Single-Cell Analysis Suggests that Ongoing Affinity Maturation Drives the Emergence of Pemphigus Vulgaris Autoimmune Disease.
Antibodies, Monoclonal
/ immunology
Autoantigens
/ immunology
Autoimmune Diseases
/ immunology
B-Lymphocytes
/ immunology
Desmoglein 3
/ chemistry
Germ Cells
/ metabolism
Humans
Immunologic Memory
Pemphigus
/ immunology
Protein Binding
Protein Domains
Single-Cell Analysis
Somatic Hypermutation, Immunoglobulin
/ genetics
B cells
autoimmunity
desmoglein 3
memory B cells
monoclonal antibody
pemphigus vulgaris
skin
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
23 07 2019
23 07 2019
Historique:
received:
10
02
2019
revised:
22
05
2019
accepted:
18
06
2019
entrez:
25
7
2019
pubmed:
25
7
2019
medline:
25
8
2020
Statut:
ppublish
Résumé
Pemphigus vulgaris (PV) is an autoimmune disease characterized by blistering sores on skin and mucosal membranes, caused by autoantibodies primarily targeting the cellular adhesion protein, desmoglein-3 (Dsg3). To better understand how Dsg3-specific autoantibodies develop and cause disease in humans, we performed a cross-sectional study of PV patients before and after treatment to track relevant cellular responses underlying disease pathogenesis, and we provide an in-depth analysis of two patients by generating a panel of mAbs from single Dsg3-specific memory B cells (MBCs). Additionally, we analyzed a paired sample from one patient collected 15-months prior to disease diagnosis. We find that Dsg3-specific MBCs have an activated phenotype and show signs of ongoing affinity maturation and clonal selection. Monoclonal antibodies (mAbs) with pathogenic activity primarily target epitopes in the extracellular domains EC1 and EC2 of Dsg3, though they can also bind to the EC4 domain. Combining antibodies targeting different epitopes synergistically enhances in vitro pathogenicity.
Identifiants
pubmed: 31340153
pii: S2211-1247(19)30846-0
doi: 10.1016/j.celrep.2019.06.066
pmc: PMC6684256
mid: NIHMS1535565
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Autoantigens
0
Desmoglein 3
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
909-922.e6Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR048266
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001880
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI057266
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI090023
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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