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.

中文翻译：

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通过对接模拟分析的免疫热点：寻常型天疱疮病理和转化的一般机制的证据。

背景 寻常型天疱疮 (PV) 是一种获得性自身免疫性水疱疾病，其中超过 80% 的活跃患者产生针对桥粒蛋白桥粒胶凝蛋白 3 (Dsg3) 的自身抗体。随着疾病的进展，40-50% 的患者也可能对桥粒复合物的第二种成分桥粒胶凝蛋白 1 (Dsg1) 产生反应。在 PV 中产生自身抗体显然需要 T 细胞。然而，迄今为止，Dsg3 或 Dsg1 中的 T 细胞特异性很少被报道，并且 T 细胞在疾病发病机制和进化中的确切作用仍然知之甚少。特别是，没有研究解决作为观察到的天疱疮临床异质性基础的免疫机制。我们在此报告了一种基于结构的技术，用于筛选 Dsg3 和 Dsg1 糖蛋白中的 DRB1*0402 特异性免疫（T 细胞表位）热点。结果 与实验数据相比，DRB1*0402（r2 = 0.90，s = 1.20 kJ/mol，q2 = 0.82，spress = 1.61 kJ/mol）预测模型获得了高预测性。Dsg3 和 Dsg1 糖蛋白中 T 细胞表位库的计算机映射显示，尽管序列同一性有限（54% 相同，72% 相似），但两种靶标自身抗原的潜在免疫热点是高度保守的。预计 Dsg3 和 Dsg1 中存在相似数量的保守（18%）高亲和力结合剂，结合寄存器的分布类似。结论 本研究为 PV 疾病进展的可能机制提供了有趣的新见解。