No abstract

No abstract

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.

Exfoliative toxin A, produced by Staphylococcus aureus, causes blisters in bullous impetigo and its more generalized form, staphylococcal scalded-skin syndrome. The toxin shows exquisite specificity in causing loss of cell adhesion only in the superficial epidermis. Although exfoliative toxin A has the structure of a serine protease, a target protein has not been identified. Desmoglein (Dsg) 1, a desmosomal cadherin that mediates cell-cell adhesion, may be the target of exfoliative toxin A, because it is the target of autoantibodies in pemphigus foliaceus, in which blisters form with identical tissue specificity and histology. We show here that exfoliative toxin A cleaved mouse and human Dsg1, but not closely related cadherins such as Dsg3. We demonstrate this specific cleavage in cell culture, in neonatal mouse skin and with recombinant Dsg1, and conclude that Dsg1 is the specific receptor for exfoliative toxin A cleavage. This unique proteolytic attack on the desmosome causes a blister just below the stratum corneum, which forms the epidermal barrier, presumably allowing the bacteria in bullous impetigo to proliferate and spread beneath this barrier.

No abstract

Langerhans cells (LC) are the principal accessory cells present in epidermis. Because LC have limited capacity for self-renewal, epidermis is continually repopulated by as-yet uncharacterized bone marrow-derived LC progenitors. In addition, although LC persist in epidermis for extended periods, LC are induced to migrate from skin to regional lymph nodes after antigen exposure. To begin to elucidate mechanisms involved in LC trafficking, we characterized LC-keratinocyte (KC) interactions. Here we report that fresh murine LC express cadherins, and that LC adhere to KC in vitro through E-cadherin. Cultured LC (which may bear a phenotypic and functional relationship to LC that have migrated to lymph nodes) express lower levels of E-cadherin and exhibit decreased affinity for KC. These results suggest that expression of E-cadherin by LC promotes persistence of these cells in epidermis, and that cadherins may play important and unanticipated roles in interactions between leukocytes and epithelia.

Complementary DNA cloning of the 130-kD pemphigus vulgaris (PV) autoantigen (PVA) has indicated that it is a member of the cadherin family of Ca2-dependent cell adhesion molecules. By homology with typical cadherins, PVA has five extracellular domains (EC1 through EC5). To localize immunogenic domains and to determine whether antibodies against them might be pathogenic, we produced,8-galactosidase fusion proteins with cDNA encoding different portions of the extracellular domains of PVA (ECi-2, EC3-5, and each individual domain). Immunoblot analysis of these fusion proteins with 23 PV patients' sera demonstrated that major immunogenic regions of PVA are located on the EC1, EC2, and EC4 domains. IgG was affinity-purified from PV sera on fusion proteins representing the amino (EC1-2) and carboxy (EC3-5) terminus of the extracellular PVA, and injected into neonatal mice. PV IgG affinity-purified on the EC1-2 fusion protein caused suprabasilar acantholysis, the typical histological finding of PV, but IgG affinity-purified on the EC3-5 fusion protein or,6-galactosidase alone did not. These results indicate that at least one pathogenic epitope, which is sufficient to cause suprabasilar acantholysis in neonatal mice, is located on the amino-terminal region of PVA, an area thought to be important in cadherin homophilic adhesion. (J. Clin. Invest. 1992. 90:919-926.)