+/+) mice, a substantial Fas-specific apoptotic defect was found in MRL (+/+) mice, suggesting a mechanism for the known tendency of this strain to develop autoimmunity.

Details

ISSN :
15216616
Volume :
93
Database :
OpenAIRE
Journal :
Clinical Immunology
Accession number :
edsair.doi.dedup.....30f31310c73b1fb7521425e5731a12a4
Full Text :
https://doi.org/10.1006/clim.1999.4767