Binding of autoantibodies is not restricted to desmosomes in pemphigus vulgaris:

Abstract

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune blistering diseases characterized by a loss of cell-cell adhesion and by autoantibodies directed against epidermal cadherins. PF antigen has been established as desmoglein I which is located strictly on the desmosome, whereas the precise ultrastructural localization of PV antigen remains unclear and controversial to date. To further investigate this question, we compared the location of immune deposits in 14 patients with PV and 10 patients with PF by both direct and indirect immunoelectron microscopy (IEM). Inclusion criteria were based upon clinical features, histological level of cleavage and characterization of circulating antibodies by Western blot on epithelial bovine tongue extracts. IEM was performed on unfixed 0.7-mm slices of skin for the direct technique or on normal skin for the indirect technique using peroxidase labelling. In PF, by both direct and indirect IEM, immune deposits were located on the extracellular part of desmosomes (desmoglea) in all the samples studied. In PV, by both direct and indirect IEM, deposits were situated on the desmoglea and along large portions of the keratinocyte membrane without desmosomal structures in 15 of the 18 samples studied and only on the desmoglea in 3 samples. These results suggest that, in contrast to PF, the target antigen in PV is not always restricted to desmosomes. As various types of adherens junctions have been reported to mediate cell adhesion in the epidermis, the PV antigen could be a component of desmosomes and of other focal adhesions.

Pemphigus autoimmunity: Hypotheses and realities

“…In fact, although Dsg molecules are indeed predominantly localized to desmosomes [168], binding of PV IgG extends well beyond the desmosomes decorating the entire surface of keratinocytes [169]. As already mentioned, the Dsg-Fc-IgG constructs were found to be not specific for Dsg 1 or 3 antibodies [18,36].…”

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

“…Although it has been postulated that binding of pemphigus IgGs to the desmosomal cadherins Dsg 1 and 3 interferes with cell-cell adhesion due to steric hindrance (42), binding of pemphigus autoantibodies to KC is not restricted to the desmosomal areas (43,44). Acantholysis in both skin and organ cultures treated with pemphigus IgGs starts from intracellular events such as retraction of tonofilaments, followed by widening of the intercellular space at the non-desmosomal areas with desmosomes remaining intact (45)(46)(47)(48)(49).…”

Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model

“…One of the earliest indications that alternative mechanisms may drive pathogenesis was the observation that IgG from PF patients could induce disease in mice without interfering with trans-adhesion of Dsg1 ( 27 ). It was noted in multiple studies that PVIgG was seen to bind extra-desmosomal spaces on the surface of keratinocytes, allowing for the possibility that binding of autoAbs outside of desmosomes may affect disease ( 3 , 28 ). It was also shown that PVIgG binding induced cytoskeletal changes and the retraction of keratin intermediate filaments before any visible changes in desmosomes ( 29 – 33 ).…”