The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus.
B cells
TLR7
autoantibodies
autoimmunity
extrafollicular responses
germinal centers
systemic lupus erythematosus
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2022
2022
Historique:
received:
17
08
2022
accepted:
02
11
2022
entrez:
2
1
2023
pubmed:
3
1
2023
medline:
4
1
2023
Statut:
epublish
Résumé
Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated GC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. We identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.
Identifiants
pubmed: 36591222
doi: 10.3389/fimmu.2022.1021370
pmc: PMC9795406
doi:
Banques de données
Dryad
['10.5061/dryad.zs7h44jc2']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1021370Informations de copyright
Copyright © 2022 Voss, Howarth, Wittenborn, Hummelgaard, Juul-Madsen, Kastberg, Pedersen, Jensen, Papanastasiou, Vorup-Jensen, Weyer and Degn.
Déclaration de conflit d'intérêts
TV-J and KJ-M are inventors on a submitted patent application PCT/EP2020/082837, owned by Aarhus University, related to human spMBL as a biomarker for SLE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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