Novel human alpha 9 acetylcholine receptor regulating keratinocyte adhesion is targeted by pemphigus vulgaris autoimmunity

Citation
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
Journal title
AMERICAN JOURNAL OF PATHOLOGY
ISSN journal
00029440 → ACNP
Volume
157
Issue
4
Year of publication
2000
Pages
1377 - 1391
Database
ISI
SICI code
0002-9440(200010)157:4<1377:NHA9AR>2.0.ZU;2-S
Abstract
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.