Mai Shoko, Mai Yosuke, Ujiie Inkin, Izumi Kentaro, Natsuga Ken, Nishie Wataru, Ujiie Hideyuki
Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Sci Adv. 2025 Aug;11(31):eadv9423. doi: 10.1126/sciadv.adv9423. Epub 2025 Aug 1.
Bullous pemphigoid (BP) is a common autoimmune skin disorder caused by autoantibodies targeting BP180. Recent evidence shows that dipeptidyl peptidase-4 inhibitors (DPP4i), used in diabetes management, can induce BP (DPP4i-BP). DPP4i-BP differs from typical BP in its genetic, clinical, and immunological features, but methods to specifically detect DPP4i-BP autoantibodies have been unavailable. This study used enzyme-linked immunosorbent assay with "domain-swapped BP180" proteins to identify autoantibodies in DPP4i-BP, which targeted BP180 regions from the seventh noncollagenous domain to the fourth collagenous domain (NC7-Col4). These epitopes were associated with DPP4i-BP-specific human leukocyte antigen class II peptide epitopes. Notably, the duration of DPP4i intake before BP onset was significantly shorter in patients with anti-NC7-Col4 autoantibodies than those without them. Measuring the autoantibodies enabled the early diagnosis of DPP4i-BP before epitope spreading. Furthermore, anti-NC7-Col4 autoantibodies were detected in some patients with diabetes taking DPP4i without BP, suggesting that these assays may offer potential tools for early identification of at-risk individuals.
大疱性类天疱疮（BP）是一种常见的自身免疫性皮肤病，由靶向BP180的自身抗体引起。最近的证据表明，用于糖尿病管理的二肽基肽酶-4抑制剂（DPP4i）可诱发BP（DPP4i-BP）。DPP4i-BP在遗传、临床和免疫学特征上与典型BP不同，但一直没有专门检测DPP4i-BP自身抗体的方法。本研究使用“结构域互换的BP180”蛋白进行酶联免疫吸附测定，以鉴定DPP4i-BP中的自身抗体，这些自身抗体靶向从第七个非胶原结构域到第四个胶原结构域（NC7-Col4）的BP180区域。这些表位与DPP4i-BP特异性的人类白细胞抗原II类肽表位相关。值得注意的是，出现抗NC7-Col4自身抗体的患者在BP发作前服用DPP4i的时间明显短于未出现该抗体的患者。检测这些自身抗体能够在表位扩散之前对DPP4i-BP进行早期诊断。此外，在一些服用DPP4i但未患BP的糖尿病患者中检测到了抗NC7-Col4自身抗体，这表明这些检测方法可能为早期识别高危个体提供潜在工具。
