Cell Stress and Chaperones (2012) 17:281–292 DOI 10.1007/s12192-011-0311-5 PERSPECTIVE AND REFLECTION ARTICLE A case of mistaken identity: HSPs are no DAMPs but DAMPERs Willem van Eden & Rachel Spiering & Femke Broere & Ruurd van der Zee Received: 9 November 2011 / Accepted: 15 November 2011 / Published online: 3 December 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Until recently, the immune system was seen solely as a defense system with its primary task being the elimination of unwanted microbial invaders. Currently, however, the functional significance of the immune system has obtained a much wider perspective, to include among others the maintenance and restoration of homeostasis following tissue damage. In this latter aspect, there is a growing interest in the identification of molecules involved, such as the so-called danger or damage-associated molec- ular patterns (DAMPs), also called alarmins. Since heat shock proteins are archetypical molecules produced under stressful conditions, such as tissue damage or inflammation, they are frequently mentioned as prime examples of DAMPs (Bianchi, J Leukoc Biol 81:1–5, 2007; Kono and Rock, Nat Rev Immunol 8:279–289, 2008; Martin-Murphy et al., Toxicol Lett 192:387–394, 2010). See for instance also a recent review (Chen and Nunez, Science 298:1395– 1401, 2010). Contrary to this description, we recently presented some of the arguments against a role of heat shock protein as DAMPs (Broere et al., Nat Rev Immunol 11:565-c1, 2011). With this perspective and reflection article, we hope to elaborate on this debate and provide additional thoughts to further ignite this discussion on this critical and evolving issue. Keywords DAMP . HSP. Treg . Inflammation . HSP70 . Danger . Arthritis . Peptides . Autoimmunity W. van Eden (*) : R. Spiering : F. Broere : R. van der Zee Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, Netherlands e-mail: w.vaneden@uu.nl What are DAMPs? In the 1990s, Polly Matzinger introduced the concept of immunological “danger” as a further refinement of Burnet’s original clonal selection theory which is the basis of self–nonself discrimination by the immune system (Fuchs and Matzinger 1996). In her “danger” concept of immune function, she proposed immune responses result from detecting and addressing danger and not just nonself. In this context, the molecules associated with distress and damage (including self molecules) are regarded as the prime stimuli for immuno- logical reactivity. Self-danger signals were postulated to originate from, for instance, necrotic cells that succumb to infection or ischemia. Subsequently, several molecules were ascribed “danger”-associated molecule (DAMPs) functions, such as high-mobility group box-1 (HMGB1) protein, the most abundant member of the HMG family of DNA-binding proteins. Other candidates include cytosolic calcium- binding proteins of the S-100 family, nucleosomes, uric acid, and antibacterial peptides (Harris and Raucci 2006). It was logical and attractive to incorporate into this concept families of heat shock proteins (HSPs) as they are upregulated during stressful cellular events such as in tissue necrosis. HSPs have since often been categorized as prototypic “danger” associated molecular patterns or DAMPs. As a brief aside, the terminology in this field exemplifies the continuing maturation of the danger concept since its original inception. The term DAMPs is given in analogy with the earlier coined PAMPs (pathogen- associated molecular patterns), which were proposed to be structures recognized by so-called pattern recognition recep-