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Damage Associated Molecular Patterns (DAMPS)

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Biological and Medical Sciences > Classification by Discipline > Immunology


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Type: General Knowledge
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22.04.2010 - Christopher Dyer  -  Sci-Mate   


Damage Associated Molecular Patterns (DAMPs) are immunologically relevant 'danger signals' released following specific forms of cell death causing inflammation and activation of APCs and lymphocytes (originally hypothesised, (Matzinger, 1994); egs, (Ma et al., 2005; Rohn et al., 2005); reviewed, (Kono et al., 2008)). DAMPS are derived from pre-existing molecules (Shi et al., 2000) released through membrane rupture, as in the case of Necrosis, or Proptosis (reviewed (Bergsbaken et al., 2009)), or from within inflammasomes (reviewed (Franchi et al., 2009)). Excessive signalling from DAMPs has been shown to contribute to allergic and autoimmune activity (missing ref.), and currently, the presence of uric acid (a DAMP, see below) is being investigated in rheumatoid arthritis (missing ref.). Obviously- understanding the role of these molecules in the immunological response to cell death shall be relevant to many diseases and treatments.

[edit] Candidate DAMPs

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.

[edit] Candidate Receptors and Signalling Pathways

Surprisingly, studies using TLR-deficient mice showed that DAMP inflammation is not dependent on any single TLR, although mice deficient in both TLR2 and TLR4 did show minor reductions in inflammation, and TLR5 and TLR8 were not tested (Chen et al., 2007).

CLEC9A 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.

[edit] References

Bergsbaken,T., Fink,S.L., and Cookson,B.T. (2009). Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7, 99-109.
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.
Franchi,L., Eigenbrod,T., Munoz-Planillo,R., and Nunez,G. (2009). The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241-247.
Kono, H., and Rock, K. L. (2008). How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279-289.
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Matzinger,P. (1994). Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991-1045.
Rohn,T.A., Schadendorf,D., Sun,Y., Nguyen,X.D., Roeder,D., Langen,H., Vogt,A.B., and Kropshofer,H. (2005). Melanoma cell necrosis facilitates transfer of specific sets of antigens onto MHC class II molecules of dendritic cells. Eur. J. Immunol. 35, 2826-2839.
Sancho,D., Joffre,O.P., Keller,A.M., Rogers,N.C., Martinez,D., Hernanz-Falcon,P., Rosewell,I., and CR,E.S. (2009). Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature.
Shi,Y., Evans,J.E., and Rock,K.L. (2003). Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516-521.
Shi,Y., Zheng,W., and Rock,K.L. (2000). Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses. Proc. Natl. Acad. Sci. U. S. A 97, 14590-14595.
Udono,H. and Srivastava,P.K. (1993). Heat shock protein 70-associated peptides elicit specific cancer immunity. J. Exp. Med. 178, 1391-1396.
Yamasaki,S., Ishikawa,E., Sakuma,M., Hara,H., Ogata,K., and Saito,T. (2008). Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat. Immunol. 9, 1179-1188.
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