Identification of Desmogleins as Disease Targets

Abstract

While it had long been known that desmosomes were crucial for interconnecting cells in laboratory experiments, the link between desmosomal adhesion and human health was bolstered by several key experiments demonstrating that desmogleins were targeted in both autoimmune and infectious diseases. In two landmark papers authored by Masayuki Amagai working with John Stanley, desmogleins 1 and 3 (Dsg1 and Dsg3) were confirmed as molecular targets in staphylococcal scalded skin syndrome (SSSS) and pemphigus vulgaris (PV), respectively. These noteworthy discoveries constitute a milestone in the science of desmosomes as they drew considerable attention to the connection between the so-called intercellular “spot welds” and specific human diseases. PV was originally described as a blistering disease characterized by splitting of the epidermis near its basal layer, a life-threatening consequence for patients. The molecular mechanism of PV remained elusive for many years, but it was discovered in 1982 by Anhalt and colleagues that PV could be phenocopied in mice by passive transfer of IgG from humans suffering from active PV, confirming the role of pathogenic antibodies (PV-IgG) in the disease. Although this report established that PV-IgG was sufficient to cause a PV-like disease in an animal model, the molecular target of these antibodies remained a mystery until 1991, when Amagai et al. (1991) successfully cloned as gene encoding a protein specifically recognized by autoantibodies present in human PV sera. Using PV-IgG to screen a keratinocyte expression library, the investigators deciphered the amino-acid sequence of the 130 kDa PV antigen (PVA). The authors reported significant homology of PVA with cadherins, most notably Dsg1, which had previously been identified as a target of antibodies in another autoimmune blistering disease, pemphigus foliaceus (PF) (Stanley et al., 1986). The conclusion that the PV antigen was a novel desmosomal cadherin (later named Dsg3) supported an earlier demonstration by Jones et al. (1984) that PV-IgG targeted the desmosome. Also, given the expression pattern of the novel cadherin in stratified epithelia, particularly the skin and mucous membranes, an explanation for the localization of blisters in PV and PF began to emerge (Figure 1). Thus, through a forward genetics approach utilizing pathogenic antibodies from patients, Amagai and colleagues established a role for a novel desmosomal component in the pathogenesis of a devastating human skin disease. In 2000, the team of Amagai and Stanley provided the pathogenic explanation of a distinct epidermal blistering disease caused by exfoliative toxin A (ETA) produced by Staphylococcus aureus. Bacterial isolates from lesions in the common blistering disease, bullous impetigo, or the more advanced SSSS reliably produce ETA, a toxin suspected to have serine protease activity based on structural analysis. Injection of this toxin into mice was sufficient to induce acantholysis in the superficial epidermis (Melish and Glasgow, 1970), yet its substrate remained unknown for many years. Interestingly, it had previously been noted that epidermal