The authors in this study injected littermates of neonatal athymic nude mice with pemphigus vulgaris (PV) to determine whether a cholinergic agonist can abolish PV IgG-induced acantholysis. Previous studies have determined the importance of cholinergic receptors in the pathogenesis of PV. The authors measured the expression of adhesion molecules in monolayers of normal human keratinocytes via in-vitro methods with the addition of carbachol. None of the mice in the current study developed skin lesions.
Carbachol is a cholinergic (parasympathomimetic) agent. Carbachol has the double action of a) stimulating the motor endplate of the muscle cell, and b) partially inhibiting cholinesterase.
The results of the study were that the phosphorylation levels of E-cadherin and plakoglobin were increased by PV IgG, and carbachol decreased PV IgG. Pyridostigmine bromide, an acetylcholinesterase (AChE) inhibitor, produced effects similar to those of carbachol, which helps explain its clinical efficacy in a patient with active PV that was resistant to treatment with systemic glucocorticosteroids. The authors then treated a steroid-recalcitrant PV patient with pyridostigmine bromide (360 mg/d) in a patient with PV. The patient was kept at a lower dose of prednisone than that used before starting pyridostigmine bromide treatment and the disease was well controlled. The authors conclude that cholinergic agents not only can treat, but can reverse the acantholysis effects of PV IgG.
JDD ARTICLE EVALUATION:
Pemphigus vulgaris (PV) is an autoimmune, IgG autoantibody-mediated disease targeting desmoglein-3 of the skin and mucosa, leading to progressive blistering and erosions. Recent studies have detected autoantibodies to keratinocyte cholinergic receptors regulating cell adhesion (1).
Acetylcholine and its nicotinic and muscarinic receptors are located in the epidermis and adnexal structures. These receptors are also found on melanocytes, fibroblasts, endothelial cells, and immune cells. Furthermore, the cholinergic system is involved in the functions of the keratinocytes such as differentiation; it is also involved in epidermal barrier formation, sweating, angiogenesis, and immune reactions.
As patients affected with PV have altered cholinergic pathways, cholinergic agonists may present new therapeutic methods in treating PV. The method of action of cholinergic agonists is not completely understood, but theories involve inhibition of AChE receptors to the phosphorylation of cell membrane-associated proteins. It seems that cholinergic agonists block alterations caused by PV IgG antibodies to the cell membrane.
All in all, cholinergic agonists block cell damage caused by PV IgG and increase desmogleins 1 and 3. The mechanism is not fully understood, but the possibility of treating other blistering disorders has been raised. The risks of this medication are the cholinergic side effects of diarrhea and muscle weakness, a point the authors failed to detail. Overall this was a good study that needs a more controlled and randomized evaluation.
1. Kurzen H. The extraneuronal cholinergic system of the skin: basic facts and clinical relevance. Hautarzt 2004 Apr: [E-pub ahead of print].
Nguyen VT, et al. Arch Dermatol 2004; 140(3):327-34.
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