The Largely Normal Response to Toll-Like Receptor 7 and 9 Stimulation and the Enhanced Expression of SIGIRR by B Cells in Systemic Lupus Erythematosus

Abstract

BackgroundAltered Toll-like receptor (TLR) signaling has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The present study was undertaken to characterize responses of B cells from SLE patients to TLR7 and TLR9 stimulation and to explore the potential role of single immunoglobulin interleukin-1 receptor related molecule (SIGIRR) in the regulation of TLR-mediated responses of SLE B cells.Methodology/Principal FindingsPeripheral blood mononuclear cells (PBMC) were isolated from 64 patients with SLE and 37 healthy donors. CD19+ B cells purified using microbeads were cultured with TLR7 or TLR9 agonists. Cell proliferation was measured by thymine incorporation and the frequency of antibody-secreting cells was determined by ELISPOT assay. SIGIRR expression in PBMCs and B cells was analyzed using flow cytometry analysis. In contrast to the enhanced proliferation following B cell receptor (BCR) engagement, B cells from SLE patients exhibited a virtually normal proliferative response to TLR7 or TLR9 stimulation. Moreover, B cells from SLE patients and healthy donors were almost equally competent to differentiate into antibody-secreting cells upon TLR engagement except for a reduction in the generation of IgG-secreting cells by TLR9-stimulated lupus B cells. In line with these somehow unexpected observations, SLE B cells were found to express a significantly higher level of SIGIRR than normal B cells.Conclusions/SignificanceDespite the reported upregulation of TLR7 and TLR9 expression in B cell from SLE patients, their responses to TLR stimulation were largely normal. The increased expression of the negative regulator SIGIRR may be partly responsible for the “balance of terror”.

The decreased frequency of SIGIRR-positive CD4+ T cells in peripheral blood of patients with SLE and its correlation with disease activity

“…T cells were observed in patients with SLE compared with healthy controls. It is consistent with previous studies [14,20,22]. Additionally, there was significant correlations between the percentages of SIGIRR-positive CD4?…”

“…T cells and ESR (r s = -0.60, P \ 0.001), C3 (r s = 0.53, P \ 0.001) as well as C4 (r s = 0.52, P \ 0.001). Zhu et al [14] observed that there was significant correlation between the expression levels of SIGIRR in B cells and serum levels of IgM antibody, disease duration of SLE patients as well as ESR, but no correlation with SLEDAI, serum IgG or IgA. The discrepancy may be explained by different disease activities at baseline, different methods and the type of sample analyzed.…”

“…However, in patients with SLE, there are few studies available on the role of SIGIRR. Zhu et al [14] found that SIGIRR expression in B Cells from SLE patients was significantly increased compared with healthy controls. The reason for the phenomenon has not been elucidated.…”

“…Another study showed that SIGIRR protects from hydrocarbon oil-induced lupus [13]. There is much difference in the role of SIGIRR in SLE patients and animal models [14,15]. Taken together, the results of these studies demonstrate that SIGIRR is a key molecule in the control of chronic autoimmune diseases, including SLE.…”

“…Individual disease activity was quantified by using the SLE disease activity index (SLEDAI) score. SLE activity was defined on basis of SLEDAI scores: no or mild activity (SLE-DAI = 0-5), moderate activity (SLEDAI = 6-10), high activity (SLEDAI = [11][12][13][14][15][16][17][18][19], and very high activity (SLEDAI C 20) [19]. The study protocol was approved by the Ethics Committee of Anhui Medical University.…”