Vt. Nguyen et al., Novel human alpha 9 acetylcholine receptor regulating keratinocyte adhesion is targeted by pemphigus vulgaris autoimmunity, AM J PATH, 157(4), 2000, pp. 1377-1391
Citations number
82
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Pemphigus vulgaris (PV) is a potentially fatal autoimmune mucocutaneous bli
stering 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-ca
using antibodies. In this study we demonstrate that rDsg3-Ig-His adsorbs ou
t autoantibodies to different keratinocyte antigens, including a non-Dsg 3
130-kd polypeptide, Because the pool of disease-causing PV IgGs contains an
tibodies against the keratinocyte acetylcholine receptor (AChR), me sought
to identify the targeted receptor(s). Preincubation of monkey esophagus wit
h PV antibodies blocked specific staining of the keratinocyte cell membrane
with rabbit monoepitopic antibody to alpha 9 AChR, indicating that this fi
rst of its kind AChR with dual, muscarinic and nicotinic pharmacology is ta
rgeted by PV autoimmunity. Anti-alpha 9 antibody stained keratinocytes in a
fishnet-like intercellular pattern, and visualized a single band at simila
r to 50 kd in Western blots of keratinocyte membrane proteins. Using step-b
y-step reverse transcription polymerase chain reactions with primers based
on known alpha 9 sequence regions, we identified the complete reading frame
of human alpha 9. Its amino acid sequence showed 85% similarity with rat a
lpha 9. Treatment of keratinocyte monolayers with anti-alpha 9 antibody ind
uced pemphigus-like acantholysis, which could be reversed either spontaneou
sly or by using the cholinergic agonist carbachol. We conclude that alpha 9
is coupled to physiological regulation of keratinocyte adhesion, and its i
nteraction with PV IgG may lead to blister development.