Department I, Faculty of Medicine, Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität, Munich, Germany.
Front Immunol. 2020 Oct 28;11:581370. doi: 10.3389/fimmu.2020.581370. eCollection 2020.
In pemphigus vulgaris (PV), autoantibodies directed against the desmosomal cadherin desmoglein (Dsg) 3 cause loss of intercellular adhesion. It is known that Dsg3 interactions are directly inhibited by autoantibody binding and that Dsg2 is upregulated in epidermis of PV patients. Here, we investigated whether heterophilic Dsg2-Dsg3 interactions occur and would modulate PV pathogenesis. Dsg2 was upregulated in PV patients' biopsies and in a human pemphigus skin model. Immunoprecipitation and cell-free atomic force microscopy (AFM) experiments demonstrated heterophilic Dsg2-Dsg3 interactions. Similarly, in Dsg3-deficient keratinocytes with severely disturbed intercellular adhesion Dsg2 was upregulated in the desmosome containing fraction. AFM revealed that Dsg2-Dsg3 heterophilic interactions showed binding frequency, strength, Ca-dependency and catch-bond behavior comparable to homophilic Dsg3-Dsg3 or homophilic Dsg2-Dsg2 interactions. However, heterophilic Dsg2-Dsg3 interactions had a longer lifetime compared to homophilic Dsg2-Dsg2 interactions and PV autoantibody-induced direct inhibition was significantly less pronounced for heterophilic Dsg2-Dsg3 interactions compared to homophilic Dsg3 interactions. In contrast, a monoclonal anti-Dsg2 inhibitory antibody reduced heterophilic Dsg2-Dsg3 and homophilic Dsg2-Dsg2 binding to the same degree and further impaired intercellular adhesion in Dsg3-deficient keratinocytes. Taken together, the data demonstrate that Dsg2 undergoes heterophilic interactions with Dsg3, which may attenuate autoantibody-induced loss of keratinocyte adhesion in pemphigus.
在寻常型天疱疮（PV）中，针对桥粒钙黏蛋白（Dsg）3 的自身抗体导致细胞间黏附丧失。已知 Dsg3 相互作用直接被自身抗体结合所抑制，并且 Dsg2 在 PV 患者的表皮中上调。在这里，我们研究了是否发生异嗜性 Dsg2-Dsg3 相互作用，以及它们是否会调节 PV 的发病机制。Dsg2 在 PV 患者的活检标本和人类天疱疮皮肤模型中上调。免疫沉淀和无细胞原子力显微镜（AFM）实验表明存在异嗜性 Dsg2-Dsg3 相互作用。同样，在细胞间黏附严重紊乱的 Dsg3 缺陷角质形成细胞中，Dsg2 在含有桥粒的部分上调。AFM 显示，Dsg2-Dsg3 异嗜性相互作用具有与同质 Dsg3-Dsg3 或同质 Dsg2-Dsg2 相互作用相当的结合频率、强度、Ca 依赖性和捕获键行为。然而，与同质 Dsg2-Dsg2 相互作用相比，异嗜性 Dsg2-Dsg3 相互作用的寿命更长，并且与同质 Dsg3 相互作用相比，PV 自身抗体诱导的直接抑制作用不那么明显。相比之下，一种单克隆抗 Dsg2 抑制性抗体降低了异嗜性 Dsg2-Dsg3 和同质 Dsg2-Dsg2 结合的程度，并进一步损害了 Dsg3 缺陷角质形成细胞中的细胞间黏附。总之，这些数据表明 Dsg2 与 Dsg3 发生异嗜性相互作用，这可能会减轻天疱疮中自身抗体诱导的角质形成细胞黏附丧失。
