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

Abstract

The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies. Herein, we describe the role of autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, as well as the annexin-like molecule pemphaxin that also binds ACh, in the immunopathogenesis of PV. The identification of targets in this disease is important, as they may lead to novel diagnostic and therapeutic options in the future for this potentially deadly disease.

A Critical Interpretive Synthesis of the Role of Arecoline in Oral Carcinogenesis: Is the Local Cholinergic Axis a Missing Link in Disease Pathophysiology?

“…Given that alpha 3, alpha 5, alpha 7, and beta 2, as well as the alpha 9 nAChR subunits, are expressed in oral keratinocytes [88], a non-neuronal cholinergic system of the oral mucosa exists that regulates key biological functions such as cell viability, proliferation, migration, adhesion, terminal differentiation, and the secretion of cytokines and growth factors [90]. This keratinocyte cholinergic system has been shown to play a role in oral mucosal diseases [91] and also mediates nicotine toxicity in oral keratinocytes and in epithelial cancers [92]. It is now known that the nAChRs expressed on the cell membrane and mitochondria mediate both growth-promoting and anti-apoptotic effects synergistically.…”

Restoring immune tolerance in pemphigus vulgaris

“…It is characterized by autoantibodies to desmosomal proteins. In addition, autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, pemphaxin, an annexin-like molecule that binds to acetylcholine, have been described to play a role in the pathogenesis of PV ( 4 ). Histology demonstrates intraepidermal vesicles with acantholysis ( 3 ).…”