TLR7 responsiveness of human transitional B cells

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is known to be associated with B cell hyperactivity and production of autoantibodies (Auto-Abs) against nucleoproteins. Auto-Abs reactive to RNA-containing antigens are found in a fraction of SLE patients, particularly those with severe disease activity. Toll-like receptor 7 (TLR7), an intracellular TLR that recognizes ssRNA, has been highly implicated in the generation of pathogenic anti-RNA autoantibodies in SLE; however, the cellular origin of anti-RNA Ab–secreting cells is not well defined. We have found that increased expression of TLR7 in TLR7Tg mice results in activation of their newly-formed (NF) transitional B cells which upon stimulation produced class-switched IgGs, including anti-RNA auto-Abs. Subsequent analysis of the B cell compartment in SLE patients revealed a correlation between the levels of TLR7 expression and increases in the frequencies of circulating CD20 + CD27 − CD10 + CD38 high CD24 high NF B cells. SLE patients with dysregulation of NF B cells were also more likely to have Sm/RNP auto-Abs. IFNa treatment induced more than a 10-fold increase in the mRNA expression of TLR7 , UNC93B and IRF7 in NF B cells isolated from umbilical cord blood. Furthermore, IFNa-primed NF B cells became highly responsive to in vitro stimulation with TLR7 ligand-R848 and differentiated into CD27 + CD38 hi CD24 lo plasmablasts in the absence of any other stimuli. Human NF B cells are enriched in polyreactive specificities and increases of NF B cells have been described in SLE patients. Our studies suggest that human NF B cells might be an important source of auto-Ab-secreting cells and provide a new link between innate IFNa and TLR7 signaling and B cell activation in SLE.