Abstract
B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.
Highlights
B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), a severe autoimmune disease with remission phases and flares [1,2,3,4]
Our patient cohort displayed an altered B cell subset repartition previously associated with SLE, which included an increase in transitional B cells, double-negative memory B cells, and circulating plasma cells combined with a decrease in conventional CD27+ memory B cells (Table 1) [32]
We found that CD21 cell surface expression was significantly lower on SLE B cells, with a 39% and 61% decrease in quiescent and active SLE patients, respectively, whereas CD81 and CD225 expression appeared normal (Figure 1A)
Summary
B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), a severe autoimmune disease with remission phases and flares [1,2,3,4]. B cell tolerance is further breached in SLE as evidenced by the detection of various anti-nuclear antibodies (ANAs) in patients’ sera [1] These autoantibodies target ribonucleoproteins SSA/Ro52 and Sm that contain singlestranded RNAs (ssRNAs) and double-stranded DNA (dsDNA), which are Toll-like receptor 7 (TLR7) and TLR9 agonists, respectively, and trigger B cell activation [9,10,11]. These nucleic acid–containing immune complexes activate myeloid and plasmacytoid dendritic cells (pDCs) leading to the secretion of type I and II interferons (IFNs), 2 key cytokines associated with SLE pathogenesis [12,13,14].
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