Abstract：
During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact calcium ion independently. Previous data indicate that hyper-adhesion protects keratinocytes from pemphigus vulgaris autoantibody-induced loss of intercellular adhesion, although the underlying mechanism remains to be elucidated. Thus, in this study, we investigated the effect of hyper-adhesion on pemphigus vulgaris autoantibody-induced direct inhibition of desmoglein (DSG) 3 interactions by atomic force microscopy. Hyper-adhesion abolished loss of intercellular adhesion and corresponding morphological changes of all pathogenic antibodies used. Pemphigus autoantibodies putatively targeting several parts of the DSG3 extracellular domain and 2G4, targeting a membrane-proximal domain of DSG3, induced direct inhibition of DSG3 interactions only in non-hyper-adhesive keratinocytes. In contrast, AK23, targeting the N-terminal extracellular domain 1 of DSG3, caused direct inhibition under both adhesive states. However, antibody binding to desmosomal cadherins was not different between the distinct pathogenic antibodies used and was not changed during acquisition of hyper-adhesion. In addition, heterophilic DSC3-DSG3 and DSG2-DSG3 interactions did not cause reduced susceptibility to direct inhibition under hyper-adhesive condition in wild-type keratinocytes. Taken together, the data suggest that hyper-adhesion reduces susceptibility to autoantibody-induced direct inhibition in dependency on autoantibody-targeted extracellular domain but also demonstrate that further mechanisms are required for the protective effect of desmosomal hyper-adhesion in pemphigus vulgaris.
摘要：
在分化过程中,角质形成细胞获得一个强大的，超粘合状态，其中桥粒钙粘蛋白独立地与Ca2+相互作用。先前的数据表明，超粘附保护角质形成细胞免受寻常性天疱疮自身抗体（PV-IgG）诱导的细胞间粘附丧失的影响，尽管潜在的机制仍有待阐明。因此，我们在这里通过原子力显微镜研究了过度粘附对PV-IgG诱导的桥粒糖蛋白（Dsg）3相互作用的直接抑制的影响。过度粘附消除了细胞间粘附的丧失以及所用所有致病性抗体的相应形态变化。天疱疮自身抗体推定靶向Dsg3胞外域（ECD）和2G4的几个部分，靶向Dsg3的膜近端域，仅在非超粘附角质形成细胞中诱导Dsg3相互作用的直接抑制。相比之下,靶向Dsg3的N末端ECD1的AK23在两种粘附状态下都引起直接抑制。然而,与桥粒钙黏着蛋白结合的抗体在使用的不同致病性抗体之间没有差异,并且在获得超粘附过程中没有变化.此外,异源性Dsc3-Dsg3和Dsg2-Dsg3的相互作用不会导致wt角质形成细胞在超粘附条件下对直接抑制的敏感性降低。一起来看,数据表明,过度粘附降低了对自身抗体诱导的依赖自身抗体靶向ECD的直接抑制的易感性,但也表明PV中桥粒过度粘附的保护作用需要进一步的机制.
