Autoantigens PLA2R and THSD7A in membranous nephropathy share a common epitope motif in the N-terminal domain.
Autoimmunity
Membranous nephropathy
PLA2R
THSD7A
Journal
Journal of autoimmunity
ISSN: 1095-9157
Titre abrégé: J Autoimmun
Pays: England
ID NLM: 8812164
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
07
05
2019
revised:
19
07
2019
accepted:
24
07
2019
pubmed:
10
8
2019
medline:
9
6
2021
entrez:
10
8
2019
Statut:
ppublish
Résumé
Patients with membranous nephropathy have autoantibodies against PLA2R (up to 80%), or THSD7A (up to 2%). We previously described the immunodominant epitope within PLA2R but epitopes in THSD7A are still unknown. To find anti-THSD7A sera for this study, we screened 1843 sera from biopsy-proven MN patients by ELISA and identified 22 sera as anti-THSD7A positive representing 1.2% of MN cases. Anti-THSD7A positive sera were further characterized by western blotting and slot blotting on THSD7A protein fragments and peptides. Real time interaction analyses and antibodies off-rate could be reliably determined using bio-layer interferometry. A signature motif in the N-terminal domain of THSD7A (T28mer) with sequence homology to the major PLA2R epitope (P28mer) was identified. B-cell epitope prediction analysis and homology modelling revealed this sequence to be antigenic and surface available suggesting it is accessible for the antibody to bind. All ten selected sera bound to the T28mer confirming this sequence as a dominant epitope in THSD7A. Reactivity to this sequence was lost following kallikrein protease cleavage within the predicted epitope. Importantly, cross-reactivity of both PLA2R and THSD7A autoantibodies was observed at the peptide but not the protein level. We propose that this common motif shared by both autoantigens could be an epitope involved in the initial B-cell triggering event in MN.
Identifiants
pubmed: 31395435
pii: S0896-8411(19)30291-4
doi: 10.1016/j.jaut.2019.102308
pmc: PMC7471840
pii:
doi:
Substances chimiques
Autoantibodies
0
Autoantigens
0
Epitopes
0
PLA2R1 protein, human
0
Receptors, Phospholipase A2
0
THSD7A protein, human
0
Thrombospondins
0
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102308Subventions
Organisme : Medical Research Council
ID : MR/J010847/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202860/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 097820
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
Références
J Am Soc Nephrol. 2017 Sep;28(9):2579-2589
pubmed: 28674044
Nat Protoc. 2009;4(3):363-71
pubmed: 19247286
J Am Soc Nephrol. 2011 Jun;22(6):1137-43
pubmed: 21566055
Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):E3095-103
pubmed: 26038575
J Am Soc Nephrol. 2016 May;27(5):1517-33
pubmed: 26567246
Proteins. 2019 Feb;87(2):136-145
pubmed: 30520531
Sci Rep. 2017 Jul 31;7(1):6876
pubmed: 28761153
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W288-93
pubmed: 22581768
J Am Soc Nephrol. 2018 May;29(5):1536-1548
pubmed: 29555830
J Autoimmun. 2018 Dec;95:100-123
pubmed: 30509385
Mod Pathol. 2016 Apr;29(4):421-6
pubmed: 26847174
Kidney Int. 2019 Mar;95(3):666-679
pubmed: 30784662
J Am Soc Nephrol. 2015 Feb;26(2):291-301
pubmed: 25205735
N Engl J Med. 2014 Dec 11;371(24):2277-2287
pubmed: 25394321
N Engl J Med. 2009 Jul 2;361(1):11-21
pubmed: 19571279
Brief Bioinform. 2019 Mar 25;20(2):638-658
pubmed: 29897410
Curr Protoc Bioinformatics. 2016 Mar 24;53:1.29.1-1.29.15
pubmed: 27010333
J Am Soc Nephrol. 2015 Feb;26(2):302-13
pubmed: 25288605
Nucleic Acids Res. 2017 Jul 3;45(W1):W24-W29
pubmed: 28472356
N Engl J Med. 2011 Feb 17;364(7):616-26
pubmed: 21323541
Clin Exp Immunol. 2019 Jan;195(1):10-14
pubmed: 30569518
Clin J Am Soc Nephrol. 2017 Oct 6;12(10):1642-1651
pubmed: 28801527
Kidney Int. 2013 May;83(5):940-8
pubmed: 23364522