What protein kinases are crucial for acantholysis and blister formation in pemphigus vulgaris? A systematic review

Abstract

Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell–cell detachment (or acantholysis) and blister formation. While the signaling mechanisms that associate with skin/mucosal blistering are being elucidated, specific treatment strategies targeting PV‐specific pathomechanisms, particularly kinase signaling, have yet to be established. Hence, the aim of this review was to systematically evaluate molecules in the class of kinases that are essential for acantholysis and blister formation and are therefore candidates for targeted therapy. English articles from PubMed and Scopus databases were searched, and included in vitro, in vivo, and human studies that investigated the role of kinases in PV. We selected studies, extracted data and assessed risk of bias in duplicates and the results were reported according to the methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA). The risk of bias assessment was performed on in vivo studies utilizing SYRCLE's risk of bias tool. Thirty‐five studies were included that satisfied the pathogenicity criterion of kinases in PV, the vast majority being experimental models that used PV sera (n = 13) and PV‐IgG (n = 22). Inhibition of kinase activity (p38MAPK, PKC, TK, c‐Src, EGFR, ERK, mTOR, BTK, and CDK2) was achieved mostly by pharmacological means. Overall, we found substantial evidence that kinase inhibition reduced PV‐associated phosphorylation events and keratinocyte disassociation, prevented acantholysis, and blocked blister formation. However, the scarce adherence to standardized reporting systems and the experimental protocols/models used did limit the internal and external validity of these studies. In summary, this systematic review highlighted the pathogenic intracellular events mediated by kinases in PV acantholysis and presented kinase signaling as a promising avenue for translational research. In particular, the molecules identified and discussed in this study represent potential candidates for the development of mechanism‐based interventions in PV.

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models

“…Yet, it has now become clear that additional mechanisms following antibody binding contribute to skin blistering in pemphigus. Pathogenic IgGs activate phosphatidylcholine specific phospholipase C (PLC), which in turn elevates intracellular free calcium, and activates various kinases including p38MAP Kinase, Akt, Src, epidermal growth factor receptor kinase (EFGRK), and protein kinase C (PKC) ( 2 , 3 ). Moreover, several lines of evidence indicate that keratinocyte apoptosis is involved in the pathological mechanisms of pemphigus [reviewed by Grando et al.…”

Mouse models of pemphigus: valuable tools to investigate pathomechanisms and novel therapeutic interventions

“…Beyond steric hindrance, signaling pathways induced by binding of pemphigus IgG have been proposed to indirectly trigger acantholysis ( 60 – 62 ). Pharmacological modulation of signaling molecules blocked blister formation in the passive transfer mouse models for pemphigus.…”

The Role of Non-Neuronal Acetylcholine in the Autoimmune Blistering Disease Pemphigus Vulgaris

“…Intriguingly, mutations of SPCA1 are associated with acantholytic skin disorders, and this supports the notion that ER stress and alterations in intracellular calcium are associated with acantholysis. The complexity of PV pathophysiology may explain the variability in treatment response and the unsuccessful attempts to find a mechanism-based pharmacological treatment for PV to date [ 45 ].…”