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Functional significance of the Fas molecule in naive lymphocytes
S Senju1, I Negishi, N Motoyama
1Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Abstract:
The Fas molecule mediates apoptotic signal in many cell types. Mouse mutations (lpr, lprcg, gld), which impair the function of Fas, cause spontaneous autoimmune disease. We generated Fas-deficient (Fas-/-) mice by homologous recombination. In embryonic stem cells Fas-/- mice developed lpr-like disease, confirming that the abnormality of Fas is causal in the lpr phenotype. We also made Fas-/- chimeric mice composed of a mixture of Fas+/+ and Fas-/- cells. The chimeric mice also showed the lpr phenotype. In Fas-/-, chimeric mice, the Fas-deficient population expanded progressively among mature T and B lymphocytes. The expansion of Fas-deficient lymphocytes occurred at the naive, pre-primed, lymphocyte stage. These results suggest that the Fas molecule functions not only after antigenic stimulation, as previously hypothesized, but also at the naive lymphocyte stage.
Insights
Fas deficiency causes autoimmune disease by allowing Fas-deficient lymphocytes to expand. This Fas molecule dysfunction impacts both naive and mature T and B cells, revealing a critical role beyond immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The Fas molecule is crucial for initiating apoptosis (programmed cell death) in various cell types.
- Genetic mutations impairing Fas function in mice (lpr, gld) lead to spontaneous autoimmune diseases.
- Previous hypotheses suggested Fas primarily acts after antigenic stimulation.
Purpose of the Study:
- To investigate the role of the Fas molecule in autoimmune disease pathogenesis.
- To confirm if Fas abnormality is the direct cause of the lpr phenotype.
- To elucidate the stage at which Fas-deficient lymphocytes expand.
Main Methods:
- Generation of Fas-deficient (Fas-/-) mice using homologous recombination.
- Creation of Fas-/- chimeric mice comprising both Fas+/+ and Fas-/- cells.
- Analysis of lymphocyte populations in Fas-/- and chimeric mice.
Main Results:
- Fas-/- mice exhibited an lpr-like autoimmune disease, confirming Fas's causal role.
- Chimeric mice also displayed the lpr phenotype.
- Fas-deficient lymphocytes progressively expanded in chimeric mice, particularly at the naive lymphocyte stage.
Conclusions:
- Fas molecule dysfunction is directly causal in the lpr autoimmune phenotype.
- The Fas molecule plays a critical role in regulating lymphocyte populations even at the naive, pre-primed stage.
- Fas's function extends beyond mediating signals after antigenic stimulation, impacting lymphocyte homeostasis.