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Immunological hotspots analyzed by docking simulations: evidence for a general mechanism in pemphigus vulgaris pathology and transformation

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Author(s): Tong Joo | Sinha Animesh

Journal: BMC Immunology
ISSN 1471-2172

Volume: 9;
Issue: 1;
Start page: 30;
Date: 2008;
Original page

ABSTRACT
Abstract Background Pemphigus vulgaris (PV) is an acquired autoimmune blistering disorder in which greater than 80% of active patients produce autoantibodies to the desmosomal protein desmogelin 3 (Dsg3). As the disease progresses, 40–50% of patients may also develop reactivity to a second component of the desmosomal complex, desmogelin 1 (Dsg1). T cells are clearly required for the production of autoantibodies in PV. However, few T-cell specificities within Dsg3 or Dsg1 have been reported to date, and the precise role of T-cells in disease pathogenesis and evolution remains poorly understood. In particular, no studies have addressed the immunological mechanisms that underlie the observed clinical heterogeneity in pemphigus. We report here a structure-based technique for the screening of DRB1*0402-specific immunological (T-cell epitope) hotspots in both Dsg3 and Dsg1 glycoproteins. Results High predictivity was obtained for DRB1*0402 (r2 = 0.90, s = 1.20 kJ/mol, q2 = 0.82, spress = 1.61 kJ/mol) predictive model, compared to experimental data. In silico mapping of the T-cell epitope repertoires in Dsg3 and Dsg1 glycoproteins revealed that the potential immunological hotspots of both target autoantigens are highly conserved, despite limited sequence identity (54% identical, 72% similar). A similar number of well-conserved (18%) high-affinity binders were predicted to exist within both Dsg3 and Dsg1, with analogous distribution of binding registers. Conclusion This study provides interesting new insights into the possible mechanism for PV disease progression. Our data suggests that the potential T-cell epitope repertoires encoded in Dsg1 and Dsg3 is substantially overlapping, and it may be possible to apply a common, antigen-specific therapeutic strategy with efficacy across distinct clinical phases of disease.
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