A 52-year-old man presents with 4 months of painful oral erosions followed by flaccid bullae on the scalp, chest, and axillae that rupture easily. Gentle lateral pressure on perilesional normal-appearing skin produces a positive Nikolsky sign. Tzanck smear shows acantholytic keratinocytes. Histopathology reveals the pattern marked **A** in the diagram—suprabasal intraepidermal acantholysis with a "tombstone" appearance of basal cells. Direct immunofluorescence shows an intercellular "fishnet" pattern of IgG deposition. Which of the following best explains the pathophysiology of this condition?

Question

Accepted Answer

C. IgG autoantibodies against desmoglein 3 disrupt keratinocyte adhesion through loss of desmosomal cohesion. ## Why option 1 is correct

The clinical presentation—painful oral erosions progressing to flaccid intraepidermal bullae with positive Nikolsky sign, suprabasal acantholysis, and intercellular IgG deposition on direct immunofluorescence—is pathognomonic for pemphigus vulgaris. The histologic pattern marked **A** (suprabasal acantholysis with tombstone appearance) and the "fishnet" pattern of IgG deposition reflect the defining pathophysiology: circulating IgG autoantibodies targeting desmoglein 3 (DSG3), a cadherin component of the desmosomal complex. These antibodies bind to the extracellular domains of DSG3, disrupting keratinocyte-to-keratinocyte adhesion and causing loss of desmosomal cohesion (acantholysis). The mucosal-dominant presentation followed by mucocutaneous disease reflects the DSG compensation hypothesis: oral mucosa expresses predominantly DSG3 (anti-DSG3 alone causes mucosal disease), while skin co-expresses DSG1 and DSG3 (skin disease appears only when anti-DSG1 antibodies also develop). This mechanism is the cornerstone of pemphigus vulgaris pathogenesis (Bolognia Dermatology 5e Ch 29; Schmidt Pemphigus Lancet 2019).

## Why each distractor is wrong

- **Option 2 (IgE-mediated mast cell degranulation)**: This describes bullous pemphigoid, which presents with tense subepidermal bullae, eosinophilic infiltration, and anti-BP180 IgG (pattern **B**). The histology is subepidermal, not intraepidermal acantholysis, and the clinical course is less severe than pemphigus vulgaris.

- **Option 3 (IgA immune complexes at dermal-epidermal junction)**: This describes linear IgA disease or dermatitis herpetiformis (patterns **C** and **D**), which present with grouped vesicles or pruritic papulovesicles, not flaccid intraepidermal bullae. The immunofluorescence pattern is linear or granular at the basement membrane, not intercellular.

- **Option 4 (IgG against BP180 with complement activation)**: This describes bullous pemphigoid (pattern **B**), a subepidermal blistering disease with tense bullae and eosinophilic infiltration. BP180 is a hemidesmosomal protein, not a desmosomal cadherin, and the clinical presentation differs fundamentally from the intraepidermal acantholysis seen in pattern **A**.

**High-Yield:** Pemphigus vulgaris = intraepidermal acantholysis + intercellular IgG + anti-DSG3 antibodies; bullous pemphigoid = subepidermal bullae + eosinophils + anti-BP180 antibodies.

[cite: Bolognia Dermatology 5e Ch 29; Schmidt Pemphigus Lancet 2019]

Answer

A. IgE-mediated mast cell degranulation triggers subepidermal blister formation with eosinophilic infiltration

Answer

B. IgA immune complexes deposit at the dermal-epidermal junction causing linear basement membrane damage

Answer

D. IgG autoantibodies against BP180 activate complement and recruit neutrophils to the basement membrane zone

Explanation

Why option 1 is correct

Why each distractor is wrong

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