Pemphigus is a life-threatening blistering skin disease in which patients’ autoantibodies are directed against desmosomal glycoproteins, resulting in the loss of keratinocyte cell–cell adhesion (1
). The two classic forms of pemphigus are pemphigus foliaceus (PF) and pemphigus vulgaris (PV) (2
). In PF, patients develop skin erosions that result from blisters within the granular layers of the superficial epidermis. Patients with PF, however, do not develop blisters or erosions of the mucous membranes. Two-thirds of patients with PV develop mucous membrane blisters early in the course of their disease, and as the disease progresses, they develop skin blisters as well (3
). Histologically, PV blisters occur deep in the epidermis between the basal and most immediate suprabasal keratinocytes, as well as between the basal cells themselves.
Pemphigus autoantibodies recognize cell-surface antigens of keratinocytes (4
). These antigens have been identified as desmogleins (Dsg's), transmembrane desmosomal glycoproteins belonging to the cadherin supergene family of calcium-dependent adhesion molecules (5
). Dsg1 is the autoantigen recognized by PF antibodies, whereas Dsg3 is specifically recognized by PV autoantibodies (8
). However, about one-half to two-thirds of PV sera also contain antibodies against Dsg1 (10
). Most patients with early PV and only mucous membrane lesions have only anti-Dsg3 antibodies, whereas most patients with later disease, involving the skin, have both anti-Dsg3 and anti-Dsg1 antibodies (13
There is compelling evidence for the pathogenicity of these autoantibodies in pemphigus. One example is the development of skin blisters in neonatal mice when injected with pemphigus IgG (17
). Similar to the pathology of human pemphigus, PF IgG induces blisters in the superficial epidermis, and PV IgG induces deep suprabasilar blisters in neonatal mice. Immunoadsorption and affinity chromatography of pemphigus sera have confirmed that the anti-desmoglein antibodies are pathogenic in pemphigus. PF sera that are immunoadsorbed with the extracellular domain of Dsg1 are no longer pathogenic in neonatal mice, whereas IgG that has been affinity purified from PF sera on Dsg1 causes superficial skin blisters (19
). Similarly, PV sera immunoadsorbed with the extracellular domain of Dsg3 lose pathogenic activity (20
Although these anti-desmoglein antibodies have been shown to cause the blister in pemphigus, the pathophysiological mechanism by which they do so has been controversial. Some studies have suggested that pemphigus antibody binding mediates protease release that, in turn, causes loss of cell adhesion (22
). However, we have postulated a more direct effect in which antibodies block the function of the Dsg's in stabilizing cell adhesion in desmosomes (7
). Lending credence to this theory has been the characterization of DSG3null
mice that are essentially equivalent to mice whose Dsg3 function has been completely blocked (26
). These mice have a similar phenotype to patients with PV, with oral mucous membrane lesions in neonates due to suckling and skin erosions at sites of trauma. Both types of lesions show histology typical of PV.
It has been suggested (27
) that the distribution and expression levels of Dsg1 and Dsg3 might account for the characteristic distribution of lesions. For example, Dsg3 is expressed throughout the oral mucosa, whereas it is only expressed in the basal and immediate suprabasal layer of the epidermis (29
). Conversely, Dsg1 is expressed throughout the epidermis and oral mucosa, but more intensely superficially, and very weakly in the deep epidermis. These type of observations have led to the hypothesis, first advanced by Shirakata et al.
), that where Dsg3 and Dsg1 are coexpressed, antibodies against either one alone are not efficient at causing spontaneous blistering (e.g.
, anti-Dsg1 in the oral mucous membrane where Dsg3 is highly expressed throughout). On the other hand, in areas where Dsg1 is expressed without concomitant Dsg3, anti-Dsg1 alone is efficient at causing spontaneous blister formation (e.g.
, in the superficial epidermis of patients with PF).
In this report, we use passive transfer of pemphigus IgG to normal and DSG3null neonatal mice to test this hypothesis. We will show that if both Dsg1 and Dsg3 are present concomitantly at a tissue site, antibodies against either alone are inefficient at causing a spontaneous blister. In contrast, antibodies against both Dsg's are highly efficient at blister formation if both are concomitantly expressed in the tissue, or antibodies against one alone are efficient if the other is not coexpressed. These findings are consistent with an explanation for blister formation in which autoantibodies against either Dsg1 or Dsg3 specifically block only its function, in contrast to causing release of proteases that nonspecifically cause loss of cell adhesion. Finally, by knowing the anti-desmoglein specificity of pemphigus sera and the Dsg distributions in stratified squamous epithelia, the localization of blister formation in PV and PF can be explained.