AUTHOR=Wang Ting , Marken John , Chen Janice , Tran Van Bao , Li Quan-Zhen , Li Mengtao , Cerosaletti Karen , Elkon Keith B. , Zeng Xiaofeng , Giltiay Natalia V. 

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01243

DOI=10.3389/fimmu.2019.01243

ISSN=1664-3224

ABSTRACT=<p>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 <italic>TLR7 rs3853839 C/G</italic> polymorphism, which affects <italic>TLR7</italic> mRNA turnover, and SLE susceptibility; however, the effects of this polymorphism on B cells have not been studied. Here we determined how changes in <italic>TLR7</italic> expression affect peripheral B cells and auto-Ab production in SLE patients. High <italic>TLR7</italic> expression in SLE patients driven by <italic>TLR7 rs3853839 C/G</italic> polymorphism was associated with more active disease and upregulation of IFN-responsive genes. TLR7<sup>hi</sup> SLE patients showed an increase in peripheral B cells. Most notably, the percentage and numbers of CD19<sup>+</sup>CD24<sup>++</sup>CD38<sup>++</sup> newly-formed transitional (TR) B cells were increased in TLR7<sup>hi</sup> SLE patients as compared to HCs and TLR7<sup>norm/lo</sup> SLE patients. Using auto-Ab arrays, we found an increase and enrichment of auto-Ab specificities in the TLR7<sup>hi</sup> SLE group, including the production of anti-RNA/RNP-Abs. Upon <italic>in vitro</italic> TLR7 ligand stimulation, TR B cells isolated from TLR7<sup>hi</sup> but not TLR7<sup>norm/lo</sup> SLE patients produced anti-nuclear auto-Abs (ANA). Exposure of TR B cells isolated from cord blood to IFNα induced the expression of <italic>TLR7</italic> and enabled their activation in response to TLR7 ligation <italic>in vitro</italic>. Our study shows that overexpression of <italic>TLR7</italic> 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.</p>