Prediction of desmoglein-3 peptides reveals multiple shared T-cell epitopes in HLA DR4- and DR6- associated Pemphigus vulgaris

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Abstract
Background: Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disorder that is strongly associated with major histocompatibility complex class II alleles DRB1*0402 and DQB1*0503. The target antigen of PV, desmoglein 3 (Dsg3), is crucial for initiating T-cell response in early disease. Although a number of T-cell specificities within Dsg3 have been reported, the number is limited and the role of T-cells in the pathogenesis of PV remains poorly understood. We report here a structure-based model for the prediction of peptide binding to DRB1*0402 and DQB1*0503. The scoring functions were rigorously trained, tested and validated using experimentally verified peptide sequences.Results: High predictivity is obtained for both DRB1*0402 (r2= 0.90,s= 1.20 kJ/mol,q2= 0.82,spress= 1.61 kJ/mol) and DQB1*0503 (r2= 0.95,s= 1.20 kJ/mol,q2= 0.75,spress= 2.15 kJ/mol) models, compared to experimental data. We investigated the binding patterns of Dsg3 peptides and illustrate the existence of multiple immunodominant epitopes that may be responsible for both disease initiation and propagation in PV. Further analysis reveals that DRB1*0402 and DQB1*0503 may share similar specificities by binding peptides at different binding registers, thus providing a molecular mechanism for the dual HLA association observed in PV.Conclusion: Collectively, the results of this study provide interesting new insights into the pathology of PV. This is the first report illustrating high-level of cross-reactivity between both PV-implicated alleles, DRB1*0402 and DQB1*0503, as well as the existence of a potentially large number of T-cell epitopes throughout the entire Dsg3 extracellular domain (ECD) and transmembrane region. Our results reveal that DR4 and DR6 PV may initiate in the ECD and transmembrane region respectively, with implications for immunotherapeutic strategies for the treatment of this autoimmune disease.