Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus.
Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus.
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天疱疮中桥粒芯糖蛋白结合的丧失不足以导致角质形成细胞解离
DOI：
10.1038/jid.2015.324
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Spindler V
中科院分区：
文献类型：
--
作者：
Vielmuth F;Waschke J;Spindler V
寻常天疱疮（PV）是一种严重的自身免疫性疾病，其中针对桥粒细胞粘附分子桥粒芯蛋白（Dsg）1和Dsg 3的自身抗体引起表皮内水疱形成。从机制上讲，细胞凝聚力的丧失是否是（1）自身抗体直接抑制Dsg相互作用或（2）细胞内信号传导事件的结果，细胞内信号传导事件响应于抗体结合而改变，最终导致桥粒不稳定，这一根本问题仍未解决。我们使用原子力显微镜（AFM）对活的角质形成细胞进行Dsg 3粘附测量，以研究自身抗体处理后直接抑制和信号传导对细胞凝聚力丧失的贡献。Dsg 3结合在抗体暴露后在没有可检测到表面Dsg 3消耗的条件下被快速阻断，证明了Dsg 3相互作用的直接抑制。p38 MAPK是PV发病机制中的一种中心信号分子，抑制p38 MAPK可消除细胞凝聚力的丧失，但对Dsg 3结合的丧失影响较小。类似地，胆固醇消耗剂甲基-β-环糊精（β-MCD）完全阻断细胞解离，但不能恢复Dsg 3相互作用或阻止p38 MAPK的激活。这些结果表明，Dsg 3结合的抑制不足以引起细胞凝聚力的丧失，而是改变信号传导事件，其以脂筏依赖性方式诱导细胞解离。
Pemphigus vulgaris (PV) is a severe autoimmune disease in which autoantibodies against the desmosomal cell adhesion molecules desmoglein (Dsg) 1 and Dsg3 cause intraepidermal blister formation. Mechanistically, the fundamental question is still unresolved whether loss of cell cohesion is a result of (1) direct inhibition of Dsg interaction by autoantibodies or (2) intracellular signaling events, which are altered in response to antibody binding and finally cause desmosome destabilization. We used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on living keratinocytes to investigate the contributions of direct inhibition and signaling to loss of cell cohesion after autoantibody treatment. Dsg3 binding was rapidly blocked following antibody exposure under conditions where no depletion of surface Dsg3 was detectable, demonstrating direct inhibition of Dsg3 interaction. Inhibition of p38MAPK, a central signaling molecule in PV pathogenesis, abrogated loss of cell cohesion, but had a minor effect on loss of Dsg3 binding. Similarly, the cholesterol-depleting agent methyl-β-cyclodextrin (β-MCD) fully blocked cell dissociation, but did not restore Dsg3 interactions or prevent the activation of p38MAPK. These results demonstrate that inhibition of Dsg3 binding is not sufficient to cause loss of cell cohesion, but rather alters signaling events which, in lipid raft-dependent manner, induce cell dissociation.
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