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Autoimmune disease results from multiple interactive defects in apoptosis induction molecules and signaling pathways
J D Mountz1, T Zhou, X Su
1University of Alabama at Birmingham 35294-0007, USA.
Abstract:
Activation induced cell death (AICD) plays a critical role in eliminating autoimmune cells and limiting inflammation after activation. The two major signaling molecules for AICD are the Fas and TNF-R pathways of apoptosis. Defective Fas apoptosis in lpr/lpr mice results in a compensatory increase in TNF-R/TNF-mediated apoptosis. TNF/TNF-R has been shown to be a compensatory pathway of apoptosis in T cells and macrophages of lpr/lpr mice. Therefore, early production of TNF/TNF-R limit an immune response by inducing AICD in the absence of an intact Fas/Fas ligand apoptosis pathway. However, increased TNF production in lpr mice also lead to increased susceptibility to septic shock and autoimmune disease such as arthritis. Therefore TNF production during an inflammatory response can downmodulate this response, but this also results in the failure to downmodulate TNF production leading to septic shock and arthritis. A second pathway of AICD is mediated by Nur77 after T cell stimulation through the CD3 molecule. Mice with defective Nur77 signaling undergo AICD using the Fas-Fas ligand pathway to eliminate autoreactive T cells. A third defect of AICD is observed in HCP-mutant me/me (motheaten) mice which develop autoimmune disease related to defective Fas apoptosis signaling. Therefore, multiple interactive pathways play a role in limiting development of autoimmunity.
Insights
Activation induced cell death (AICD) is vital for controlling autoimmune cells. Multiple pathways, including Fas, TNF-R, and Nur77, regulate AICD to prevent autoimmunity, but defects can lead to disease.
Area of Science:
- Immunology
- Cellular Biology
- Autoimmunity
Background:
- Activation-induced cell death (AICD) is crucial for immune homeostasis.
- Fas and TNF-R pathways are key mediators of AICD.
- Defects in AICD signaling are linked to autoimmune diseases.
Purpose of the Study:
- To investigate the roles of Fas, TNF-R, and Nur77 pathways in AICD.
- To understand how defects in these pathways contribute to autoimmunity.
- To explore the compensatory mechanisms in AICD signaling.
Main Methods:
- Analysis of lpr/lpr mice with defective Fas apoptosis.
- Investigation of TNF/TNF-R-mediated apoptosis in T cells and macrophages.
- Study of Nur77-mediated AICD following T cell stimulation.
- Examination of HCP-mutant me/me mice with defective Fas signaling.
Main Results:
- Defective Fas apoptosis in lpr/lpr mice leads to compensatory TNF-R/TNF-mediated apoptosis.
- Early TNF/TNF-R production can limit immune responses in the absence of functional Fas.
- Increased TNF production in lpr mice exacerbates susceptibility to septic shock and arthritis.
- Nur77 signaling defects result in Fas-mediated AICD for autoreactive T cell elimination.
- HCP-mutant me/me mice exhibit autoimmune disease due to impaired Fas apoptosis signaling.
Conclusions:
- Multiple, interactive pathways regulate AICD to prevent autoimmunity.
- Dysregulation of AICD pathways, particularly Fas and TNF-R, contributes to autoimmune diseases.
- Understanding these pathways is critical for developing therapeutic strategies for autoimmune disorders.