Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction1
Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction1
复制标题
寻常型天疱疮 IgG 直接抑制桥粒芯糖蛋白 3 介导的反式相互作用1
作者：
Wolfgang;D. Zillikens;D. Drenckhahn;J. Waschke
天疱疮是一种自身免疫性起泡性皮肤病，由抗角质形成细胞表面抗原的自身抗体引起。在寻常型天疱疮（PV）中，自身抗体主要针对桥粒钙粘蛋白桥粒芯蛋白（Dsg）3和Dsg 1，而落叶型天疱疮（PF）患者仅具有针对Dsg 1的Ab。目前尚不清楚Dsg自身抗体是否通过直接抑制Dsg相互作用而参与天疱疮的发病机制。使用原子力显微镜，我们提供的证据表明，PV-IgG直接干扰同嗜性DSG 3，但类似于PF-IgG，而不是同嗜性DSG 1的相互作用，表明在PV和PF发病机制的分子机制有很大的不同。PV-IgG（含有Dsg 3或Dsg 1和Dsg 3自身抗体）以及PV-IgG Fab使Dsg 3的结合活性降低约60%，与Ca 2+耗竭相当。类似地，靶向N-末端Dsg 3结构域的小鼠单克隆PV Ab AK 23和AK 23 Fab降低了Dsg 3的反式相互作用。相反，PV-IgG和PF-IgG都不能阻断Dsg 1的反式相互作用。然而，在HaCaT单层中，PV-和PF-IgG引起角质形成细胞解离以及Dsg 1和Dsg 3相互作用的损失，如激光镊子测定所揭示的。这些数据表明PV-IgG和PF-IgG通过细胞依赖性机制降低Dsg反式相互作用，并表明另外，针对Dsg 3的Ab通过直接抑制Dsg反式相互作用而有助于PV。
The autoimmune blistering skin disease pemphigus is caused by autoantibodies against keratinocyte surface Ags. In pemphigus vulgaris (PV), autoantibodies are primarily directed against desmosomal cadherins desmoglein (Dsg) 3 and Dsg 1, whereas pemphigus foliaceus (PF) patients only have Abs against Dsg 1. At present, it is unclear whether Dsg autoantibodies contribute to pemphigus pathogenesis by direct inhibition of Dsg transinteraction. Using atomic force microscopy, we provide evidence that PV-IgG directly interfere with homophilic Dsg 3 but, similar to PF-IgG, not with homophilic Dsg 1 transinteraction, indicating that the molecular mechanisms in PV and PF pathogenesis substantially differ. PV-IgG (containing Dsg 3 or Dsg 1 and Dsg 3 autoantibodies) as well as PV-IgG Fab reduced binding activity of Dsg 3 by ∼60%, comparable to Ca2+ depletion. Similarly, the mouse monoclonal PV Ab AK 23 targeting the N-terminal Dsg 3 domain and AK 23 Fab reduced Dsg 3 transinteraction. In contrast, neither PV-IgG nor PF-IgG blocked Dsg 1 transinteraction. In HaCaT monolayers, however, both PV- and PF-IgG caused keratinocyte dissociation as well as loss of Dsg 1 and Dsg 3 transinteraction as revealed by laser tweezer assay. These data demonstrate that PV-IgG and PF-IgG reduce Dsg transinteraction by cell-dependent mechanisms and suggest that in addition, Abs to Dsg 3 contribute to PV by direct inhibition of Dsg transinteraction.
影响因子：
158.5
作者：
ANHALT, GJ;LABIB, RS;DIAZ, LA
通讯作者：
DIAZ, LA
影响因子：
15.9
作者：
Nguyen, VT;Ndoye, A;Grando, SA
通讯作者：
Grando, SA