288 Fig. 1 The immune system will restore homeostasis when the latter is challenged by sterile damage, pathogens, or com- mensals. In all cases, HSPs are present and even upregulated host responses are terminated by regulation. In the host response, the HSP can be the targets for the regulation, such as for the regulation exerted by Treg cells W. van Eden et al. Challengers of host immune -homeostasis Challenge: Elicitor: Sterile tissue damage Pathogen invasion Commensalism/Symbiosis Self HSP + DAMPs Host response: Tissue repair, regulation Microbial HSP + PAMPs + self HSP + DAMPs PAMPs+ microbial HSP Full response, elimination of Regulation, maintenance of infection symbiosis Regulation nogenic, tolerogenic, or “silent” is, these days, one of the central issues in immunology. There is ample evidence that apoptosis is non-immunogenic. However, the activation state of dying cells seems relevant (Green et al. 2009). Activated apoptotic cells have adjuvant properties and induce expression of maturation markers (CD80, CD83, and CD86) and secretion of pro-inflammatory cytokines in DCs (Johansson et al. 2007). In contrast to this, T cells that succumb to activation-induced cell death after clonal expansion promote tolerance by stimulating regulatory CD8+ T cells (Herndon et al. 2005). Thus, timing of cell death seems important: cell death at the peak of the immune response produces immune activation, whereas cell death during a waning immune response supports regulation. Most necrotic cells are considered to produce an immune response, but also here the cell type, the history of the cell, its mode of activation, and the manner of stress imposed on the cell may determine whether or not this form of cell death is immunogenic (Green et al. 2009). In other words, as long as we do not know exactly how to correlate the Hsp: Extracellular versus Intracellular? Fig. 2 Extracellular HSPs are released from necrotic cells when cells die from infection. The released HSP will be seen by receptors on antigen- presenting cells such as DC in combination with PAMPs. It is possible that HSPs do contribute to the PAMP-elicited inflammatory response, thereby enhancing collateral tissue damage. Sterile inflam- mation will upregulate intracel- lular HSP in antigen-presenting cells such as DC which leads to the triggering of regulatory T cells that dampen inflammation DC DC Infection Sterile inflammation (AID) Extracellular hsp (and PAMPs) (Innate) Receptors? Necrosis Upregulated cellular hsp T cell DC DC T cell T-cell activation T-cell regulation Inflammation Collateral tissue damage Control of inflammation