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”.
Highlights
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease affecting multiple tissues and organs with a diverse array of clinical manifestations
There was no major difference between B cells from systemic lupus erythematosus (SLE) patients and those from healthy donors except for the slightly increased response of SLE B cells to the co-stimulation of B cell receptor (BCR) and TLR9, which was most likely due to the augmented BCR signaling in these cells (Figure 1B)
These results indicate that SLE B cells are comparable with normal B cells in their proliferative response to Toll-like receptor (TLR) stimulation, either by itself or in combination with BCR stimulation
Summary
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease affecting multiple tissues and organs with a diverse array of clinical manifestations. A pioneering study by Marshak-Rothstein’s group demonstrated that effective activation of transgenic B cells expressing antigen receptor specific for IgG2a (AM14 B cells) was only induced by IgG2a-chromatin immune complexes and requires the synergistic engagement of BCR and TLR9 [9]. Recent studies revealed that this locus contained a duplication of Tlr7 [13,14], and the majority of the autoimmune phenotype associated with Yaa appeared to be conferred by the two-fold increase in TLR7 expression [15]. In one initial study with the lupus model induced by anti-DNA BCR transgene and homozygous deficiency of the inhibitory receptor FccIIB, lack of Tlr was found to block class switching of autoreactive B cells to the pathogenic IgG2a and 2b subclasses with reduced pathology and mortality [16]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
