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Delayed kinetics of T lymphocyte anergy and deletion in lpr mice
P F Mixter1, J Q Russell, R C Budd
1Department of Medicine, University of Vermont College of Medicine, Burlington 05405-0068.
Abstract:
The Fas/APO-1 (Fas) antigen is a cell surface protein that mediates apoptosis and belongs to the tumor necrosis factor receptor family. The lymphoproliferative (lpr) anomaly in mice results from a retroviral disruption within the fas gene. Mice that are homozygous for the lpr mutation accumulate large numbers of T lymphocytes and exhibit an autoimmune syndrome resembling systemic lupus erythematosus. A possible explanation for this process is that in the absence of Fas antigen, lpr T cells may be resistant to normal peripheral deletional signals. The bacterial superantigen staphylococcal enterotoxin B (SEB) rapidly induces anergy and deletion by apoptosis of reactive T lymphocytes in normal mice. Administration of SEB to adult lpr mice results in the delayed induction of both unresponsiveness and deletion of V beta 8+ lymph node cells. This is not due merely to an increased thymic output in lpr mice; the delayed induction of tolerance and elimination of reactive lpr T cells by superantigens are intrinsic properties of the cells. The progressive lymphadenopathy in lpr mice may reflect a process of lymphoaccumulation rather than lymphoproliferation. A delay in tolerance induction and elimination of self-reactive T cells could have profound influence on the autoimmune diathesis of lpr mice.
Insights
Mice with the Fas/APO-1 (Fas) gene disruption resist T cell deletion, leading to autoimmune disease. Bacterial superantigens delay this T cell elimination in these mice, impacting autoimmunity.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The Fas/APO-1 (Fas) antigen, a TNF receptor family member, mediates apoptosis and is crucial for immune regulation.
- The lymphoproliferative (lpr) mutation disrupts the Fas gene, causing T cell accumulation and autoimmune syndrome in mice.
- Fas-deficient T cells may resist normal peripheral deletion signals, contributing to autoimmune pathology.
Purpose of the Study:
- To investigate the impact of Fas deficiency on T cell deletion induced by bacterial superantigens.
- To determine if delayed T cell elimination in lpr mice is due to intrinsic cellular properties or thymic output.
- To explore the relationship between T cell tolerance induction and the autoimmune diathesis in lpr mice.
Main Methods:
- Administration of staphylococcal enterotoxin B (SEB) to adult lpr mice and normal littermates.
- Analysis of T lymphocyte unresponsiveness and apoptosis following SEB exposure.
- Assessment of V beta 8+ T cell populations in lymph nodes.
Main Results:
- SEB administration induced delayed unresponsiveness and deletion of V beta 8+ T cells in lpr mice compared to normal mice.
- The delayed elimination of reactive T cells in lpr mice is an intrinsic property of the cells, not solely due to increased thymic output.
- Progressive lymphadenopathy in lpr mice may represent lymphoaccumulation rather than proliferation.
Conclusions:
- Fas-deficient T cells exhibit intrinsic resistance to superantigen-induced deletion.
- Delayed tolerance induction and elimination of self-reactive T cells contribute significantly to the autoimmune phenotype in lpr mice.
- Understanding these mechanisms is critical for addressing autoimmune diseases.