Greatly accelerated lymphadenopathy and autoimmune disease in lpr mice lacking tumor necrosis factor receptor I.
Fas and TNF receptor I (TNF-RI) share homology at their cytoplasmic death domain and belong to the same gene family, but utilize different pathways to signal activation-induced cell death. To determine the combined effects of defective TNF-RI and Fas signaling on lymphadenopathy and autoimmune disease, we backcrossed TNF-RI knockout mice (Tnfr1(0/0)) with Fas-deficient C57BL/6-lpr/lpr mice. Tnfr1(0/0)lpr/lpr mice developed greatly accelerated lymphadenopathy and autoantibody production compared with C57BL/6-lpr/ lpr mice. Tnfr1(0/0)-lpr/lpr mice also exhibited high mortality and early onset autoimmune disease characterized by massive mononuclear cell infiltration in liver, kidney, lung, and knee joints. These results indicate that the Fas-mediated apoptosis defect in lpr mice is accelerated in the absence of TNF-RI and that normal expression of TNF-RI might partially compensate for the Fas-mediated apoptosis defect of mononuclear cells in lpr mice.
Zhou
T
T
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294, USA.
Edwards
C K
CK
Yang
P
P
Wang
Z
Z
Bluethmann
H
H
Mountz
J D
JD
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D008198:Lymph Nodes / Q000473:pathology*; D008206:Lymphatic Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics*
D001323:Autoantibodies; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor