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The Pathophysiological Significance of Nondesmoglein Targets of Pemphigus Autoimmunity
Development of Antibodies Against Keratinocyte Cholinergic Receptors in Patients With Pemphigus Vulgaris and Pemphigus Foliaceus
Vu Thuong Nguyen;
Tou X. Lee, MS;
Assane Ndoye, MD;
Leonard D. Shultz, PhD;
Mark R. Pittelkow, MD;
Mark V. Dahl, MD;
Peter J. Lynch, MD;
Sergei A. Grando, MD, PhD, DSc
Arch Dermatol. 1998;134:971-980.
Objectives To determine whether nondesmoglein (non-Dsg) autoantibodies are pathogenic and whether they recognize keratinocyte cholinergic receptors that control cell adhesion because antikeratinocyte autoimmunity in patients with pemphigus vulgaris is not limited to the development of autoantibodies to Dsg.
Design To determine whether non-Dsg autoantibodies are pathogenic, we sought to induce pemphigus in genetically engineered neonatal mice lacking Dsg 3 using pemphigus vulgaris IgGs that did not cross-react with Dsg 1. To determine whether pemphigus autoimmunity involves keratinocyte cholinergic receptors, the latter were separated from cell membranes of human keratinocytes, tagged with the covalent label [3H]propylbenzilylcholine mustard, and used as an antigen in a radioimmunoprecipitation assay of 34 pemphigus vulgaris and 6 pemphigus foliaceus serum samples.
Setting The dermatologic clinics of the University of Minnesota, Minneapolis; the Mayo Clinic, Rochester, Minn; and the University of California–Davis Medical Center, Sacramento.
Patients Serum samples were collected from 34 patients with pemphigus vulgaris and 6 patients with pemphigus foliaceus (aged 31-89 years) and from 7 age-similar patients of both sexes with nonpemphigus blistering or the following immune-mediated conditions: pemphigoid gestationis, bullous drug eruption, lupus erythematosus, erythema nodosum, urticaria, acute contact dermatitis, and skin ulcers.
Main Outcome Measures Clinical, laboratory, and histopathologic findings.
Results Extensive skin blistering accompanied by the Nikolsky sign and suprabasilar acantholysis was induced in the Dsg3null mice that received pemphigus, but not normal human IgGs. In the radioimmunoprecipitation assays for reactivity with cholinergic receptors, the mean radioactivity precipitated by pemphigus serum samples significantly exceeded both normal- and disease-control levels (P=.001-.02). The mean individual levels of radioactivity precipitated by 34 pemphigus vulgaris and pemphigus foliaceus serum samples (85%) exceeded control values by a mean of approximately 2.6 times.
Conclusions Autoantibodies to keratinocyte cell-surface molecules other than Dsg 1 and Dsg 3 can induce clinical features of pemphigus vulgaris. Patients with pemphigus vulgaris and those with pemphigus foliaceus develop IgG antibodies that precipitate radiolabeled cholinergic receptors. Because these receptors control keratinocyte adhesion and motility, their inactivation by autoantibodies may elicit intracellular signals that cause disassembly of desmosomes, leading to acantholysis and blistering.
From the Department of Dermatology, University of California–Davis Medical Center, Sacramento (Mr Nguyen and Drs Ndoye, Lynch, and Grando); the Department of Dermatology, University of Minnesota, Minneapolis (Mr Lee and Dr Dahl); The Jackson Laboratory, Bar Harbor, Me (Dr Shultz); and the Department of Dermatology, Mayo Clinic, Rochester, Minn (Dr Pittelkow).
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