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

Simple Summary Pemphigus is a group of diseases of the immune system manifesting as blisters localized to the skin and mucosae, such as in the mouth or on the genitals. Pemphigus vulgaris (PV), the most common and severe form of pemphigus, is potentially fatal, and its long-term treatment with corticosteroids and immunosuppressants is associated with significant side effects. Current treatments are not specific to the mechanisms causing the disease. The discovery that PV autoimmunity targets acetylcholine receptors in addition to cell adhesion molecules opened the way to novel pharmacological treatments for this life-threatening disease. In this article, we review the evidence supporting the role of the non-neuronal cholinergic system in PV. 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.