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

Journal of Autoimmunity
Flor EvangelistaLuis A Diaz

Abstract

Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 autoantibodies 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 (A129LNSMGQDLERPLELR144) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule. Mutation of Dsg1 residues M133 and Q135 reduced the binding of FS IgG4 autoantibodies to Dsg1 by ∼50%. Molecular modeling identified two nearby EC1 domain residues (Q82 and V83) 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.

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Citations

May 7, 2020·Veterinary Dermatology·Britt J LevyPetra Bizikova
May 3, 2018·Frontiers in Immunology·Dario Didona, Giovanni Di Zenzo
Nov 5, 2019·Frontiers in Immunology·Valéria Bumiller-BiniAngelica Beate Winter Boldt
Aug 30, 2018·Anais Brasileiros De Dermatologia·Günter Hans-FilhoGuilherme Canho Bittner
Mar 24, 2020·The Journal of Investigative Dermatology·Christoph M Hammers, John R Stanley
Jan 1, 2018·Anais Brasileiros De Dermatologia·Günter Hans-FilhoGuilhermeCanho Bittner
May 4, 2020·The Journal of Investigative Dermatology·Luis A DiazUNKNOWN Cooperative Group of Fogo Selvagem Research

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