Van der Wier G, Jonkman MF, Pas HH et al.Ultrastructure of acantholysis in pemphigus foliaceus re-examined from the current perspective. Br J Dermatol 167:1265-1271

Centre for Blistering Diseases, Department of Dermatology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
British Journal of Dermatology (Impact Factor: 4.28). 07/2012; 167(6). DOI: 10.1111/j.1365-2133.2012.11173.x
Source: PubMed


Background Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering disease that is characterized by superficial blistering of the skin, and according to the current perspective is caused by autoantibodies directed against desmoglein (Dsg) 1.
Objectives To examine early acantholysis in the skin of patients with PF at an ultrastructural level.
Methods Two Nikolsky-negative (N−), five Nikolsky-positive (N+) and two lesional skin biopsies from immunoserologically defined patients with PF were studied by light and electron microscopy.
Results We found no abnormalities in N− PF skin, whereas all the N+ skin biopsies displayed intercellular widening between desmosomes, a decreased number of desmosomes and hypoplastic desmosomes in the lower epidermal layers. Acantholysis was present in two of five N+ biopsies, but only in the upper epidermal layers. The lesional skin biopsies displayed acantholysis in the higher epidermal layers. Hypoplastic desmosomes were partially (pseudo-half-desmosomes) or completely torn off from the opposing cell.
Conclusion We propose the following mechanism for acantholysis in PF: initially PF IgG causes a depletion of nonjunctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of nonjunctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic desmosomes and a decreased number of desmosomes. In addition, antibodies might promote disassembly of desmosomes. In the upper layers of the epidermis, where Dsg3 is not expressed and cannot compensate for Dsg1 loss, ongoing depletion of Dsg1 will finally result in a total disappearance of desmosomes and subsequent acantholysis.

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Available from: Gerda van der Wier, Jun 18, 2014
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    • "Intercellular widening is defined as 40.5 μm gap between two neighboring cells, which are still in contact. Until recently, this widening was considered to be the first evidence of acantholysis; however, it is also present in basal and suprabasal layers of the skin and mucosa of PF patients where acantholysis is absent (Guedes et al., 2002; Oktarina et al., 2011; van der Wier et al., 2012). Thus, nonjunctional Dsg1 apparently is, in a yet-to-be uncovered way, important for interdesmosomal cohesion as loss is associated with widening. "
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    ABSTRACT: Large-scale electron microscopy ("nanotomy") allows straight forward ultrastructural examination of tissue, cells, organelles and macromolecules in a single dataset. Such dataset equals thousands of conventional electron microscopy images and is freely accessible. The software allows zooming in and out of the image from total overview to nanometer scale resolution in a 'Google Earth' approach. We studied the life-threatening human autoimmune blistering disease pemphigus, using nanotomy. The pathomechanism of cell-cell separation (acantholysis) that underlies the blistering is poorly understood. Ultrastructural examination of pemphigus tissue revealed previously unreported findings: (i) presence of double membrane structures between cells in all pemphigus types; (ii) absence of desmosomes around spontaneous blisters in pemphigus foliaceus; (iii) lower level blistering in pemphigus foliaceus when force induced, and (iv) intercellular widening at non-acantholytic cell layers. Thus, nanotomy delivers open-source electron microscopic maps of patient tissue, which can be analyzed for additional anomalies from any computer by experts from different fields.Journal of Investigative Dermatology accepted article preview online, 19 March 2015. doi:10.1038/jid.2015.109.
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    • "In a subsequent study, we observed that, to a limited extent, the desmosomes were smaller in the lower but not in the higher epidermal layers of N þ PF skin. The reduction of desmosome size extends to the higher layers and advances further in the higher layers of lesional PF skin, where spontaneous acantholysis occurred (Van der Wier et al., 2012). With this morphometric study, we have shown that desmosomal size is decreased in the lower layers of N þ PF skin and N þ mcPV skin, but not in mdPV skin. "
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    ABSTRACT: Abbreviations: Dsg1, desmoglein 1; Dsg3, desmoglein 3; ECS, epithelial cell surface; mcPV, mucocutaneous pemphigus vulgaris; mdPV, mucosal-dominant pemphigus vulgaris; N−, Nikolsky negative; N+, Nikolsky positive; PF, pemphigus foliaceus; PV, pemphigus vulgaris
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