An Electron Microscopic Study of Acantholysis in Pemphigus Vulgaris*

Wilgram, George F.; Caulfield, James; Lever, Walter F.

doi:10.1038/jid.1961.58

Cited by 171 publications

(66 citation statements)

References 12 publications

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“…Braun-Falco and Vogell (16) suggested that a loss of cell adhesion in pemphigus may be related to alterations in desmosome structure. However, Wilgram et al (17) proposed that desmosome disintegration is secondary to changes in the tonofilaments of epidermal cells in diseased patients. Others have refuted both of these proposals and claim that the primary effect of pemphigus is on the intercellular cement, with secondary effects on the desmosome-tonofilament complex (18 (20) -and yet these tissues appear unaffected by pemphigus autoantibodies.…”

Section: Resultsmentioning

confidence: 99%

Human autoantibodies against desmosomes: possible causative factors in pemphigus.

Jones¹,

Arnn²,

Staehelin³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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Pemphigus is a human disease that causes extensive blistering of the skin. This blistering is related to a loss of epidermal cell cohesion and is accompanied by circulating autoantibodies that stain epidermal cell surfaces, as shown by immunofluorescence microscopy. One of the major components involved in epidermal cell cohesion is the desmosome. The pathological changes that accompany pemphigus led us to determine whether the autoantibodies are specific for desmosomes. Incubation of cultured mouse keratinocytes in medium containing pemphigus antiserum leads to cell separation at cell-cell contact sites, which possess desmosomes. Tissue sections of mouse skin processed for indirect immunofluorescence, using pemphigus antiserum or a rabbit antiserum directed against components of desmosomes, show similar punctate cell-surface staining patterns within the epidermis. Cultured mouse keratinocytes possessing well-defined intermediate filament bundles (tonofilaments) and desmosomes were processed for double indirect immunofluorescence, using a monoclonal antibody directed against mouse skin keratin and either pemphigus antiserum or the desmosome antiserum. The keratinocytes exhibit a complex system of keratin-containing tonofilaments. Tonofilaments in contacting cells are separated by thin dark bands at the cell surface, which correspond precisely to desmosomal plaques seen by phase-contrast microscopy. These bands specifically stain with both pemphigus antiserum and the desmosome antiserum. Double indirect immunofluorescence of the cultured mouse keratinocytes, using pemphigus antiserum and the desmosome antiserum, reveals that the pemphigus autoantibodies stain the same areas of cellcell contact as the desmosome antibodies. Our evidence supports the idea that pemphigus blisters form, at least in part, from a specific antibody-induced disruption of desmosomes in the epidermis.

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Section: Resultsmentioning

confidence: 99%

Human autoantibodies against desmosomes: possible causative factors in pemphigus.

Jones¹,

Arnn²,

Staehelin³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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“…49 In PV, the earliest acantholytic changes occur among basal cells and between them and the first row of suprabasal keratinocytes and consist of detachment of tonofilaments from the attachment plate of the desmosomes. 50 Thereafter, tonofilaments retract into the perinuclear region, followed by disintegration of the desmosomes and the appearance of variable signs of degeneration, such as vacuolization, nuclear pyknosis, and abnormalities with the mitochondria and the endoplasmic reticulum. 5,51 In some mitochondria, cristae are preserved and are partially destroyed in the others.…”

Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

Arredondo

Chernyavsky

Karaouni

et al. 2005

The American Journal of Pathology

112

139

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“…In contrast to epidermolysis bullosa KCs, in which keratin filaments break, pemphigus KCs develop collapse of the tonofilaments, due to their dissociation from the cadherin/plakin complexes. The electron microscopic studies in pemphigus revealed that detachment of tonofilaments occurs before the desmosomes show any visible alterations (32)(33)(34)(35). Although phosphorylation of the adhesion molecules seems to be a major mechanism by which PVIgG induces collapse of the cytoskeleton (36), the role for keratin hyperphosphorylation cannot be excluded (37).…”

Section: Discussionmentioning

confidence: 99%

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Chernyavsky

Arredondo

Kitajima

et al. 2007

Journal of Biological Chemistry

128

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Although it is accepted that pemphigus antibody binding to keratinocytes (KCs) evokes an array of intracellular biochemical events resulting in cell detachment and death, the triggering events remain obscure. It has been postulated that the binding of pemphigus vulgaris IgG (PVIgG) to KCs induces "desmosomal" signaling. Because in contrast to integrins and classical cadherins, desmoglein (Dsg) molecules are not known to elicit intracellular signaling, and because PV patients also produce non-Dsg autoantibodies, we investigated the roles of both Dsg and non-desmoglein PV antigens. The time course studies of KCs treated with PVIgG demonstrated that the activity of Src peaked at 30 min, EGF receptor kinase (EGFRK) at 60 min, and p38 MAPK at 240 min. The Src inhibitor PP2 decreased EGFRK and p38 activities by ϳ45 and 30%, respectively, indicating that in addition to Src, PVIgG evokes other triggering events. The shrinkage of KCs (cell volume reduction) became significant at 120 min, keratin aggregation at 240 min, and an increase of TUNEL positivity at 360 min. Pretreatment of KCs with PP2 blocked PVIgG-dependent cell shrinkage and keratin aggregation by ϳ50% and TUNEL positivity by ϳ25%. The p38 MAPK inhibitor PD169316 inhibited these effects by ϳ15, 20, and 70%, respectively. Transfection of KCs with small interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked ϳ50% of p38 MAPK activity but did not significantly alter the PVIgG-dependent rise in Src and EGFRK activities. These results indicate that activation of p38 MAPK is a late signaling step associated with collapse of the cytoskeleton and disassembly of desmosomes caused by upstream events involving Src and EGFRK. Therefore, the early acantholytic events are triggered by non-Dsg antibodies.

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An Electron Microscopic Study of Acantholysis in Pemphigus Vulgaris*

Cited by 171 publications

References 12 publications

Human autoantibodies against desmosomes: possible causative factors in pemphigus.

Human autoantibodies against desmosomes: possible causative factors in pemphigus.

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

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