A 72-year-old man presents with a 6-week history of severe pruritus followed by the appearance of fluid-filled blisters on his abdomen, inner thighs, and axillae. On examination, the lesions marked **A** in the diagram are dome-shaped, intact, and do not rupture easily when pressure is applied. His Nikolsky sign is negative. He has been on vildagliptin for type 2 diabetes for the past 8 months. Direct immunofluorescence of perilesional skin shows linear IgG and C3 deposition along the basement membrane zone. Which of the following best explains the pathogenesis of the lesions marked **A**?

Explanation

## Why IgG autoantibodies against hemidesmosomal proteins (BP180 and BP230) leading to complement activation and subepidermal cleavage is right Bullous pemphigoid is characterized by IgG autoantibodies targeting hemidesmosomal proteins BP180 (collagen XVII, BPAG2) and BP230 (BPAG1) at the basement membrane zone. These autoantibodies activate complement, recruit eosinophils and neutrophils, and trigger protease release, resulting in subepidermal cleavage and the formation of tense, dome-shaped bullae (marked **A**). The clinical presentation—elderly patient, flexural/trunk distribution, negative Nikolsky sign, tense intact bullae, and linear IgG/C3 on DIF—is pathognomonic for bullous pemphigoid. The DPP-4 inhibitor (vildagliptin) is a well-recognized trigger for drug-induced BP. (Bolognia Dermatology 5e Ch 30; Harrison 21e Ch 59) ## Why each distractor is wrong - **IgA immune complex deposition in dermal papillae causing granular inflammation**: This describes dermatitis herpetiformis (DH), which presents with symmetric extensor pruritic vesicles and is associated with celiac disease. DH shows granular IgA deposition in dermal papillae, not linear IgG/C3 along the BMZ. - **Intraepidermal acantholysis due to anti-desmoglein 3 autoantibodies**: This is the pathogenesis of pemphigus vulgaris, which presents with flaccid intraepidermal bullae, positive Nikolsky sign, and intraepidermal cleavage on histology—opposite of the tense, subepidermal bullae seen here. - **Circulating immune complexes targeting type VII collagen in the sub-basal lamina zone**: This describes epidermolysis bullosa acquisita (EBA), which shows IgG binding to the dermal (floor) side of salt-split skin, not the epidermal (roof) side as in BP. EBA also presents with trauma-induced blistering and scarring. **High-Yield:** Tense bullae + elderly + flexural distribution + negative Nikolsky + linear IgG/C3 on DIF = bullous pemphigoid with subepidermal cleavage from anti-hemidesmosomal IgG autoantibodies. [cite: Bolognia Dermatology 5e Ch 30; Harrison 21e Ch 59]