Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope
| Autor: | Ye Qian, O.J. Harrison, Lawrence Shapiro, Phillip Prisayanh, A. Roth, Ning Li, Barry Honig, Luis A. Diaz, Julia Brasch, Zhi Liu, Flor Evangelista, Brenda Temple, Donna A. Culton |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Endemic Diseases Protein Conformation Immunology Epitope Article 03 medical and health sciences Mice 0302 clinical medicine Desmosome parasitic diseases medicine Immunology and Allergy Animals Humans Binding site Pemphigus foliaceus Cells Cultured Autoantibodies Mice Inbred BALB C integumentary system Chemistry Cadherin Desmoglein 1 Autoantibody Immunization Passive Desmosomes medicine.disease Molecular biology 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunoglobulin G Mutagenesis Site-Directed Epitopes B-Lymphocyte Peptides Brazil Epitope Mapping Pemphigus Conformational epitope Protein Binding |
| Zdroj: | Journal of autoimmunity. 89 |
| ISSN: | 1095-9157 |
| Popis: | 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 (A(129)LNSMGQDLERPLELR(144)) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule. Mutation of Dsg1 residues M(133) and Q(135) reduced the binding of FS IgG4 autoantibodies to Dsg1 by ~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. |
| Databáze: | OpenAIRE |
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