Anti-desmoglein 3 (Dsg3) monoclonal antibodies deplete desmosomes of Dsg3 and differ in their Dsg3-depleting activities related to pathogenicity
Anti-desmoglein 3 (Dsg3) monoclonal antibodies deplete desmosomes of Dsg3 and differ in their Dsg3-depleting activities related to pathogenicity
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DOI：
10.1074/jbc.m607963200
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发表时间：
2007-06-15
影响因子：
4.8
通讯作者：
Kitajima, Yasuo
中科院分区：
文献类型：
--
作者：
Yamamoto, Yukari;Aoyama, Yumi;Kitajima, Yasuo
寻常型天疱疮(PV)是一种自身免疫性水疱性疾病，其特征是表皮角质形成细胞之间的细胞间黏附丧失以及抗桥粒蛋白3(Dsg3)自身抗体的存在，Dsg3为相邻角质形成细胞之间的桥粒提供黏附完整性。我们之前已经证明，从患者身上提纯的PV-IgG可以耗尽Dsg3的桥粒。然而，PV-Ig G不仅含有针对Dsg3各种不同表位的抗体，而且还含有针对其他未知抗原的抗体。因此，我们使用四种不同的致病和非致病的抗Dsg3的单抗，在人鳞状细胞癌细胞系(DJM-1)和正常人角质形成细胞中检测了PV-Ig G的Dsg3耗竭活性是否是由抗Dsg3的特异性产生的。我们证明这些单抗可以耗尽Dsg3的细胞和桥粒，就像PV-Ig G一样。单个抗Dsg3单抗对其Dsg3耗竭活性表现出特有的限制，这与其致病活性有关。这些抗体结合在一起，发挥累积或协同作用，这可能解释了PV-IgG具有强大的Dsg3耗竭能力的多克隆。最后，尽管在小鼠模型中，Dsg3的耗尽活性与AK单抗的致病性相关，但在本研究中，Dsg3的残留水平低于50%时，与黏附强度指数无关。这可能表明，尽管Dsg3的缺失不能指示粘附力，但Dsg3的水平可以作为细胞内致病变化的读数，桥粒中的Dsg3的缺失在PV患者的皮肤脆性或水泡形成的易感性中起着重要作用。
Pemphigus vulgaris (PV) is an autoimmune blistering disease, characterized by the loss of cell-cell adhesion between epidermal keratinocytes and the presence of autoantibody against desmoglein 3 (Dsg3), which provides adhesive integrity to desmosomes between adjacent keratinocytes. We have previously shown that PV-IgG purified from patients depletes desmosomes of Dsg3. However, PV-IgG contains not only antibodies against a variety of different epitopes of Dsg3 but also against other unknown antigens. Therefore, we examined whether the Dsg3-depleting activity of PV-IgG is generated specifically by antiDsg3 activity in a human squamous cell carcinoma cell line (DJM-1) and normal human keratinocytes by using four different pathogenic and nonpathogenic monoclonal antibodies against Dsg3. We demonstrate that these monoclonal antibodies deplete cells and desmosomes of Dsg3, as PV-IgG does. Individual monoclonal anti-Dsg3 antibodies display characteristic limits to their Dsg3-depleting activity, which correlates with their pathogenic activities. In combination, these antibodies exert a cumulative or synergistic effect, which may explain the potent Dsg3-depleting capability of PV-IgG, which is polyclonal. Finally, although Dsg3-depletion activity correlated with AK-monoclonal antibody pathogenicity in mouse models, the residual level of Dsg3, when below similar to 50%, does not correlate with the adhesive strength index in the present study. This may suggest that although the Dsg3 depletion is not indicative for adhesive strength, the level of Dsg3 can be used as a read-out of pathogenic changes within the cell and that the Dsg3 depletion from desmosomes plays an important role in skin fragility or susceptibility to blister formation in PV patients.