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

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 the 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. 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. 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.