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The role of CD91 and heat shock proteins in psoriasis

This issue of the BJD contains a fascinating article by Boyman et al. in which they observe a striking increase in CD91+ dendritic cells in newly formed psoriatic plaques, juxtaposed to keratinocytes expressing excess heat shock proteins (HSPs). This has enormous significance in the dynamic interplay between innate and adaptive immunity and provides new insights into mechanisms underlying chronic inflammation, including the necrotic response to infection and cancer. The history of this particular story began with chance events in 1962 when the temperature on an incubator full of fruit flies was inadvertantly turned up to 60 C. Under light microscopy, the salivary gland chromosomes of the fruit flies, thus ‘heat-shocked’, showed dilated puffs indicative of transcriptional activity at discrete loci. These loci are now known to encode HSPs which have since been identified in all species, expressed in all cells, in all forms of life and in a wide variety of intracellular locations. Organisms from bacteria to humans respond to high temperatures by inducing the synthesis of HSPs and decreasing the production of other proteins. The synthesis of HSPs is induced not only by heat but also by other stressors such as oxidation, pH change, carbon monoxide, nicotine, H2O2, benzene, teratogens, dust, ultraviolet radiation and a host of carcinogens found in the environment, and thus, they have a particular role in the skin. HSPs are the oldest known proteins, remarkably conserved between species and constituting the single most abundant group of proteins inside cells, forming a family of intracellular chaperones that facilitate protein folding and assembly and act as buffers to stochastic and potentially destabilizing environmental forces. In doing so, HSPs protect proteins from stress. One of the most important characteristics of HSPs is that they bind peptides from inflamed, tumour or virally infected cells, and engagement of HSP–peptide complexes with antigen-presenting cells leads to expression of costimulatory molecules, maturation and cytokine release. Activated antigen-presenting cells such as dendritic cells then present the previously bound peptides efficiently and activate specific CD8+ T cells, independent of CD4+ T-cell help. In transferring or ‘cross-presenting’ antigenic peptides from outside the cell on to the ‘endogenous’ class I pathway, they are capable of eliciting cellular CD8+ cytotoxic T cell-mediated immunity. The idea of an HSP receptor was, however, at first considered something of an aberration: receptors were thought exclusively suited to the detection of secreted molecules such as hormones or cytokines, not intracellular molecules. However, uptake of antibody-bound fragments was shown to occur through Fc receptors on macrophages and the existence of an HSP receptor was subsequently hypothesized to explain the ability of HSP–peptide complexes to pulse antigenpresenting cells and lead to a cytotoxic T-cell response. CD91 had been identified previously as a receptor for the serum protein a2-macroglobulin, a ‘natural’ protease inhibitor that, like HSPs, is found across many species. Pathogens often utilize their own proteases in establishing successful infection and a2-macroglobulin ‘baits’ these by acting at first as a substrate for pathogenic proteases and then by trapping them in an altered conformation prior to endocytosis through CD91. The foreign protease is then digested into amino acids, acting as a source of host nutrition. However, as the molecular arms race between hosts and pathogens (and inflammation and ‘anergy’, tumour cells and ‘rejection’) has progressed over evolutionary epochs, pathogens have acquired ever more fashionable and sophisticated means to evade host responses. In turn, hosts have developed the means to overcome such subversion strategies. In this scenario, viruses or other pathogens infect cells, replicate and destroy host cells akin to psoriatic inflammatory processes, but the HSPs contained therein transfer information (the foreign peptides) regarding the environment to CD91. This large highly conserved cell surface dimer, along with the HSPs, is internalized and, while a proportion of it enters an acidic compartment for digestion (once again providing nutrition for the host), the remainder enters a neutral pH compartment that funnels peptides into the classical class I presenting pathway. The major histocompatibility complexes (MHCs) bind and present them to CD8+ T cells. On recognizing nonself, such T cells are induced, clonally proliferate and mediate (perforin is secreted) killing, prior to apoptosis of many of these effectors and subsequent persistence of long-lived memory cells. CD91 was first identified by Binder et al. as the receptor for gp96 and then by Basu et al. as a common receptor for other HSPs such as HSP70, HSP90 and calreticulin (the numbers providing information regarding molecular weight and subcellular location). Srivastava and his colleagues have made the interesting observation that CD91 appears to be a common receptor for all identified other HSPs, and blocking of CD91 with antibodies completely inhibits the phenomenon of representation of peptides that are carried or chaperoned by HSPs. CD91 has recently been demonstrated to bind and internalize a-defensins in a saturable and dose-dependent manner. These small molecules are secreted from stimulated CD8+ T cells in the rare minority of individuals who are infected with human immunodeficiency virus (HIV) type 1 for more than 10 years with no evidence of progressive disease, while