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PV is caused by autoantibodies that target cadherins, specifically desmogleins, though there may be some role for desmocollin; thus, this is a type 2 hypersensitivity reaction.[24][25] Acantholysis, or the loss of keratinocyte–keratinocyte adhesion, is interrupted by circulating IgG autoantibodies to intercellular adhesion molecules.[26][27] Acantholysis is seen as a result of the autoantibodies destroying the intracellular connections, leading to bullae that can easily rupture (known clinically as the Nikolsky sign). A “super-compensation hypothesis” recently submitted by Sinha et al. proposes that additional factors may also play a role in PV.[28] Multiple mechanisms for antibody-induced acantholysis have been suggested, including the induction of signal transduction and the inhibition of adhesive molecule function through steric hindrance, which can trigger cell separation.[29] The pathogenesis of PV has been described in more detail by Hammers et al.[30] In patients with PV, autoantibodies against desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) is the purported cause.[31] Desmogleins are transmembrane glycoproteins that are an integral part of desmosomes which, in part, are required for cell–cell adhesion via interaction with intermediate filaments. The most common targets of desmoglein for IgG antibodies are the extracellular cadherin domains, which can result in the loss of desmosome-adhesive properties. These signaling pathways trigger endocytosis, depletion, and direct inhibition of Dsg 3 interactions.[32] It is generally believed that the amino portion of the cadherin proteins is most implicated in the pathogenesis of acantholysis leading to PV.[33] Many animal models have shown that enzymatic inactivation of Dsg 1 and gene deletion of Dsg 3 results in pathology similar to PV.[34][35] This phenomenon was observed to be dose-dependent and suggests that reducing the circulating levels of IgG against Dsg 1 and Dsg 3 can improve patient outcomes.[36] In patients with primarily cutaneous disease, Dsg 1 likely plays a role more superficially, whereas Dsg 3 is more likely to be found in deeper cutaneous structures and mucous membranes.[37][38] The implication is that Dsg 3 can compensate for the absence of Dsg 1 in mucosal structures (thus demonstrating PV in cutaneous lesions only). In contrast, Dsg 1 without Dsg 3 is insufficient to manage mucous membranes or cutaneous lesions alone, implying that Dsg 1 is in lower proportion in mucous membranes. The binding of antibodies to desmogleins has been confirmed by epitope mapping and is presumed to disrupt desmoglein binding by affecting steric hindrance.[39] Another theory for the pathophysiology of PV is the desmoglein nonassembly depletion hypothesis. This theory suggests that autoantibodies not only bind desmoglein but that they also bind each other, leading to crosslinking and the inability of desmosomes to maintain cell–cell adhesion.[40][41] Read less