Pemphigus, Bullous Impetigo, and the Staphylococcal Scalded-Skin Syndrome

Abstract

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.

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

“…Based on the targeted Ags, AIBDs can be divided into pemphigus and pemphigoid diseases. In pemphigus disease, autoantibodies to desmosomal proteins directly cause blister formation, whereas in pemphigoid disease, blister formation requires the activation of immune mechanisms through the Fc portion of the autoantibodies (1,2). Despite improved therapeutic options, the mortality of patients with pemphigus and pemphigoid remains high (3); this can be attributed, in part, to the extent of immunosuppressive therapy (4).…”

Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus

“…In contrast to classical cadherins present in adherens junctions that primarily undergo homophilic trans-interaction, desmosomal cadherins are generally believed to mediate both homo-and heterophilic binding (9). Recently, an important role of Dsc3 for integrity of murine epidermis was demonstrated in animals with conditional epidermal Dsc3 deficiency that suffered from severe intraepidermal blister formation (10) comparable with the phenotype of the autoimmune bullous skin disease pemphigus vulgaris (PV) (11). PV is associated with antibodies (Abs) against Dsg3, in part combined with Abs targeting Dsg1, whereas Dsg1 Abs alone are associated with pemphigus foliaceus (PF).…”

Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus

“…Autoantibodies in pemphigus vulgaris (PV) 4 are mainly directed against the adhesion molecules desmoglein (Dsg) 3 and Dsg1 (1,2). Recently, we provided direct evidence that PV autoantibodies directly block Dsg3 transinteraction (3).…”