Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope

Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 auto-antibodies against the amino-terminal extracellular cadherin domain of the desmosomal cadherin desmoglein 1 (Dsg1). Here we define the detailed epitopes of these pathogenic antibodies. Proteolytic footprinting showed that IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide (A(129)LNSMGQDLERPLELR(144)) from the EC1 domain of Dsgl that overlaps the binding site for an adhesive partner desmosomal cadherin molecule. Mutation of Dsgl residues M-133 and Q(135) reduced the binding of FS IgG4 autoantibodies to Dsgl by similar to 50%. Molecular modeling identified two nearby EC1 domain residues (Q(82) and V-83) likely to contribute to the epitope. Mutation of these residues completely abolished the binding of FS IgG4 to Dsg1. Bead aggregation assays showed that native binding interactions between Dsg1 and desmocollin 1 (Dsc1), which underlie desmosome structure, were abolished by Fab fragments of FS IgG4. These results further define the molecular mechanism by which FS IgG4 autoantibodies interfere with desmosome structure and lead to cell-cell detachment, the hallmark of this disease. (C) 2018 Elsevier Ltd. All rights reserved.