A case of mistaken identity: HSPs are no DAMPs but DAMPERs position of HSPs with the type and circumstances of cell death, it will be hard to fully grasp the immunological role of HSP in cell death. One of the problems that is associated with the immunogenicity of cell death is that cell death due to infection needs to be immunogenic, at least to some extent. When dying cells would provide antigens, let us say HSP, that would lead to a firm tolerance or suppressive regulation, such tolerance or suppressive regulation would possibly include the microbial invader that led to cell death. This scenario is incompatible with effective antimicrobial defense. The alternative possibility is that DAMPs of dying cells would always promote immune responses. This is also problematic since this would convey the risk of autoimmu- nity. Again, given the complexity of cell death immunoge- nicity, there may not be a simple one-dimensional role in cell death for HSP. In the case of cell death due to infection, PAMPs may have an overriding effect driving a pro-inflammatory response, at least at the start of infection. One cannot exclude that extracellular HSPs contribute a positive pro- inflammatory effect of PAMP-activated cells, such as activated DCs by possibly amplifying their TLR signaling. It is also possible that HSPs form complexes with PAMPs to support pro-inflammatory activity by chaperoning the PAMPs involved or by synergistic effects. A similar discussion has been active with respect to HMGB-1. It was proposed that HMGB-1 released in the presence of TLR-binding PAMPs acted to promote inflammation, whereas HMGB-1 released in an environment devoid of PAMPs promoted tissue repair (Harris and Raucci 2006). If this were the case, then it seems reasonable to assume a similar situation for HSP. Necrosis resulting from infection will lead to a pro- inflammatory response based on recognition of both PAMPs/DAMPs and possibly HSPs. The ensuing elimina- tion of the invaders would coincide with collateral damage. At this point, regulation in the form of active resolution, in part based on HSP recognizing Treg cell, would kick-in and contribute to restoration of tissue homeostasis. From another point, intracellular HSP would, besides their main task in safeguarding against intracellular protein misfolding under stress, find its way to the cell surface in the context of MHC molecules and trigger a presumably regulatory response at the level of T cells. In addition, there may be still be the somewhat theoretical issue of active concentrations of HSP. At low, more or less constitutive concentrations, HSP may help to maintain immune homeostasis by promoting Treg cell activities. However, it is theoretically possible that relative- ly high concentrations of HSP that are liberated at sites of tissue damage or infection cause a loss of regulatory capacity and contribute to pro-inflammatory responses. 289 This would imply that when cellular stress decreases, resolution would set in and Treg cells would become prominent responders when local HSP concentrations fall (Quintana and Cohen 2011). Irrespective of possible pro-inflammatory effects of supra-constitutive concentrations of HSP, under physiolog- ical conditions, a dampening effect on the immune system would prevail. Mounting experimental findings seem to support the latter supposition. HSP can therefore be called DAMPERs rather than DAMPs. This may be very much in line with the recent successful clinical interventions in autoimmune inflammatory diseases based on the adminis- tration of HSP peptides (Albani et al. 2011; Fischer et al. 2010; van Eden et al. 2010). 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