title: The extent of desmoglein 3 depletion in pemphigus vulgaris is dependent on Ca(2+)-induced differentiation: a role in suprabasal epidermal skin splitting?
abstract: Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes and is characterized by development of autoantibodies against the desmosomal cadherins desmoglein (Dsg) 3 and Dsg1 and formation of intraepidermal suprabasal blisters. Depletion of Dsg3 is a critical mechanism in PV pathogenesis. Because we did not detect reduced Dsg3 levels in keratinocytes cultured for longer periods under high-Ca(2+) conditions, we hypothesized that Dsg depletion depends on Ca(2+)-mediated keratinocyte differentiation. Our data indicate that depletion of Dsg3 occurs specifically in deep epidermal layers both in skin of patients with PV and in an organotypic raft model of human epidermis incubated using IgG fractions from patients with PV. In addition, Dsg3 depletion and loss of Dsg3 staining were prominent in cultured primary keratinocytes and in HaCaT cells incubated in high-Ca(2+) medium for 3 days, but were less pronounced in HaCaT cultures after 8 days. These effects were dependent on protein kinase C signaling because inhibition of protein kinase C blunted both Dsg3 depletion and loss of intercellular adhesion. Moreover, protein kinase C inhibition blocked suprabasal Dsg3 depletion in cultured human epidermis and blister formation in a neonatal mouse model. Considered together, our data indicate a contribution of Dsg depletion to PV pathogenesis dependent on Ca(2+)-induced differentiation. Furthermore, prominent depletion in basal epidermal layers may contribute to the suprabasal cleavage plane observed in PV.
authors.affiliation: Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Spindler
authors.forename: Alexander
authors.initials: A
authors.lastname: Endlich
authors.forename: Eva
authors.initials: E
authors.lastname: Hartlieb
authors.forename: Franziska
authors.initials: F
authors.lastname: Vielmuth
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001768:Blister / Q000150:complications / Q000473:pathology; D002118:Calcium / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D051183:Desmoglein 1 / Q000378:metabolism; D051301:Desmoglein 2 / Q000378:metabolism; D051184:Desmoglein 3 / Q000172:deficiency* / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010392:Pemphigus / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051183:Desmoglein 1; D051301:Desmoglein 2; D051184:Desmoglein 3; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D002118:Calcium