Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig Maximilian University of Munich, Munich, Germany.
Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.
J Invest Dermatol. 2024 Dec;144(12):2682-2694.e10. doi: 10.1016/j.jid.2024.03.042. Epub 2024 Apr 26.
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.
在分化过程中，角质形成细胞获得了一种强烈的、超黏附的状态，其中桥粒钙黏蛋白独立于钙离子相互作用。先前的数据表明，超黏附可以保护角质形成细胞免受寻常型天疱疮自身抗体诱导的细胞间黏附丧失，尽管其潜在机制仍有待阐明。因此，在这项研究中，我们通过原子力显微镜研究了超黏附对寻常型天疱疮自身抗体诱导的桥粒芯糖蛋白 3（DSG3）相互作用直接抑制的影响。超黏附消除了所有致病性抗体引起的细胞间黏附丧失和相应的形态变化。寻常型天疱疮自身抗体可能靶向 DSG3 细胞外结构域的几个部分和 2G4，靶向 DSG3 的膜近端结构域，仅在非超黏附的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 细胞外结构域 1 的 AK23 在两种黏附状态下均引起直接抑制。然而，不同致病性抗体之间桥粒钙黏蛋白的抗体结合没有差异，并且在获得超黏附过程中没有改变。此外，在野生型角质形成细胞中，异嗜性 DSC3-DSG3 和 DSG2-DSG3 相互作用不会导致在超黏附条件下直接抑制的敏感性降低。总之，数据表明，超黏附降低了对自身抗体诱导的直接抑制的敏感性，这依赖于自身抗体靶向的细胞外结构域，但也表明需要进一步的机制来解释寻常型天疱疮中桥粒超黏附的保护作用。
