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A Truncated Alternative Spliced Isoform of Human Desmoglein 1 Contains a Specific T Cell Epitope Binding to the Pemphigus Foliaceus-Associated HLA Class II DR1*0102 Molecule¹

Hugo Mouquet^*, Sandrine Farci, Pascal Joly^*, Bernard Maillère, Jonathan Leblond^*, Laurent Drouot^*, Jérôme Leprince, Marie Christine Tonon, Pascale Loiseau, Dominique Charron, François Tron^2,* and Danièle Gilbert^*

^* Institut National de la Santé et de la Recherche Médicale, Unité 519, Faculté de Médecine et de Pharmacie, Rouen, France; Département d’Ingénierie et d’Etudes des Protéines, Commissariat à l’Energie Atomique-Saclay, Gif sur Yvette, France; Institut National de la Santé et de la Recherche Médicale, Unité 413, Mont Saint Aignan, France; and Laboratoire d’Immunologie et d’Histocompatibilite, Institut National de la Santé et de la Recherche Médicale, Unité 396, Paris, France

Desmogleins (Dsg) are transmembrane glycoproteins of the desmosome that allow a cell-cell adhesion between keratinocytes and comprise four different isoforms (Dsg1 to Dsg4). Two Dsg are targeted by pathogenic autoantibodies produced in the course of autoimmune bullous skin diseases, Dsg1 in pemphigus foliaceus (PF), and Dsg3 and Dsg1 in pemphigus vulgaris. The genetic susceptibility to PF is associated with certain HLA class II alleles, which are thought to participate in disease pathogenesis through their capacity to accommodate autoantigen-derived peptides and present them to autoreactive T cells. So far, a unique isoform of Dsg1 has been described in humans, which includes several immunodominant T cell epitopes. In this study, we describe an alternative transcript of DSG1, which contains a 101-bp insertion corresponding to the 3' end of DSG1-intron 6 and introducing a stop codon in the nucleotide sequence. This alternative transcript leads to the synthesis of a truncated isoform of Dsg1 expressed in normal human epidermis. This isoform bears a specific peptide sequence that binds to the PF-associated HLA class II DR1*0102 molecule as shown in a HLA-DR peptide-binding assay, and induces PF T cell proliferation. These data provide an illustration of an autoantigen encoded by alternative spliced transcript that may participate in the pathogenesis of the disease by bearing PF-associated HLA class II restricted-epitope.

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 funds from the Institut National de la Santé et de la Recherche Médicale. H.M. is the recipient of a fellowship from the Conseil Régional de Haute-Normandie.

² Address correspondence and reprint requests to Dr. François Tron, Institut National de la Santé et de la Recherche Médicale, Unité 519, Faculté de Médecine et de Pharmacie, 22 boulevard Gambetta, 76183 Rouen Cedex 1, France. E-mail address: francois.tron{at}chu-rouen.fr

³ Abbreviations used in this paper: Dsg, desmoglein; EC, extracellular; PF, pemphigus foliaceus; PV, pemphigus vulgaris; BP, bullous pemphigoid; BT, bovine thyroglobulin; IRF, infrared fluorescent; SI, stimulation index; pI, isoelectric point; MBP, myelin basic protein; NZ, New Zealand.