C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies
C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies
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XVII 胶原蛋白的 C 端加工诱导线性 IgA 皮肤病自身抗体的新表位
DOI：
10.1016/j.jid.2017.07.831
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发表时间：
2017
影响因子：
6.5
通讯作者：
Shimizu Hiroshi
中科院分区：
文献类型：
--
作者：
Toyonaga Ellen;Nishie Wataru;Izumi Kentaro;Natsuga Ken;Ujiie Hideyuki;Iwata Hiroaki;Yamagami Jun;Hirako Yoshiaki;Sawamura Daisuke;Fujimoto Wataru;Shimizu Hiroshi
跨膜型XVII胶原(COL17)是基底角质形成细胞的半染色体组分，自身抗体可作为自身免疫性水疱病的靶点，包括线状IgA皮肤病(LAD)。COL17可以在膜外NC16A结构域内被生理切割，LAD自身抗体优先与处理后的胞外结构域反应，表明处理诱导了新的表位。然而，新表位如何发展的细节还没有阐明。在这项研究中，我们表明COL17的C末端处理在诱导LAD自身抗体的新表位方面也起到了作用。首先制备了针对COL17第15胶原区的单抗hC17-ect15，该单抗具有与LAD自身抗体相似的特性。这些单抗优先与C端缺失(最多682个氨基酸)的重组COL17反应，表明C端处理在第15个胶原区显示了新的表位。LAD自身抗体也与C末端缺失的COL17发生反应。因此，LAD自身抗体的新表位也是经过C-末端处理后形成的。最后，将mAbhC17-ect15被动转移到表达人COL17的转基因小鼠中，未能诱发水疱病，这表明新表位靶向抗体并不总是致病的。综上所述，本研究表明，C-末端处理诱导了COL17上LAD自身抗体的动态结构变化和新的表位。
Transmembrane collagen XVII (COL17) is a hemidesmosomal component of basal keratinocytes that can be targeted by autoantibodies in autoimmune blistering disorders, including linear IgA dermatosis (LAD). COL17 can be physiologically cleaved within the juxtamembranous extracellular NC16A domain, and LAD autoantibodies preferentially react with the processed ectodomains, indicating that the processing induces neoepitopes. However, the details of how neoepitopes develop have not been elucidated. In this study, we show that C-terminal processing of COL17 also plays a role in inducing neoepitopes for LAD autoantibodies. First, the mAb hC17-ect15 targeting the 15th collagenous domain of COL17 was produced, which showed characteristics similar to LAD autoantibodies. The mAbs preferentially reacted with C-terminally deleted (up to 682 amino acids) recombinant COL17, suggesting that C-terminal processing shows neoepitopes on the 15th collagenous domain. The LAD autoantibodies also react with C-terminal deleted COL17. Therefore, neoepitopes for LAD autoantibodies also develop after C-terminal processing. Finally, the passive transfer of the mAb hC17-ect15 into human COL17-expressing transgenic mice failed to induce blistering disease, suggesting that neoepitope-targeting antibodies are not always pathogenic. In summary, this study shows that C-terminal processing induces dynamic structural changes and neoepitopes for LAD autoantibodies on COL17.