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Expression in Transgenic Mice of Dominant Interfering Fas Mutations: A Model for Human Autoimmune Lymphoproliferative Syndrome
- 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.
- Subjects :
- Genetically modified mouse
Mice, Inbred MRL lpr
Fas Ligand Protein
T-Lymphocytes
Transgene
Immunology
Apoptosis
Mice, Transgenic
Biology
urologic and male genital diseases
medicine.disease_cause
Autoimmune Diseases
Autoimmunity
Mice
immune system diseases
Lymphocyte homeostasis
medicine
Animals
Humans
Immunology and Allergy
skin and connective tissue diseases
Lymphatic Diseases
Genes, Dominant
Mutation
Membrane Glycoproteins
Liver Diseases
Fas receptor
medicine.disease
Lymphoproliferative Disorders
Phenotype
Liver
Antibodies, Antinuclear
Autoimmune lymphoproliferative syndrome
Antigens, Surface
Splenomegaly
Lymph Nodes
Spleen
Subjects
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