Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
08 04 2023
08 04 2023
Historique:
received:
09
06
2022
accepted:
27
03
2023
revised:
23
03
2023
medline:
11
4
2023
entrez:
8
4
2023
pubmed:
9
4
2023
Statut:
epublish
Résumé
Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.
Identifiants
pubmed: 37031195
doi: 10.1038/s41419-023-05783-3
pii: 10.1038/s41419-023-05783-3
pmc: PMC10082781
doi:
Substances chimiques
Immunoglobulin G
0
Complement System Proteins
9007-36-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
254Subventions
Organisme : NIMH NIH HHS
ID : R21 MH118174
Pays : United States
Organisme : NIMH NIH HHS
ID : R33 MH118174
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS048154
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116073
Pays : United States
Informations de copyright
© 2023. The Author(s).
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