A novel explanation for acantholysis in pemphigus vulgaris: The basal cell shrinkage hypothesis

Bystryn, Jean‐Claude; Grando, Sergei A.

doi:10.1016/j.jaad.2005.12.003

Cited by 66 publications

(74 citation statements)

References 43 publications

(39 reference statements)

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“…This supports the hypothesis recently proposed that some cellular signaling mechanisms specific for basal cells might be responsible for deep blistering in PV. 10 Because activation of Rho A by CNFy and CNF-1 abolished autoantibodyinduced epidermal splitting 23 and inactivation of Rho GTPases resulted in keratinocyte dissociation in the same epidermal layers as pemphigus IgG, we conclude that inactivation of Rho A is the major mechanism underlying splitting in human skin in vitro. This supports our recent finding that both PV-IgG and PF-IgG reduced activity of Rho A by approximately 50% and also decreased CNF-1-mediated activation of Rho A by 60 to 70%, indicating that some of the signaling mechanisms induced by pemphigus IgG interfered with Rho A signaling.…”

Section: Skin Blistering As a Multistep Process Involving Different Mmentioning

confidence: 74%

“…2,10,11 i) The model does not explain why blistering in patients with mucocutaneous PV, where Dsg 1-and Dsg 3-specific autoantibodies are present, occurs suprabasally and not throughout the epidermis. ii) The desmoglein compensation hypothesis postulates that the different forms of pemphigus and the clinical stages of PV are distinguishable by antibody profiles and histology.…”

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confidence: 98%

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Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Spindler

Drenckhahn

Zillikens

et al. 2007

The American Journal of Pathology

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According to the desmoglein (Dsg) compensation concept, different epidermal cleavage planes observed in pemphigus vulgaris and pemphigus foliaceus have been proposed to be caused by different autoantibody profiles against the desmosomal proteins Dsg 1 and Dsg 3. According to this model, Dsg 1 autoantibodies would only lead to epidermal splitting in those epidermal layers in which no Dsg 3 is present to compensate for the functional loss of Dsg 1. We provide evidence that both pemphigus foliaceus-IgG containing Dsg 1-but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were equally effective in causing epidermal splitting in human skin and keratinocyte dissociation in vitro. These effects were present where keratinocytes expressed both Dsg 1 and Dsg 3, demonstrating that Dsg 3 does not compensate for Dsg 1 inactivation. Rather, the cleavage plane in intact human skin caused by pemphigus autoantibodies was similar to the plane of keratinocyte dissociation in response to toxin B-mediated inactivation of Rho GTPases. Because we recently demonstrated that pemphigus-IgG causes epidermal splitting by inhibition of Rho A, we propose that Rho GTPase inactivation contributes to the mechanisms accounting for the cleavage plane in pemphigus skin splitting. Pemphigus is an autoimmune blistering skin disease caused by autoantibodies directed to the cadherin-type adhesion molecules desmoglein (Dsg) 1 and 3.1-4 Antibodies against other antigens, including cholinergic receptors, have also been implicated in the pathogenesis.5-9 Several theories have been proposed to explain the mechanisms underlying blister formation by Dsg autoantibodies. However, the different clinical phenotypes of pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are still not fully understood. 10 -12 It is well established that PV is characterized by deep (suprabasal) epidermal blistering, whereas PF exhibits superficial blistering (involving granular or spinous cell layers). In PF, mucous membranes are not involved; whereas in PV, mucosal disease is a regular finding, and skin involvement may occur in addition. 4 Interestingly, these phenotypes usually correlate with different autoantibody profiles. PV patients with only mucosal lesions show autoantibodies to Dsg 3 but not to Dsg 1. PF patients (skin involvement only) reveal autoantibodies to Dsg 1 but not to Dsg 3. In PV patients with both mucous membrane and skin involvement, autoantibodies to Dsg 3 and Dsg 1 may be detected. 4,13,14 These observations, together with studies reporting that Dsg 1 is predominantly expressed in superficial epidermal layers but absent in the suprabasal layer, whereas Dsg 3 is restricted to deep epidermal layers, and that Dsg 1 is less abundantly expressed in mucosal epithelia, have led to the desmoglein compensation hypothesis as an explanation for the different epidermal cleavage planes in PV and PF. 3,4,[15][16][17] According to this model, in the deep epidermis, Dsg 3 compensates for the functional loss of Dsg 1 induced by Ds...

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Section: Skin Blistering As a Multistep Process Involving Different Mmentioning

confidence: 74%

mentioning

confidence: 98%

Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Spindler

Drenckhahn

Zillikens

et al. 2007

The American Journal of Pathology

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“…The pathobiologic outcome of the PVIgG-induced signaling is induction of the apoptotic and/or oncotic pathways, associated with collapse of the cytoskeleton, because of keratin filament retraction and actin reorganization, cell shrinkage, caused by cell volume decrease, and, finally, cellcell dyshesion (acantholysis) (reviewed in Ref. 6). …”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 99%

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Chernyavsky

Arredondo

Kitajima

et al. 2007

Journal of Biological Chemistry

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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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“…In PV, the pathobiological action of AMA synergizes with that of autoantibodies to Dsg molecules uniquely expressed by KCs, so the irreversible damage becomes specific only to this cell type, as in PV. The fact that FcRn is predominantly expressed within the basal epidermal layer (23) may render basal KCs a preferred "functional" target for PVIgGs, explaining why they shrink more than suprabasal KCs (43), despite the fact that both basal and suprabasal KCs are targeted by PVIgGs (44). Our organ culture experiments demonstrated that a combination of AMA and anti-Dsg3 or Dsg1 antibodies induced epidermal splitting at the levels of predominant localization of corresponding Dsg molecules in the epidermis (36).…”

Section: Discussionmentioning

confidence: 84%

Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

Chen

Chernyavsky

Webber

et al. 2015

Journal of Biological Chemistry

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Background:Patients with pemphigus vulgaris develop antibodies to both cell adhesion molecules and intracellular proteins. Results: On the keratinocyte cell membrane, pemphigus autoantibodies form complexes with FcRn internalizing and trafficking them to mitochondria. Conclusion:The pathogenic role of antimitochondrial autoantibodies is complementary to that of anti-desmoglein autoantibodies, because both are required to disrupt the epidermal barrier. Significance: FcRn represents a common acceptor protein for internalization of autoantibodies to intracellular proteins.

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A novel explanation for acantholysis in pemphigus vulgaris: The basal cell shrinkage hypothesis

Cited by 66 publications

References 43 publications

Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

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