Apoptosis defects analyzed in TcR transgenic and fas transgenic lpr mice

Int Rev Immunol. 1994;11(4):321-42. doi: 10.3109/08830189409051178.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Antigens, Surface / genetics*
  • Apoptosis / genetics*
  • Apoptosis / immunology*
  • Autoimmune Diseases / genetics
  • Female
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutation
  • Receptors, Antigen, T-Cell / genetics*
  • Retroelements
  • Self Tolerance
  • T-Lymphocytes / immunology
  • fas Receptor


  • Antigens, Surface
  • Receptors, Antigen, T-Cell
  • Retroelements
  • fas Receptor