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Antibodies to the Desmoglein 1 Precursor Proprotein but Not to the Mature Cell Surface Protein Cloned from Individuals without Pemphigus¹

Jun Yamagami,^* Stephen Kacir, Ken Ishii,^* Aimee S. Payne,^* Don L. Siegel, and John R. Stanley^2*

Departments of ^*Dermatology and Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

In pemphigus foliaceus (PF), autoantibodies against desmoglein 1 (Dsg1) cause blisters. Using Ab phage display, we have cloned mAbs from a PF patient. These mAbs, like those from a previous patient, were directed against mature Dsg1 (matDsg1) on the cell surface of keratinocytes and precursor Dsg1 (preDsg1) in the cytoplasm. To determine whether individuals without pemphigus have B cell tolerance to Dsg1, we cloned mAbs from two patients with thrombotic thrombocytopenic purpura and a healthy person. We found mAbs against preDsg1, but not matDsg1. All but 1 of the 23 anti-preDsg1 mAbs from PF patients and those without PF used the VH3-09 (or closely related VH3-20) H chain gene, whereas no PF anti-matDsg1 used these genes. V_H cDNA encoding anti-preDsg1 had significantly fewer somatic mutations than did anti-matDsg1 cDNA, consistent with chronic Ag-driven hypermutation of the latter compared with the former. These data indicate that individuals without PF do not have B cell tolerance to preDsg1 and that loss of tolerance to matDsg1 is not due to epitope shifting of anti-preDsg1 B cells (because of different V_H gene usage). However, presentation of peptides from Dsg1 by preDsg1-specific B cells may be one step in developing autoimmunity in PF.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AR052672 (to J.R.S.) and K08 AR053505 (to A.S.P.) from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and P50-HL81012 (to D.L.S.) from the National Heart, Lung and Blood Institute, respectively.

² Address correspondence and reprint requests to Dr. John R. Stanley, Department of Dermatology, University of Pennsylvania School of Medicine, 211 CRB, 415 Curie Boulevard, Philadelphia, PA 19104. E-mail address: jrstan{at}mail.med.upenn.edu

³ Abbreviations used in this paper: PF, pemphigus foliaceus; DIF, direct immunofluorescence; Dsg, desmoglein; FR, framework region; IIF, indirect immunofluorescence; matDsg1, mature Dsg1; NAA, natural autoantibody; preDsg1, precursor Dsg1; scFv, single-chain variable fragment; TTP, thrombotic thrombocytopenic purpura.