Nicotine and Pemphigus

We read with interest the article by Mehta and Martin¹ titled "A Case of Pemphigus Vulgaris Improved by Cigarette Smoking." We have a better explanation why cigarette smoking might be expected to improve skin lesions of patients with pemphigus vulgaris, particularly when nicotine in cigarette smoke contacts mucous membranes.

Human keratinocytes contain an elaborate acetylcholine network. Specifically, human keratinocytes synthesize, store, release, and degrade acetylcholine.² Keratinocytes contain choline acetyltransferase and acetylcholinesterase,² and have on their cell membranes both muscarinic and nicotinic receptors for acetylcholine.^{3 - 4} Both nicotinic and muscarinic acetylcholine receptors regulate cell-to-cell adhesion of human keratinocytes (reviewed in Grando⁵ ). Interaction of nicotine (and other nicotinic agonists) with nicotinic acetylcholine receptors on keratinocytes opens ion gates in the cell membrane to help increase cell-to-cell adherence, stop acantholysis, and stimulate keratinocytes to move laterally to heal erosions.⁶

We believe the keratinocyte cholinergic system is altered in pemphigus.⁷ Keratinocytes undergoing acantholysis in a tissue culture plate can be quickly restored to confluence by adding acetylcholine.⁸ Therefore, in a patient such as the one described by Mehta and Martin,¹ nicotine might (1) compete with the disease-causing pemphigus antibodies preventing them from attaching to keratinocytes or (2) block the intracellular signaling pathways that mediate the acantholytic effects of pemphigus antibodies. Approximately 85% of patients with pemphigus develop antibodies in their serum to one or more types of keratinocyte acetylcholine receptors.⁹

Since human keratinocytes have nicotinic acetylcholine receptors, and since nicotine can bind to them, and since activation of nicotinic cholinergic receptors increases cell-to-cell adhesion and promotes lateral migration of keratinocytes, one might predict that smoking would, indeed, improve pemphigus. Nicotine could be delivered to keratinocytes of mucous membranes either topically through the smoke or systemically via absorbed nicotine.

One might also predict that nicotinamide, like nicotine, might improve pemphigus, since it too is a nicotinic agonist.¹⁰ Additionally, nicotinamide inhibits the enzyme acetylcholinesterase that degrades acetylcholine.¹¹ Indeed, nicotinamide has helped patients with pemphigus too (reviewed in Chaffins et al¹² ).

Thus, the observation that a patient's erosions of the buccal mucosa and blisters on his face and body improved after cigarette smoking suggests that nicotine and other cholinergic agents might help certain patients with pemphigus. The results of our studies defining the keratinocyte cholinergic network provide a rationale for their use.