PT  - JOURNAL ARTICLE
AU  - Lasse F. Voss
AU  - Amanda J. Howarth
AU  - Thomas R. Wittenborn
AU  - Sandra Hummelgaard
AU  - Kristian Juul-Madsen
AU  - Kristian S. Kastberg
AU  - Mathias K. Pedersen
AU  - Lisbeth Jensen
AU  - Anastasios D. Papanastasiou
AU  - Thomas Vorup-Jensen
AU  - Kathrin Weyer
AU  - Søren E. Degn
TI  - Germinal center block exacerbates extrafollicular responses and accelerates autoimmune disease progression in a murine lupus model
AID  - 10.1101/2022.03.04.482991
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.03.04.482991
4099  - http://biorxiv.org/content/early/2022/03/25/2022.03.04.482991.short
4100  - http://biorxiv.org/content/early/2022/03/25/2022.03.04.482991.full
AB  - Systemic lupus erythematosus and numerous other autoimmune diseases are characterized by affinity-matured, class-switched autoantibodies to nuclear antigens. Such antibodies are generally thought to arise in germinal centers (GCs). Several strategies to block GC formation and progression are currently being explored clinically. However, recent studies have suggested a key role for extrafollicular responses in driving the early events in autoimmune development. To investigate the relative contribution of these two pathways in autoimmune disease development, we leveraged a lupus murine model, where we could genetically block the GC pathway. We find that a B cell intrinsic block in GC formation accelerates extrafollicular responses and exacerbates autoimmune progression. The manifestations included higher levels of circulating, class-switched autoantibodies, as well as antibody- and complement-deposition in the kidney glomeruli. GC B cell cultures in vitro showed that loss of the GC transcription factor Bcl-6 prevents cellular expansion and accelerates plasma cell differentiation. This suggests that the in vivo phenotype was a direct consequence of rewiring of B cell intrinsic transcriptional programming. In a competitive scenario in vivo, in autoreactive mixed bone marrow chimeras, B cells harboring the genetic GC block contributed disproportionately highly to the plasma cell output. Taken together, this emphasizes the extrafollicular pathway as a key contributor to autoimmune pathogenesis and suggests that strategies aimed at blocking GCs should simultaneously target this pathway to avoid rerouting the pathogenic response.Highlights- Genetic GC block exacerbates autoimmune progression in a lupus model- An intrinsic GC block drives B cell differentiation into terminally differentiated plasma cells in vitro- B cells harboring a GC block competitively contribute to the plasma cell compartment in an autoreactive setting in vivo- Lupus mice with a GC block display immune complex deposition in kidney glomeruli that is indistinguishable from their wild-type counterpartsCompeting Interest StatementTV-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. All other 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.