Identification of distinct epitopes in dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid

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.