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Identification of Desmogleins as Disease Targets

      While it had long been known that des-mosomes 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
      • Anhalt G.J.
      • Labib R.S.
      • Voorhees J.J.
      • Beals T.F.
      • Diaz L.A.
      Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease.
      by Anhalt and colleagues that PV could be pheno- copied 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 M.
      • Klaus-Kovtun V.
      • Stanley J.R.
      Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.
      successfully cloned as gene encoding a protein specifically recognized by autoantibodies present in human PV sera. Using PV-IgG to screen a keratino- cyte 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 J.R.
      • Koulu L.
      • Klaus-Kovtun V.
      • Steinberg M.S.
      A monoclonal antibody to the desmosomal glycoprotein desmoglein I binds the same polypeptide as human autoantibodies in pemphigus foliaceus.
      ). The conclusion that the PV antigen was a novel desmosomal cadherin (later named Dsg3) supported an earlier demonstration by
      • Jones J.C.
      • Arnn J.
      • Staehelin L.A.
      • Goldman R.D.
      Human autoantibodies against desmosomes: possible causative factors in pemphigus.
      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.
      Figure thumbnail gr1
      Figure 1Desmogleins are targeted in epidermal blistering diseases. Dsg1 is expressed most highly in the superficial epidermis, whereas Dsg3 is more restricted to the lower layers. (Left) In pemphigus vulgaris (PV), autoantibodies (PV-IgG) bind Dsg3 and result in splitting near the basal layer of the epidermis. (Right) Binding of Dsg1 by PF-IgG in pemphigus foliaceus (PF) or cleavage by ETA in staphylococcal scalded skin syndrome (SSSS) leads to superficial acantholysis.
      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 M.E.
      • Glasgow L.A.
      The staphylococcal scalded-skin syndrome.
      ), yet its substrate remained unknown for many years. Interestingly, it had previously been noted that epidermal samples from PF patients with anti-Dsg1 antibodies looked identical to histological specimens from patients suffering from SSSS. This shared phenotype led Amagai and co-workers to investigate whether Dsg1 was a substrate for ETA. Through in vitro and in vivo studies, the investigators confirmed that exposure of cultured keratinocytes or mice to ETA produced Dsg1 degradation and showed direct cleavage of the Dsg1 ectodomain in solution, whereas the similar cadherin, Dsg3, remained intact (
      • Amagai M.
      • Matsuyoshi N.
      • Wang Z.H.
      • Andl C.
      • Stanley J.R.
      Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1.
      ). The toxin's exquisite specificity explained why ETA-induced blisters are always limited to the superficial epidermis, where the target, Dsg1, is most highly expressed and required for resisting mechanical stress (Figure 1). This conclusion advanced our understanding of bullous impetigo and SSSS pathogenesis and once again brought the desmosome to the forefront of molecular medicine.
      Given the prevalence of desmo- somes in the stratified epidermal layers, it was not surprising that the adhesive function of desmogleins was compromised in diseases characterized by acantholysis among epidermal keratinocytes. However, the finding that the desmosome was the common molecular denominator of two dermatologic diseases of distinct etiologies was a significant scientific achievement. By firmly establishing the role of desmosomes in human disease, these discoveries by Amagai, Stanley and co-workers paved the way for the myriad publications that have followed, each advancing our understanding of pathologies that result from disrupting these all-important adhesive structures.

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