Abstract
Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention.
Highlights
Apoptosis is conserved among all metazoans and in vertebrates two main signalling pathways converge at the level of shared cysteine-dependant aspartic acid-specific proteases, known as caspases, that execute cell death by the cleavage of vital cellular substrates.[1]
The ‘extrinsic’ pathway to apoptotic cell death is initiated by the ligation of so-called death receptors (DRs) on the cell surface of a target cell with the specific ‘death ligand’ on an opposing cell, which triggers the formation of the death-inducing signalling complex (DISC)
Multimerization of trimeric receptors leads to direct or indirect recruitment of the adaptor protein FADD allowing for engagement and activation of initiator pro-caspase 8 or in humans pro-caspase 10 molecules into the DISC and subsequent activation of effector caspases 3, 6 and 7.2,3 The importance of this cell death pathway that co-evolved in vertebrates with the ability to launch an adoptive immune response, for the suppression of autoimmunity is exemplified in Fas-deficient lpr[4] and FasL-deficient gld mice[5] and in patients suffering from autoimmune lymphoproliferative syndrome (ALPS) that can present with a variety of different pathologies and harbor mutations either in Fas, FasL or caspase-8/10 genes, respectively.[6]
Summary
Apoptosis is conserved among all metazoans and in vertebrates two main signalling pathways converge at the level of shared cysteine-dependant aspartic acid-specific proteases, known as caspases, that execute cell death by the cleavage of vital cellular substrates.[1]. Defects in the clearance of apoptotic cells and subsequent secondary necrosis or impaired degradation of their cellular contents by phagocytes, for example because of loss of or reduced function of engulfment genes such as MFG-8, complement factor C1q or the lysosomal DNA-degrading enzyme, DNAaseII, leads to the development of autoimmune disease in mice and men. These observations highlight the relevance of efficient corpse clearance and cell content degradation by phagocytes for the maintenance of tolerance (for detailed review, see Nagata et al.[11]). Thymocytes that lack a functional (pre)TCR die by neglect, whereas those expressing an ‘above-threshold’ highaffinity TCR die by apoptosis during negative selection, both processes regulated to a large extent by induction of different
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
