Autoimmune kidney disease and lymphadenopathy in NODlpr mice are not modified by deficiency in tumor necrosis factor receptor 1 or beta 2-microglobulin.
Fas and TNFRI, two members of the tumor necrosis factor receptor family with an intracellular death domain, each play critical roles in apoptotic death of lymphocytes and certain other cell types. We determined the overlapping functions of Fas and TNFRI by breeding non-obese diabetic (NOD) mutant mice that lacked both receptors. NODlpr mice developed extensive lymphadenopathy, splenomegaly, CD4(-)CD8(-) B220(+) alpha beta TCR(+) T cells and autoimmune kidney disease. This pathology was not modified by concomitant deficiency in TNFRI as was reported for lpr mice on a B6 background. NODlpr mice lacking CD8(+) T cells, because of a null mutation in beta(2)-microglobulin (beta(2)m), also developed a similar disease profile to NODlpr animals, but the CD4(-)CD8(-) B220(+) alpha beta TCR(+) T cells now derived from a CD4(+) T cell lineage. These results demonstrate that, as in the autoimmune-prone MRL stain, the NOD genetic background promotes lupus nephritis-like pathology and extensive lymphadenopathy when lpr is present. Loss of TNFRI does not exacerbate the pathology caused by deficiency in Fas and loss of beta(2)m does not reduce it.
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Tara
T
Catterall
Dina
D
Stockwell
Vikki
V
Marshall
Andreas
A
Strasser
Janette
J
Allison
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D007674:Kidney Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008206:Lymphatic Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency*; D013601:T-Lymphocytes / Q000276:immunology; D001613:beta 2-Microglobulin / Q000172:deficiency*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D001613:beta 2-Microglobulin