Immunofluorescence of a skin biopsy from a patient with pemphigus vulgaris shows intercellular IgG deposits in the epidermis. The autoantibody target antigen is desmoglein 3 (Dsg3). At the molecular level, the mechanism by which anti-Dsg3 antibodies cause acantholysis involves:

• A Complement-mediated lysis of keratinocytes
• B Direct cytotoxic T-cell killing of desmoglein-expressing keratinocytes
• C Deposition of immune complexes in desmosome junctions activating local complement
• D Steric hindrance and/or signaling through p38 MAPK and RhoA leading to desmoglein internalization and desmosome disassembly ✓

Explanation

Anti-Dsg3 antibodies cause acantholysis by two complementary mechanisms: (1) direct steric hindrance of Dsg3 trans-adhesion between adjacent keratinocytes, and (2) outside-in signaling through activation of p38 MAPK, RhoA GTPase inactivation, and EGFR pathways, which collectively lead to phosphorylation and internalization of desmogleins, disassembly of desmosomes, and retraction of keratin intermediate filaments. Complement is not required for acantholysis in pemphigus (passive transfer of IgG alone reproduces the lesion in neonatal mice). T-cells are not directly involved in the acantholytic process.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.