The extend of desmoglein 3 depletion in pemphigus vulgaris is dependent on Ca2+‐induced differentiation – a role in suprabasal epidermal skin splitting?

Abstract

Pemphigus vulgaris (PV) is an autoimmune disease of skin and mucous membranes characterized by formation of intraepidermal blisters. Patients develop autoantibodies against the desmosomal cadherins desmoglein (Dsg) 3 and 1, leading to suprabasal keratinocyte detachment. Depletion of Dsg3 was reported to be a critical mechanism in PV pathogenesis. Because we did not detect reduced Dsg3 levels in keratinocytes cultured for longer time periods in high Ca2+ conditions, we hypothesized that Dsg depletion was dependent on Ca2+-mediated keratinocyte differentiation. Our data indicate that depletion of Dsg3 occurs specifically in deep epidermal layers both in PV patient skin and an organotypic raft model of human epidermis. Also, depletion was prominent in cultured primary keratinocytes as well as in HaCaT cells incubated in high Ca2+ media for 3d but is less pronounced in HaCaT cultures after 8d. These effects were dependent on protein kinase C alpha (PKCα) signaling because inhibition of PKCα blunted both Dsg3 depletion and loss of intercellular adhesion. Moreover, PKCα inhibition blocked suprabasal Dsg3 depletion in cultured human epidermis and blister formation in a neonatal mouse model. Taken together, our data indicate a contribution of Dsg depletion to PV pathogenesis dependent on Ca2+-induced differentiation, which may contribute to the suprabasal cleavage plane observed in PV.