Cellular interactions in the lpr and gld models of systemic autoimmunity.
The lpr and gld murine models have been important contributors to our understanding of systemic autoimmune diseases. Mice homozygous for either of these autosomal recessive genes develop a phenotypically identical disease characterized by the accumulation of CD4-CD8- T-cells and the production of a wide spectrum of autoantibodies. The lpr (lymphoproliferation) mutation encodes a defective Fas apoptosis receptor gene. More recently, gld (generalized lymphadenopathy) has been shown to be a point mutation in the Fas ligand gene. Despite the molecular characterization of these mutations, the exact mechanism by which tolerance is lost is still unknown, although in vivo cell transfer studies have provided clues. Chimera studies, in which normal and lpr bone marrow were co-infused into lpr mice, demonstrated not only that the normal Fas receptor is functionally expressed in both T- and B-cells, but that the Fas mutation is required in both for full expression of the lpr phenotype. Conversely, in analogous experiments with gld mice, co-infusion of normal and gld bone marrow largely prevented the development of autoantibodies. Sporadic autoantibody titers were seen in some mice, but were derived from both donors. The effects on T-cells were subtly different: The CD4-CD8- T-cells were also greatly reduced in number, but all were of gld origin. These data indicate that the gld defect is extrinsic to B-cells but only partially extrinsic to T-cells, and suggest that Fas ligand in T-cells may have an autocrine and paracrine function.
Sobel
E S
ES
Department of Medicine, University of Florida, Gainesville 32610, USA.
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D015870:Gene Expression; D007108:Immune Tolerance; D008214:Lymphocytes / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor