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9 Acetylcholine Receptor Regulating Keratinocyte Adhesion is Targeted by Pemphigus Vulgaris Autoimmunity
From the Department of Dermatology, University of California at Davis, Sacramento, California
Pemphigus vulgaris (PV) is a potentially fatal autoimmune
mucocutaneous blistering disease. It was assumed that PV is caused by
anti-desmoglein (Dsg) 3 autoimmunity because absorption of PV sera with
a chimeric baculoprotein containing the Dsg 3 and IgG1
portions, rDsg3-Ig-His, eliminated
disease-causing antibodies. In this study we demonstrate that
rDsg3-Ig-His adsorbs out autoantibodies to different
keratinocyte antigens, including a non-Dsg 3 130-kd
polypeptide. Because the pool of disease-causing PV IgGs contains
antibodies against the keratinocyte acetylcholine receptor
(AChR), we sought to identify the targeted receptor(s).
Preincubation of monkey esophagus with PV antibodies blocked specific
staining of the keratinocyte cell membrane with rabbit monoepitopic
antibody to 
9 AChR, indicating that this first of its kind
AChR with dual, muscarinic and nicotinic pharmacology is
targeted by PV autoimmunity. Anti-9 antibody stained keratinocytes
in a fishnet-like intercellular pattern, and visualized a
single band at 
50 kd in Western blots of keratinocyte membrane
proteins. Using step-by-step reverse transcription polymerase chain
reactions with primers based on known 9 sequence
regions, we identified the complete reading frame of human
9. Its amino acid sequence showed 85% similarity with rat 9.
Treatment of keratinocyte monolayers with anti-9 antibody induced
pemphigus-like acantholysis, which could be reversed
either spontaneously or by using the cholinergic agonist carbachol. We
conclude that 9 is coupled to physiological regulation of
keratinocyte adhesion, and its interaction with PV IgG may lead
to blister development.
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