Shoko Mai

Mucous membrane pemphigoid (MMP) is a chronic autoimmune subepithelial blistering disorder of mucosal surfaces that can cause irreversible scarring, blindness, or dysphagia. Early diagnosis is challenging because histopathology is nonspecific and conventional BP180 NC16A ELISAs have limited sensitivity. We evaluated ELISAs using full‐length recombinant BP180 and a native BP180‐α6β4 integrin complex in six patients with suspected oral or ocular MMP. The conventional NC16A ELISA was negative in four of six patients, and biopsy alone was often insufficient. Both assays provided useful serological support in a subset of cases when interpreted alongside direct immunofluorescence (DIF) and clinical phenotype, whereas in others DIF remained the primary basis for diagnosis. These assays can therefore complement, but not replace, clinicopathological assessment in suspected MMP.

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.

Bullous pemphigoid is generally caused by immunoglobulin (Ig)G autoantibodies against hemidesmosomal BP180 and/or BP230. Recently, the concept of IgM pemphigoid has been proposed. A 23‐year‐old Japanese woman presented with a 4‐month history of severely itchy papules showing subepidermal separations with mild neutrophil infiltration. Direct immunofluorescence (DIF) revealed IgM deposits at the dermoepidermal junction, but neither IgG nor IgA deposits. Indirect immunofluorescence on 1 M NaCl‐split skin demonstrated deposits on the epidermal side. The optical density (OD) value of a modified IgM enzyme‐linked immunosorbent assay for full‐length BP180, but not for BP180‐NC16A, was increased. The patient was diagnosed with IgM pemphigoid and was treated with diphenyl sulfone at 50 mg/day without recurrence. To confirm the precise autoantigen, we tried to obtain super‐resolution imaging. The deposition pattern of IgM autoantibodies seemed to be oriented parallel to that of BP180. The detailed images detect DIF deposits apart from BP180‐NC16A staining, but are close to type VII collagen‐NC1 staining. This result suggests that the IgM autoantibodies in the patient might target the C‐terminus of BP180. IgM pemphigoid is still not a widely accepted concept, and the clinical course remains unknown. We will carefully follow‐up the patient. Super‐resolution images may help to detect precise autoantigens in autoimmune blistering diseases.