The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus.

Autor:	Voss LF; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Howarth AJ; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Wittenborn TR; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Hummelgaard S; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Juul-Madsen K; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Kastberg KS; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Pedersen MK; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Jensen L; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Papanastasiou AD; Department of Biomedical Sciences, University of West Attica, Athens, Greece., Vorup-Jensen T; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Weyer K; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Degn SE; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Dec 14; Vol. 13, pp. 1021370. Date of Electronic Publication: 2022 Dec 14 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.1021370
Abstrakt:	Introduction: 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. Methods: 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 in vitro and in autoreactive mixed bone marrow chimeras. Results: 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. In vitro , loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo , B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Discussion: 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. Competing Interests: 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. (Copyright © 2022 Voss, Howarth, Wittenborn, Hummelgaard, Juul-Madsen, Kastberg, Pedersen, Jensen, Papanastasiou, Vorup-Jensen, Weyer and Degn.)
Databáze:	MEDLINE
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