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Immunology of Cell Death
From Sci-Mate WikiBiological and Medical Sciences > Classification by Discipline > Immunology
Type: General Knowledge
Intention: For Publication
Read/Write Permissions: Open Access
22.04.2010 - Christopher Dyer - Sci-Mate
immune system to consider, as it seeks to prevent ongoing damage from infection or mutation.
The two major pathways of cell death have been shown to generally lead in two directions- Necrosis, towards inflammation; and Apoptosis, towards a more controlled reabsorbtion of dead cells.
 Antigen Presentation
Both forms of cell death have been shown to be efficient sources for antigen presentation to the immune system. Antigen derived from apoptotic cells is generally shown to be less immunogenic (eg, (Rohn et al., 2005); Reviewed, (Albert, 2004)) and even toleragenic (missing ref.), while antigens from cells whose membrane is disrupted (including necrosis, proptosis (reviewed (Bergsbaken et al., 2009)), and cells with recently described inflammasomes (reviewed (Franchi et al., 2009))) have been shown to be both inflammatory and immuno-stimulatory (eg, (Ma et al., 2005; Rohn et al., 2005), reviewed (Fink and Cookson, 2005)). Membrane disruption, therefore, is believed to release 'danger signals' or 'damage associated molecular patterns' (DAMPs, orig.: Matzinger, 1994), which have been shown to pre-exist in healthy cells through inhibition of protein synthesis and rapid cell death (Shi et al., 2000).
 Danger Signals
Recognising both the ligand released by the dying cell, and the receptor on the surface of immune cell is a current focus of much research.
Several molecules, which might be expected to be released following necrosis, including uric acid (Shi et al., 2003) and heat-shock proteins (HSPs) (Binder et al., 2000; Udono and Srivastava, 1993), have been shown to enhance both cellular activation, and inflammation. What is less clear is which of these candidate DAMPs are physiologically relevant under what circumstances.
Finding the correct receptor for danger signals from necrotic cells has the potential to connect this specific form of immune activation with our broader understanding ofimmune activation pathways. Very recently, CLEC9A, for example, has been reported to provide stimulation for dead-cell associated antigens via SYK signalling, thereby implicating the SRC family of kinases (Sancho et al., 2009). Previously, other SYK-coupled C-type lectins have been implicated in inflammatory responses to necrotic cells (Yamasaki et al., 2008; Ziegenfuss et al., 2008), so this latest finding represents a critical step forward that will likely stimulate considerable interest and ongoing research.
Surprisingly, studies using TLR-deficient mice showed that inflammation is not dependent on any single TLR (TLR5 and TLR8 were not tested), although mice deficient in both TLR2 and TLR4 did show minor reductions in inflammation (Chen et al., 2007). Earlier reports suggesting the involvement of TLRs (reviewed, (Marshak-Rothstein, 2006)) may be the result of the now known sensitivity of these receptors to bacterial contamination and bystander effects.
 Reference List
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Binder,R.J., Anderson,K.M., Basu,S., and Srivastava,P.K. (2000). Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J. Immunol. 165, 6029-6035.
Chen,C.J., Kono,H., Golenbock,D., Reed,G., Akira,S., and Rock,K.L. (2007). Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat. Med. 13, 851-856.
Fink,S.L. and Cookson,B.T. (2005). Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73, 1907-1916.
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