Salato Valerie K, Hacker-Foegen Mary K, Lazarova Zelmira, Fairley Janet A, Lin Mong-Shang
Department of Dermatology, MFRC 4001, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Clin Immunol. 2005 Jul;116(1):54-64. doi: 10.1016/j.clim.2005.03.005.
Pemphigus vulgaris (PV) is an acquired immunobullous disorder. At the early stage of the disease (mucosal PV), patients display only autoimmunity to desmoglein (Dsg) 3 and develop mucosal blisters; while at the later stage of the disease (mucocutaneous PV), patients exhibit non-cross-reactive autoimmunity to both Dsg3 and Dsg1 and acquire cutaneous as well as mucosal blisters. At these two disease stages, Dsg3 autoantibodies exhibit different tissue-binding patterns and pathogenic activities, suggesting that they may recognize distinct epitopes. To test this hypothesis and to investigate the mechanism underlying the disease transition, we studied Dsg3 autoantibody epitopes from mucosal PV patients and patients exhibiting disease transition to mucocutaneous PV. We demonstrated that autoantibodies from the majority of mucosal PV patients target epitopes at the COOH-terminal portion of the Dsg3 ectodomain. Interestingly, only autoantibodies against the Dsg3 NH2-terminal epitope(s) are able to bind human skin. Moreover, we discovered that the intramolecular epitope spreading from Dsg3(87-566) to Dsg3(1-88) is a critical step that precedes the intermolecular epitope spreading from Dsg3 to Dsg1. During disease transition, this mechanism dictates the development of Dsg3 autoantibodies that recognize human skin and lead to expression of cutaneous PV lesions.
寻常型天疱疮（PV）是一种获得性免疫性大疱性疾病。在疾病早期（黏膜型PV），患者仅表现出对桥粒芯糖蛋白（Dsg）3的自身免疫，并出现黏膜水疱；而在疾病后期（黏膜皮肤型PV），患者对Dsg3和Dsg1均表现出非交叉反应性自身免疫，并出现皮肤和黏膜水疱。在这两个疾病阶段，Dsg3自身抗体表现出不同的组织结合模式和致病活性，提示它们可能识别不同的表位。为了验证这一假设并研究疾病转变的潜在机制，我们研究了黏膜型PV患者以及疾病转变为黏膜皮肤型PV患者的Dsg3自身抗体表位。我们发现，大多数黏膜型PV患者的自身抗体靶向Dsg3胞外域COOH末端部分的表位。有趣的是，只有针对Dsg3 NH2末端表位的自身抗体能够结合人皮肤。此外，我们发现从Dsg3（87 - 566）到Dsg3（1 - 88）的分子内表位扩展是从Dsg3到Dsg1的分子间表位扩展之前的关键步骤。在疾病转变过程中，这一机制决定了能够识别人类皮肤并导致皮肤型PV病变表达的Dsg3自身抗体的产生。
