Pemphigus Vulgaris and Pemphigus Foliaceus Sera Show an Inversely Graded Binding Pattern to Extracellular Regions of Desmosomes in Different Layers of Human Epidermis

Shimizu, Hiroshi; Masunaga, Takuji; Ishiko, Akira; Kikuchi, Arata; Hashimoto, Takashi; Nishikawa, Takeji

doi:10.1111/1523-1747.ep12316695

Cited by 88 publications

(60 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have established previously that different Dsc isoforms can be located in the same individual desmosomes (20,21), and the same probably is true for Dsgs (59). We detected no patterned arrangement of the different Dsc isoforms in epidermal desmosomes, although the immuno-gold labeling technique may not have sufficient resolution to resolve such a pattern (21).…”

Section: Discussionsupporting

confidence: 48%

Membrane-impermeable Cross-linking Provides Evidence for Homophilic, Isoform-specific Binding of Desmosomal Cadherins in Epithelial Cells

Nie

Merritt

Rouhi-Parkouhi

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Desmosomes and adherens junctions are cadherin-based protein complexes responsible for cell-cell adhesion of epithelial cells. Type 1 cadherins of adherens junctions show specific homophilic adhesion that plays a major role in developmental tissue segregation. The desmosomal cadherins, desmocollin and desmoglein, occur as several different isoforms with overlapping expression in some tissues where different isoforms are located in the same desmosomes. Although adhesive binding of desmosomal cadherins has been investigated in a variety of ways, their interaction in desmosome-forming epithelial cells has not been studied. Here, using extracellular homobifunctional cross-linking, we provide evidence for homophilic and isoform-specific binding between the Dsc2, Dsc3, Dsg2, and Dsg3 isoforms in HaCaT keratinocytes and show that it represents trans interaction. Furthermore, the cross-linked adducts are present in the detergent-insoluble fraction, and electron microscopy shows that extracellular cross-linking probably occurs in desmosomes. We found no evidence for either heterophilic or cis interaction, but neither can be completely excluded by our data. Mutation of amino acid residues Trp-2 and Ala-80 that are important for trans interaction in classical cadherin adhesive binding abolished Dsc2 binding, indicating that these residues are also involved in desmosomal adhesion. These interactions of desmosomal cadherins may be of key importance for their ordered arrangement within desmosomes that we believe is essential for desmosomal adhesive strength and the maintenance of tissue integrity.

show abstract

Section: Discussionsupporting

confidence: 48%

Membrane-impermeable Cross-linking Provides Evidence for Homophilic, Isoform-specific Binding of Desmosomal Cadherins in Epithelial Cells

Nie

Merritt

Rouhi-Parkouhi

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…It has been suggested (27)(28)(29)(30) that the distribution and expression levels of Dsg1 and Dsg3 might account for the characteristic distribution of lesions. For example, Dsg3 is expressed throughout the oral mucosa, whereas it is only expressed in the basal and immediate suprabasal layer of the epidermis (29,30).…”

Section: Introductionmentioning

confidence: 99%

Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris

et al. 1999

View full text Add to dashboard Cite

“…19 iv) To visualize the desmoglein localization pattern in human epidermis, autoantibodies from patients with PV and PF have been applied. 15,20 In these studies, either whole sera of PV and PF patients were used without characterization of the autoantibody profile 20 or IgG fractions were used after immunosabsorption with recombinant Dsg extracellular domains fused to the Fc portion of human IgG. 15 More recently, it has been suggested that immunoabsorption using this fusion protein containing the extracellular domain of desmogleins is not entirely specific.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Pemphigus Vulgaris and Pemphigus Foliaceus Sera Show an Inversely Graded Binding Pattern to Extracellular Regions of Desmosomes in Different Layers of Human Epidermis

Cited by 88 publications

References 38 publications

Membrane-impermeable Cross-linking Provides Evidence for Homophilic, Isoform-specific Binding of Desmosomal Cadherins in Epithelial Cells

Membrane-impermeable Cross-linking Provides Evidence for Homophilic, Isoform-specific Binding of Desmosomal Cadherins in Epithelial Cells

Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris

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

Contact Info

Product

Resources

About