Antibodies to desmoglein 1 and 3, and the clinical phenotype of pemphigus vulgaris

Jamora, Maria Jasmin J.; Jiao, Diane; Bystryn, Jean‐Claude

doi:10.1067/mjd.2003.438

Cited by 71 publications

(84 citation statements)

References 5 publications

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“…According to the Dsg compensation hypothesis, such patients should have acantholysis involving all epidermal layers as the adhesion properties of both molecules would be blocked. One cannot argue that the Dsg 1 antibodies are present in low and, thus, ineffective levels because their levels can be as high or higher than those against Dsg 3 [13][14][15] ; nor that the anti-Dsg 1 antibodies are directed against nonpathogenic epitopes as anti-Dsg 1 isolated from patients with PV causes acantholysis in neonatal mice. 16 Both observations point to factors other than Dsg compensation as being involved in the localization of PV lesions to basal cells.…”

Section: The Restriction Of Acantholysis To the Basal Layer In Pv Doementioning

confidence: 91%

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

Bystryn¹,

Grando²

2006

Journal of the American Academy of Dermatology

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Section: The Restriction Of Acantholysis To the Basal Layer In Pv Doementioning

confidence: 91%

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

Bystryn¹,

Grando²

2006

Journal of the American Academy of Dermatology

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“…In (PV) patients showing both mucous membrane and skin involvement, Abs to both Dsg 3 and Dsg 1 may be detected (2,16,17). However, there are also cases where the Ab profile against Dsg 1 and 3 in PV does not strictly correlate with these clinical phenotypes (18,19). At present, direct evidence that the presence of Dsg 3-specific Abs in PV but not in PF may account for the more severe clinical phenotype of PV compared with PF patients is lacking.…”

mentioning

confidence: 98%

Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction

Heupel

Zillikens

Drenckhahn

et al. 2008

The Journal of Immunology

124

135

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The autoimmune blistering skin disease pemphigus is caused by autoantibodies against keratinocyte surface Ags. In pemphigus vulgaris (PV), autoantibodies are primarily directed against desmosomal cadherins desmoglein (Dsg) 3 and Dsg 1, whereas pemphigus foliaceus (PF) patients only have Abs against Dsg 1. At present, it is unclear whether Dsg autoantibodies contribute to pemphigus pathogenesis by direct inhibition of Dsg transinteraction. Using atomic force microscopy, we provide evidence that PV-IgG directly interfere with homophilic Dsg 3 but, similar to PF-IgG, not with homophilic Dsg 1 transinteraction, indicating that the molecular mechanisms in PV and PF pathogenesis substantially differ. PV-IgG (containing Dsg 3 or Dsg 1 and Dsg 3 autoantibodies) as well as PV-IgG Fab reduced binding activity of Dsg 3 by ∼60%, comparable to Ca2+ depletion. Similarly, the mouse monoclonal PV Ab AK 23 targeting the N-terminal Dsg 3 domain and AK 23 Fab reduced Dsg 3 transinteraction. In contrast, neither PV-IgG nor PF-IgG blocked Dsg 1 transinteraction. In HaCaT monolayers, however, both PV- and PF-IgG caused keratinocyte dissociation as well as loss of Dsg 1 and Dsg 3 transinteraction as revealed by laser tweezer assay. These data demonstrate that PV-IgG and PF-IgG reduce Dsg transinteraction by cell-dependent mechanisms and suggest that in addition, Abs to Dsg 3 contribute to PV by direct inhibition of Dsg transinteraction.

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“…8 ACh signaling in keratinocytes linked to the regulation of expression and function of adhesion molecules and cholinergic drugs affects cell shape, adhesion, and cytoplasm motility (reviewed by Grando 49 ). Because of the lack of a strong correlation between the clinical phenotype of PV and the presence of anti-desmoglein 1 and 3 antibodies 50 and since PV-like lesions can be induced in neonatal mice in the absence of these antibodies, 9 the immunopathogenesis of PV can be explained through the "multiple hit" hypothesis. We propose that acantholysis in PV results from synergistic and cumulative effects of autoantibodies targeting keratinocyte cell membrane antigens of different kinds, including (1) molecules that regulate cell shape and adhesion (eg, ACh receptors) and (2) molecules that mediate cell-tocell adhesion (eg, desmosomal cadherins).…”

Section: Commentmentioning

confidence: 99%