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Signaling through Toll-like receptor 7 (TLR7) drives the production of type I IFN and promotes the activation of autoreactive B cells and is implicated in the pathogenesis of systemic lupus erythematosus (SLE). While TLR7 has been extensively studied in murine lupus, much less is known about its role in the pathogenesis of human SLE. Genetic studies support a link between the  TLR7 rs3853839 C/G  polymorphism, which affects  TLR7  mRNA turnover, and SLE susceptibility; however, the effects of this polymorphism on B cells have not been studied. Here we determined how changes in  TLR7  expression affect peripheral B cells and auto-Ab production in SLE patients. High  TLR7  expression in SLE patients driven by  TLR7 rs3853839 C/G  polymorphism was associated with more active disease and upregulation of IFN-responsive genes. TLR7 hi  SLE patients showed an increase in peripheral B cells. Most notably, the percentage and numbers of CD19 + CD24 ++ CD38 ++  newly-formed transitional (TR) B cells were increased in TLR7 hi  SLE patients as compared to HCs and TLR7 norm/lo  SLE patients. Using auto-Ab arrays, we found an increase and enrichment of auto-Ab specificities in the TLR7 hi  SLE group, including the production of anti-RNA/RNP-Abs. Upon  in vitro  TLR7 ligand stimulation, TR B cells isolated from TLR7 hi  but not TLR7 norm/lo  SLE patients produced anti-nuclear auto-Abs (ANA). Exposure of TR B cells isolated from cord blood to IFNα induced the expression of  TLR7  and enabled their activation in response to TLR7 ligation  in vitro . Our study shows that overexpression of  TLR7  in SLE patients drives the expansion of TR B cells. High TLR7 signaling in TR B cells promotes auto-Ab production, supporting a possible pathogenic role of TR B cells in human SLE.

High TLR7 Expression Drives the Expansion of CD19+CD24hiCD38hi Transitional B Cells and Autoantibody Production in SLE Patients