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

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

doi:10.3389/fimmu.2019.01243

Abstract

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. TLR7hi 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 TLR7hi SLE patients as compared to HCs and TLR7norm/lo SLE patients. Using auto-Ab arrays, we found an increase and enrichment of auto-Ab specificities in the TLR7hi SLE group, including the production of anti-RNA/RNP-Abs. Upon in vitro TLR7 ligand stimulation, TR B cells isolated from TLR7hi but not TLR7norm/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.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyperactivation, associated with the production of antinuclear autoantibodies and the formation of immune complexes (IC)
We explored how changes in TLR7 expression, including an increase in TLR7 due Abbreviations: Ab, antibody; Auto-Ab, autoantibody; BAFF, B-Cell-Activating Factor; BCR, B-cell receptor; CB, cord blood; DN B cells, double–negative B cells; IFNstimulated genes (ISGs), interferon (IFN)-stimulated genes; IFN, interferon; Peripheral blood mononuclear cells (PBMC), peripheral blood mononuclear cells; PCR, polymerase chain-reaction; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; TLR7, Toll-like receptor 7; TLR9, Toll-like receptor 9; TR B cells, Transitional B cells; ssRNA, single-stranded RNA; Sm, Smith Antigen
To assess the effects of TLR7 overexpression on peripheral B cell populations, we first analyzed the expression of TLR7 in total PBMCs, isolated from 47 SLE patients and 16 healthy controls (HC)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyperactivation, associated with the production of antinuclear autoantibodies (auto-Abs) and the formation of immune complexes (IC). A subset of SLE patients has auto-Abs, which are reactive to RNA and ribonucleoproteins (RNPs), including anti-Ro, anti-Sm, and antiRNP and, are associated with increased expression of IFNstimulated genes (ISGs) and worse disease severity [1,2,3]. Despite their contribution to SLE pathogenesis, the immune sensors that drive the production of anti-RNA/RNP auto-Abs in human SLE are not well-established. TLR7 mediates type I IFN production in human pDC [9, 10]. Increased type I IFNs can indirectly, promote B cell survival and activation by driving the production of B cell-activating factor (BAFF) and other cytokines by myeloid cells and/or T cells [12, 13]

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