Significant role for Fas in the pathogenesis of autoimmune diabetes.
Programmed cell death represents an important pathogenic mechanism in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T cell-dependent autoimmune disease resulting in selective destruction of the beta cells of the islets of Langerhans. beta cell apoptosis has been associated with IDDM onset in both animal models and newly diagnosed diabetic patients. Several apoptotic pathways have been implicated in beta cell destruction, including Fas, perforin, and TNF-alpha. Evidence for Fas-mediated lysis of beta cells in the pathogenesis of IDDM in nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice bearing the lpr mutation (NOD-lpr/lpr) fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on beta cells in NOD mice may result in accelerated IDDM; and 3) irradiated NOD-lpr/lpr mice are resistant to adoptive transfer of diabetes by cells from NOD mice. However, the interpretation of these results is complicated by the abnormal immune phenotype of NOD-lpr/lpr mice. Here we present novel evidence for the role of Fas/FasL interactions in the progression of NOD diabetes using two newly derived mouse strains. We show that NOD mice heterozygous for the FasL mutation gld, which have reduced functional FasL expression on T cells but no lymphadenopathy, fail to develop IDDM. Further, we show that NOD-lpr/lpr mice bearing the scid mutation (NOD-lpr/lpr-scid/scid), which eliminates the enhanced FasL-mediated lytic activity induced by Fas deficiency, still have delayed onset and reduced incidence of IDDM after adoptive transfer of diabetogenic NOD spleen cells. These results provide evidence that Fas/FasL-mediated programmed cell death plays a significant role in the pathogenesis of autoimmune diabetes.
Su
X
X
Alexion Pharmaceuticals, New Haven, CT 06511, USA.
Hu
Q
Q
Kristan
J M
JM
Costa
C
C
Shen
Y
Y
Gero
D
D
Matis
L A
LA
Wang
Y
Y
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D019014:fas Receptor / Q000502:physiology*
D019014:fas Receptor