English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

E ven by clinical and histologic findings alone it is reasonable to suspect that the pathogenesis of certain blistering skin diseases might involve abnormalities in adhesion structures. The best defined buUous diseases in this regard are pemphigus (of which there are two basic types: vulgaris and foliaceus) and bullous pemphigoid (BP) (1-3). Histology shows that the blisters in pemphigus result from a loss of cell-tocell adhesion, a pathologic process called acantholysis. In pemphigus vulgaris (PV) loss of adhesion occurs deep in the epidermis, just above the basal layer, whereas in pemphigus foliaceus (PF) the defective adhesion is more superficial, in the granular layer. In BP blisters result from loss of adhesion of the basal cells to the basement membrane. The next clue that adhesion structures might be involved in these diseases came when immunofluorescence studies demonstrated that both pemphigus and BP patients have autoantibodies in their skin as well as in their serum (4). In pemphigus the autoantibodies were shown to be directed against the keratinocyte cell surface. In fact, investigators were so sure that these antibodies interfered directly with adhesion, they were termed, somewhat fancifully, anti-intercellular cement substance antibodies (5). In BP the antibodies are directed against the epidermal basement membrane zone. In both instances, the findings of autoantibodies in areas of defective epidermal cell adhesion suggested that these antibodies might be directed against adhesion structures or molecules. The next stage in the evolution of our knowledge about these diseases came when models were developed to test whether patients' autoantibodies are pathogenic. In pemphigus of both types the answer became dear: pemphigus IgG autoantibodies can cause disease (i.e., loss of cell adhesion) without the additional contribution of complement or inflammatory cells. This was shown by both a skin organ culture model (6) and passive transfer of autoantibodies to neonatal mice (7,8). However, in BP the pathogenicity of the antibodies is not so clear-cut. Probably fixation of complement and recruitment of inflammatory cells is necessary for blister formation (9). Until recently, there has not been a good animal model to test this hypothesis. Now, however, it has been shown that rabbit antibodies raised to a major antigenic epitope of one of the BP antigens (defined below as BPAG2) can induce disease when passively transferred to neonatal mice (10). From the above data, we know that pemphigus and BP are diseases with pathogenic autoantibodies directed against areas of the epidermis in which loss of cell-cell or cell-substrate adhesion occurs. Therefore, it was reasonable to hypothesize that these autoantibodies are directed against adhesion molecules or structures. This hypothesis has been confirmed (Table 1). Immunochemical studies demonstrated that PF antigen is desmoglein 1 (Dsgl), a transmembrane glycoprotein of desmosomes (11-13). Molecular cloning of Dsgl indicated that it is a member of the cadherin supergene family of calciumdependent cell adhesion molecules (14). Molecular cloning also revealed that PV antigen is a desmoglein (Dsg3) (14a). Both Dsgl and Dsg3 have been localized by immunoelectron microscopy to desmosomes (15, 16) and, in keratinocytes, both bind plakoglobin, a desmosomal plaque protein (17). Autoantibodies from PV patients, affinity purified on the extracellular region of Dsg3, cause blisters when passively transferred to neonatal mice, and the extracellular region of Dsg3 can completely absorb all pathogenic antibodies from PV sera (18, 19). Immunochemical studies indicated that BP autoantibodies actually identify two distinct proteins, now termed BPAG1 and BPAG2. BPAG1 was characterized by SDS-PAGE as an approximately 230-kD polypeptide, whereas BPAG2 was approximately 180 kD (20, 21). Molecular cloning has confirmed that these two BP antigens are distinct gene products. BPAG1 was found to be homologous in amino acid sequence and structure to desmoplakins I/II, alternatively spliced desmosomal plaque proteins (22-24). Antibodies raised against BPAG1 have been localized by immunoelectron microscopy to the plaque of the hemidesmosome (25), a ceil-basement membrane adhesion junction. Therefore BPAG1 and desmoplakins I/II were the first members of a gene family of cell adhesion junction plaque proteins. Molecular cloning of BPAG2 indicated that it is a transmembrane protein with a COOH-terminal extracellular colhgenous domain, also localized by immunoelectron microscopy to the hemidesmosome (26-30). Once the antigens in the classical autoantibody-mediated blistering diseases were defined at a molecular level, it became clear that certain diseases defied easy classification, and new diseases were thereby defined. One of these is paraneoplastic pemphigus (31). This disease shares clinical and histological features of PV and erythema multiforme (32). These patients have in vivo-bound antibodies against their epidermal basement membrane as well as cell surface, and they have serum antibodies that immunoprecipitate a distinct set of polypeptides from epidermal extracts, dearly different from pemphigus antigens. Among these immunoprecipitated polypeptides are desmoplakins I/II as well as BPAG1, but the others are not

Autoantibodies against adhesion molecules and structures in blistering skin diseases.