Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes

Abstract

Abstract. Pemphigus vulgaris antigen (PVA) is a member of the desmoglein subfamily of cadherin cell adhesion molecules. Because autoantibodies in this disease cause blisters due to loss of epidermal cell adhesion, and because desmoglein is found in the desmosome cell adhesion junction, we wanted to determine if PVA is also found in desmosomes. By immunofluorescence, PV IgG bound, in a dotted pattern, to the cell surface of cultured human keratinocytes induced to differentiate with calcium, suggesting junctional staining. However, by preembedding, immunogold electron microscopic studies only slight labeling could be detected in desmosomes, presumably because of difficulty in gold penetration of intact desmosomes. We therefore treated the keratinocytes with 0.01% trypsin in 1 mM calcium, conditions known to preserve cadherin antigenicity but that caused slight separation of desmosomes, before immunogold staining. In this case there was extensive labeling of the extracellular part of desmosomes but not of the interdesmosomal cell membrane which was stained with anti-/32-microglobulin antibodies. To confirm the specificity of this binding we showed that antibodies raised in rabbits against the extracellular portions of PVA also bound desmosomes in these cultures. In intact mouse epidermis we could also show slight, but specific, immunogold desmosomal labeling with PV IgG. Furthermore, neonatal mice injected with PV IgG affinity purified on PVA showed desmosomal separation with the IgG localized to desmosomal cores. These results indicate that PVA is organized and concentrated within the desmosome where it presumably functions to maintain the integrity of stratifying epithelia. p EMPHIGUS vulgaris (PV) ~ is an autoimmune diseasein which blisters of skin and mucous membranes result from loss of epithelial cell-to-cell adhesion, a pathologic process called acantholysis (31). Immunofluorescence studies demonstrate that PV patients have IgG bound on their epidermal cell surfaces in vivo and also have circulating IgG that binds to the cell surface of normal stratified squamous epithelia (5, 6). These PV autoantibodies have been shown to be pathogenic by both clinical and experimental observations (for review see reference 29).The antigen (PVA) recognized by PV autoantibodies has been characterized by immunochemical methods. Immunoprecipitation of cultured keratinocyte and normal human epidermal extracts demonstrates that PV sera bind a 130-kD glycoprotein which forms a stoichiometric complex with plakoglobin (22), a plaque protein of intercellular adhering junctions (i.e., desmosomes and adherens junctions) (8).Recent eDNA cloning has demonstrated that the PVA is a member of the cadherin supergene family (3). The origi-

Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce pemphigus vulgaris–like lesions

“…Further, IgGs eluted from recombinant Dsg molecules elicit acantholysis and gross skin blisters in neonatal BALB/c mice (19)(20)(21)(22)(23). Surprisingly, although both the recombinant protein representing the extracellular epitope of Dsg 3 and a chimeric baculoprotein combining sequences of the extracellular epitope of Dsg 3 and of the Fc portion of human IgG1 effectively absorb anti-Dsg 3 antibody from PV sera, only absorption on the chimeric baculoprotein can eliminate the antibodies capable of causing gross skin blisters in neonatal mice.…”

Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris

“…These antigens have been identified as desmogleins (Dsg's), transmembrane desmosomal glycoproteins belonging to the cadherin supergene family of calcium-dependent adhesion molecules (5)(6)(7). Dsg1 is the autoantigen recognized by PF antibodies, whereas Dsg3 is specifically recognized by PV autoantibodies (8)(9)(10)(11)(12)(13).…”

Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris.

“…Dsg3 is a transmembrane protein localized in the desmosome (11), a structure that is involved in epidermal cell-cell adhesion and, hence, in maintaining the structural integrity of the epidermis. The intracellular domain of Dsg3 appears to interact with a desmosomal plaque component, plakoglobin, linking it to the cytoskeleton, whereas the extracellular domain mediates homophilic interactions that bring about cell adhesion (10,12).…”