Abstract
Pemphigus vulgaris (PV) is an autoimmune skin blistering disease effecting both cutaneous and mucosal epithelia. Blister formation in PV is known to result from the binding of autoantibodies (autoAbs) to keratinocyte antigens. The primary antigenic targets of pathogenic autoAbs are known to be desmoglein 3, and to a lesser extent, desmoglein 1, cadherin family proteins that partially comprise the desmosome, a protein structure responsible for maintaining cell adhesion, although additional autoAbs, whose role in blister formation is still unclear, are also known to be present in PV patients. Nevertheless, there remain large gaps in knowledge concerning the precise mechanisms through which autoAb binding induces blister formation. Consequently, the primary therapeutic interventions for PV focus on systemic immunosuppression, whose side effects represent a significant health risk to patients. In an effort to identify novel, disease-specific therapeutic targets, a multitude of studies attempting to elucidate the pathogenic mechanisms downstream of autoAb binding, have led to significant advancements in the understanding of autoAb-mediated blister formation. Despite this enhanced characterization of disease processes, a satisfactory explanation of autoAb-induced acantholysis still does not exist. Here, we carefully review the literature investigating the pathogenic disease mechanisms in PV and, taking into account the full scope of results from these studies, provide a novel, comprehensive theory of blister formation in PV.
Highlights
Pemphigus vulgaris (PV) is an autoimmune skin blistering disease characterized by the presence of autoantibodies directed against keratinocyte surface antigens
Studies showing that staphylococcal exfoliative toxins, which cleave desmoglein 1 (Dsg1), could produce blisters similar to those seen in PF, indicated that disturbance of desmosomal proteins was capable of causing a loss of cell–cell adhesion [5, 6]
One of the earliest studies that indicated that autoAbs may exert their pathogenic effect through the activation of intracellular cascades demonstrated that plakoglobin (Pkg)-deficient mice were protected from PVIgG-induced blister formation [45]
Summary
Pemphigus vulgaris (PV) is an autoimmune skin blistering disease characterized by the presence of autoantibodies (autoAbs) directed against keratinocyte surface antigens. PV lesions keratinocytes first separate at inter-desmosomal areas and desmosomes are still intact and interacting with neighboring desmosomes [29, 34,35,36] Together, these findings suggested that desmosomal separation may be downstream of other processes induced by the binding of autoAbs. Recently, one research group used AFM to demonstrate that the loss of Dsg binding alone was not sufficient to cause a loss of cell adhesion, strongly indicating that steric hindrance by itself cannot sufficiently explain acantholysis in PV [37]. One of the earliest studies that indicated that autoAbs may exert their pathogenic effect through the activation of intracellular cascades demonstrated that plakoglobin (Pkg)-deficient mice were protected from PVIgG-induced blister formation [45]. All MAPKs require dual phosphorylation for enzymatic activity, and each contains a TABLE 1 | Evidence supporting steric hindrance vs. intracellular signaling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
