Combining Fas mutation with interleukin-2 deficiency prevents Colitis and Lupus: implicating interleukin-2 for auto-reactive T cell expansion and Fas ligand for colon epithelial cell death.
Both the lpr gene defect and interleukin 2-targeted mutation (IL-2 KO) in mice are lethal. Interestingly, mice bearing both mutations live significantly longer than mice with either of the single mutant genes, approximating the life span of normal controls. They do not display the major disease phenotypes of lpr and IL-2 KO mice. Systemic autoimmune response, the accumulation of the abnormal CD4-CD8-B220+ double-negative T cells, kidney disease pathology, anemia, colon damage, and lethality are prevented. Our data indicate that IL-2 is mandatory for the expansion of auto-reactive T cells in lpr mice and that CD95 (Fas) is the critical target for the development of anemia and ulcerative colitis in IL-2 KO mice in which CD178 (FasL) on intraepithelial T cells is the major effector responsible for colon damage and lethality.
Xiao
Sheng
S
Division of Rheumatology and Immunology, Department of Internal Medicine, and Special Center of Research on Systemic Lupus Erythematosus, University of Virginia, Charlottesville, Virginia 22908, USA.
Sung
Sun-Sang J
SS
Fu
Shu Man
SM
Ju
Shyr-Te
ST
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D016923:Cell Death; D003092:Colitis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism; D004847:Epithelial Cells; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006454:Hemoglobins / Q000378:metabolism; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000235:genetics* / Q000502:physiology*; D008177:Lupus Vulgaris / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008214:Lymphocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000235:genetics*
D015704:CD4 Antigens; D016827:CD8 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006454:Hemoglobins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D019014:fas Receptor