A truncated alternative spliced isoform of human desmoglein 1 contains a specific T cell epitope binding to the pemphigus foliaceus-associated HLA class II DRbeta1*0102 molecule.
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 DRbeta1*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.
Mouquet
Hugo
H
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.
Farci
Sandrine
S
Joly
Pascal
P
Maillère
Bernard
B
Leblond
Jonathan
J
Drouot
Laurent
L
Leprince
Jérôme
J
Tonon
Marie Christine
MC
Loiseau
Pascale
P
Charron
Dominique
D
Tron
François
F
Gilbert
Danièle
D
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000906:Antibodies / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D051183:Desmoglein 1 / Q000235:genetics* / Q000276:immunology*; D004817:Epidermis / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010392:Pemphigus / Q000276:immunology*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic
D000906:Antibodies; D001324:Autoantigens; D051183:Desmoglein 1; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C515436:HLA-DRB1*01:02 antigen; D000949:Histocompatibility Antigens Class II; D020033:Protein Isoforms; D011994:Recombinant Proteins