Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin
Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin
复制标题
寻常型天疱疮和绿叶天疱疮自身抗体直接阻断桥粒芯糖蛋白与桥粒芯胶原的异嗜性相互作用
DOI：
10.1016/j.jid.2020.02.010
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发表时间：
2020-10-01
影响因子：
6.5
通讯作者：
Ishiko, Akira
中科院分区：
文献类型：
--
作者：
Ishii, Ken;Yoshida, Kenji;Ishiko, Akira
落叶型天疱疮和寻常型天疱疮中的抗桥粒芯糖蛋白（Dsg）1和Dsg 3 IgG自身抗体通过桥粒粘附的丧失引起水疱。水泡的形成是否是由于Dsg的直接抑制、引起桥粒不稳定的细胞内信号传导事件或两者都是有争议的。最近的研究表明，Dsg和桥粒胶蛋白（Dsc）之间的异嗜性结合是桥粒的基本粘附单位。为了消除天疱疮抗体的潜在致病性的细胞贡献，开发了用重组Dsg 1、Dsc 1、Dsg 3或Dsc 3胞外域包被的珠测定。Dsg珠粒和Dsc珠粒的混合物形成大的聚集体，证实了异嗜性结合占主导地位。致病性抗Dsg 1和抗Dsg 3单克隆抗体，结合的transadhesive接口，阻止Dsg 1/Dsc 1和Dsg 3/Dsc 3珠的聚集，分别，而非致病性单克隆抗体没有。从8例落叶型天疱疮患者和8例活动性疾病粘膜寻常型天疱疮患者中检测的所有血清分别抑制Dsg 1/Dsc 1和Dsg 3/Dsc 3珠的粘附。当配对血清从7例落叶型天疱疮患者和6例寻常型天疱疮患者在活动期和缓解期进行了比较，前者抑制聚集优于后者。这些研究结果强烈表明，DSG和DSC之间的异嗜性反式相互作用的空间位阻是重要的落叶型天疱疮和寻常型天疱疮的疾病病理。
Anti-desmoglein (Dsg) 1 and Dsg3 IgG autoantibodies in pemphigus foliaceus and pemphigus vulgaris cause blisters through loss of desmosomal adhesion. It is controversial whether blister formation is due to direct inhibition of Dsg, intracellular signaling events causing desmosome destabilization, or both. Recent studies show that heterophilic binding between Dsg and desmocollin (Dsc) is the fundamental adhesive unit of desmosomes. To eliminate cellular contributions to potential pathogenicity of pemphigus antibodies, bead assays coated with recombinant Dsg1, Dsc1, Dsg3, or Dsc3 ectodomains were developed. A mixture of Dsg beads and Dsc beads formed large aggregates, confirming that the heterophilic binding is dominant. The pathogenic anti-Dsg1 and anti-Dsg3 mAbs, which bind the transadhesive interface, blocked the aggregation of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively, whereas nonpathogenic mAbs did not. All sera tested from eight patients with pemphigus foliaceus and eight patients with mucosal pemphigus vulgaris with active disease inhibited the adhesion of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively. When paired sera obtained from seven patients with pemphigus foliaceus and six patients with pemphigus vulgaris in active disease and remission were compared, the former inhibited aggregation better than the latter. These findings strongly suggest that steric hindrance of heterophilic transinteraction between Dsg and Dsc is important for disease pathology in both pemphigus foliaceus and pemphigus vulgaris.