Apoptosis defects analyzed in TcR transgenic and fas transgenic lpr mice.
Although autoreactive T cells are thought to play a prominent role in autoimmune disease in MRL-lpr/lpr mice, it has been difficult to directly determine if autoreactive T cells escape from the thymus and react with self-antigens in the periphery. Defective expression of the Fas apoptosis antigen in MRL-lpr/lpr mice results from the insertion of the ETn retrotransposon. The fas defect can be partially corrected in CD2-fas transgenic mice in which the expression of fas is corrected in T cells. To identify a possible defect in clonal deletion or clonal anergy induction of auto-specific T cells, we have studied C57BL/6-lpr/lpr transgenic mice that express TcR genes that recognize a known self-antigen, the male H-Y antigen. In addition, we have analyzed clonal deletion and tolerance induction after neonatal tolerance induction and superantigen-induced arthritis with the class II MHC reactive superantigen staphylococcal enterotoxin B (SEB) in V beta 8 TcR transgenic and non-transgenic MRL-lpr/lpr mice. Neonatal tolerance induction to SEB was normal in lpr/lpr mice. However, over time a loss of tolerance (thymic or peripheral) was observed in lpr/lpr mice but not in +/+ TcR transgenic mice. This defect in lpr/lpr mice was thymic-dependent and was due to increased CD28/CTLA4 signaling. These results suggest that an apoptosis defect involving both thymocytes and peripheral lymphoid cells leads to autoimmune disease in lpr/lpr mice. The challenge in the future will be to determine the role of defective apoptosis in other autoimmune diseases.
Mountz
J D
JD
Department of Medicine, University of Alabama at Birmingham.
Zhou
T
T
Bluethmann
H
H
Wu
J
J
Edwards
C K
CK
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics; D005260:Female; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D018626:Retroelements; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor
D000954:Antigens, Surface; D011948:Receptors, Antigen, T-Cell; D018626:Retroelements; D019014:fas Receptor