Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Front Immunol. 2019 May 29;10:1224. doi: 10.3389/fimmu.2019.01224. eCollection 2019.
Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies target the hemidesmosomal components BP180 and/or BP230 in basal keratinocytes. In BP, 80 to 90% of autoantibodies target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. Recently, the administration of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used as antihyperglycemic drugs, has been recognized to be a causative factor for BP. DPP4i-associated BP (DPP4i-BP) autoantibodies tend to target epitopes on non-NC16A regions of BP180, and the pathomechanism for the development of the unique autoantibodies remains unknown. To address the characteristics of DPP4i-BP autoantibodies in detail, we performed epitope analysis of 18 DPP4i-BP autoantibodies targeting the non-NC16A domains of BP180 using various domain-specific as well as plasmin-digested polypeptides derived from recombinant BP180. Firstly, Western blotting showed that only one DPP4i-BP serum reacted with the epitopes on the intracellular domain of BP180, and no sera reacted with the C-terminal domain of the molecule. In addition, only 2 DPP4i-BP sera reacted with BP230 as determined by enzyme-linked immunosorbent assay. Thus, DPP4i-BP autoantibodies were found to mainly target the non-NC16A mid-portion of the extracellular domain of BP. Interestingly, Western blotting using plasmin-digested BP180 as a substrate revealed that all of the DPP4i-BP sera reacted more intensively with the 97-kDa processed extracellular domain of BP180, which is known as the LABD97 autoantigen, than full-length BP180 did. All of the DPP4i-BP autoantibodies targeting the LABD97 autoantigen were IgG1, and IgG4 was observed to react with the molecule in only 7 cases (38.9%). In summary, the present study suggests that IgG1-class autoantibodies targeting epitopes on the processed extracellular domain of BP180, i.e., LABD97, are the major autoantibodies in DPP4i-BP.
大疱性类天疱疮（BP）是一种常见的自身免疫性水疱病，自身抗体针对基底角质形成细胞中的半桥粒成分 BP180 和/或 BP230。在 BP 中，80%至 90%的自身抗体针对 BP180 的跨膜细胞外非胶原 16 区（NC16A）域。最近，二肽基肽酶-IV 抑制剂（DPP4i）的给药被认为是 BP 的一个致病因素，DPP4i 被广泛用作抗高血糖药物。DPP4i 相关的 BP（DPP4i-BP）自身抗体往往针对 BP180 的非 NC16A 区域的表位，而发展这种独特自身抗体的发病机制尚不清楚。为了详细研究 DPP4i-BP 自身抗体的特征，我们使用来自重组 BP180 的各种结构域特异性和纤溶酶消化多肽，对针对 BP180 非 NC16A 结构域的 18 种 DPP4i-BP 自身抗体进行了表位分析。首先，Western blot 显示只有一种 DPP4i-BP 血清与 BP180 细胞内域的表位反应，没有血清与分子的 C 末端域反应。此外，通过酶联免疫吸附试验仅发现 2 种 DPP4i-BP 血清与 BP230 反应。因此，发现 DPP4i-BP 自身抗体主要针对 BP 细胞外域的非 NC16A 中部分。有趣的是，使用纤溶酶消化的 BP180 作为底物的 Western blot 显示，所有 DPP4i-BP 血清与已知的 LABD97 自身抗原的 97kDa 处理的细胞外 BP180 域反应更强烈，而全长 BP180 则没有。所有针对 LABD97 自身抗原的 DPP4i-BP 自身抗体均为 IgG1 类，仅在 7 例（38.9%）中观察到 IgG4 与该分子反应。综上所述，本研究表明，针对 BP180 处理的细胞外域表位的 IgG1 类自身抗体，即 LABD97，是 DPP4i-BP 中的主要自身抗体。
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