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In patients with pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell–cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmogleins in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 −/− mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. These mice were normal at birth, but by 8–10 d weighed less than DSG3 +/− or +/+ littermates, and at around day 18 were grossly runted. We speculated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies showed erosions with histology typical of PV, including suprabasilar acantholysis and “tombstoning” of basal cells. EM showed separation of desmosomes. Traumatized skin also had crusting and suprabasilar acantholysis. Runted mice showed hair loss at weaning. The runting and hair loss phenotype of DSG3 −/− mice is identical to that of a previously reported mouse mutant, balding (bal). Breeding indicated that bal is coallelic with the targeted mutation. We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation. These results demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia and suggest that pemphigus autoantibodies might interfere directly with such a function.

P emphigus, which is caused by autoantibodies, and bullous impetigo (including its generalized form, the staphylococcal scalded-skin syndrome), which is caused by Staphylococcus aureus, are seemingly unrelated diseases. However, 200 years ago, astute clinicians realized that these diseases had enough clinical similarities to call bullous impetigo and the scalded-skin syndrome in infants "pemphigus neonatorum." 1,2 In this review we explain how a common mechanism accounts for the clinical overlap of these blistering diseases of the skin, and how the unraveling of the molecular pathophysiology of pemphigus provided the clues that were necessary to determine the mechanism of the formation of blisters in bullous impetigo and the staphylococcal scalded-skin syndrome. We also discuss how this new understanding of the pathophysiology of pemphigus could improve the diagnosis and treatment of this potentially life-threatening disease. PemphigusThere are two major types of pemphigus, pemphigus vulgaris and pemphigus foliaceus. 3 Patients with pemphigus vulgaris present with blisters and erosions of mucous membranes and skin. There are two subtypes of pemphigus vulgaris: the mucosal-dominant type, with mucosal lesions but minimal skin involvement, and the mucocutaneous type, with extensive skin blisters and erosions in addition to mucosal involvement (Fig. 1A). Patients with pemphigus foliaceus have scaly and crusted superficial erosions of the skin but not of mucous membranes (Fig. 1B).The blisters of pemphigus vulgaris are characterized by a loss of cell adhesion in the deep epidermis, just above the basal layer (Fig. 1C), whereas in pemphigus foliaceus, the loss of cell adhesion is in the more superficial epidermis, just below the stratum corneum, which is the layer of dead keratinocytes that forms the barrier of the skin (Fig. 1D).The blood of patients with pemphigus contains IgG antibodies that bind to the surface of normal keratinocytes; this binding is shown with the use of immunofluorescence ( Fig. 1E and 1F). Immunofluorescence staining also shows IgG antibodies on the surface of the keratinocytes in biopsy specimens of the skin from patients with pemphigus.These antibodies, which are autoantibodies because they react with the patient's own cells, are directly pathogenic -that is, they can cause loss of adhesion between keratinocytes, which results in blistering. When injected into neonatal mice, human IgG from patients with pemphigus vulgaris or pemphigus foliaceus binds to the surface of the epidermal keratinocytes (Fig. 1I) and causes blisters (Fig. 1G) with the typical histologic features of pemphigus vulgaris (Fig. 1H) or pemphigus foliaceus (Fig. 2D). 4,5 Therefore, pemphigus vulgaris and pemphigus foliaceus are related in that they The New England Journal of Medicine Downloaded from nejm.org at SHIRP on October 8, 2012. For personal use only. No other uses without permission.