Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu.
Adult
Aged
Astrocytes
/ immunology
Autoantibodies
/ immunology
Autoantigens
/ immunology
Endothelial Cells
/ immunology
Female
HEK293 Cells
Hemangioma, Cavernous, Central Nervous System
/ immunology
Humans
Male
Middle Aged
Myosin Heavy Chains
/ immunology
Plasma Cells
/ immunology
Tubulin
/ immunology
Vimentin
/ immunology
Autoimmunity
Cerebral cavernous malformation
Cytoskeleton proteins
Recombinant monoclonal antibody
Journal
Journal of autoimmunity
ISSN: 1095-9157
Titre abrégé: J Autoimmun
Pays: England
ID NLM: 8812164
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
09
03
2020
revised:
13
04
2020
accepted:
17
04
2020
pubmed:
5
5
2020
medline:
12
10
2021
entrez:
5
5
2020
Statut:
ppublish
Résumé
Previous studies have reported robust inflammatory cell infiltration, synthesis of IgG, B-cell clonal expansion, deposition of immune complexes and complement within cerebral cavernous malformation (CCM) lesions. B-cell depletion has also been shown to reduce the maturation of CCM in murine models. We hypothesize that antigen(s) within the lesional milieu perpetuate the pathogenetic immune responses in CCMs. This study aims to identify those putative antigen(s) using monoclonal antibodies (mAbs) derived from plasma cells found in surgically removed human CCM lesions. We produced human mAbs from laser capture micro-dissected plasma cells from four CCM patients, and also germline-reverted versions. CCM mAbs were assayed using immunofluorescence on central nervous system (CNS) tissues and immunocytochemistry on human primary cell lines. Antigen characterization was performed using a combination of confocal microscopy, immunoprecipitation and mass spectrometry. Affinity was determined by enzyme-linked immunosorbent assay, and specificity by multi-color confocal microscopy and quantitative co-localization. CCM mAbs bound CNS tissue, especially endothelial cells and astrocytes. Non-muscle myosin heavy chain IIA (NMMHCIIA), vimentin and tubulin are three cytoskeleton proteins that were commonly targeted. Selection of cytoskeleton proteins by plasma cells was supported by a high frequency of immunoglobulin variable region somatic hypermutations, high affinity and selectivity of mAbs in their affinity matured forms, and profoundly reduced affinity and selectivity in the germline reverted forms. Antibodies produced by plasma cells in CCM lesions commonly target cytoplasmic and cytoskeletal autoantigens including NMMHCIIA, vimentin and tubulin that are abundant in endothelial cells and astrocytes. Binding to, and selection on autoantigen(s) in the lesional milieu likely perpetuates the pathogenetic immune response in CCMs. Blocking this in situ autoimmune response may yield a novel treatment for CCM.
Identifiants
pubmed: 32362501
pii: S0896-8411(20)30085-8
doi: 10.1016/j.jaut.2020.102469
pmc: PMC7483292
mid: NIHMS1589926
pii:
doi:
Substances chimiques
Autoantibodies
0
Autoantigens
0
MYH9 protein, human
0
Tubulin
0
VIM protein, human
0
Vimentin
0
Myosin Heavy Chains
EC 3.6.4.1
Types de publication
Journal Article
Observational Study
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
102469Subventions
Organisme : NINDS NIH HHS
ID : P01 NS092521
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM108569
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : NIH HHS
ID : S10 OD025194
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI082724
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000430
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD007009
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
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