However, it remains to be determined whether the upregulation of TLR9 and TLR7 would lead to altered B cell responses to the cognate ligands. The present study was focused on two major aspects of B cell activation, namely cell proliferation and antibody production. As previously reported, human B cells proliferated vigorously in response to CpGODN stimulation whereas CL097 induced only minimal proliferation. Nevertheless, B cells from SLE patients and healthy donors showed no difference in their proliferative response to either CpGODN or CL097. As for antibody production, B cells from the two groups yielded similar numbers of IgM- or IgG-secreting cells when treated with the TLR7 agonist. Under TLR9 stimulation, however, IgGsecreting cells were found to be reduced for SLE B cells even though IgM-secreting cells remained comparable. These results are apparently contradictory to the prediction that increased receptor expression would result in augmented responses to the ligands. Moreover, a few previous studies did show enhanced activation of SLE B cells as measured by certain parameters. Nakano et al., for example, reported that TLR9 engagement led to the production of anti-dsDNA antibody and IL-10 in SLE B cells but not in normal B cells. Another study demonstrated that the upregulation of TLR9 expression was associated with enhanced induction of HLA-DR in lupus B cells. Still another study, however, revealed SCH772984 comparable TLR9-induced secretion of IgM and IL-10 by PBMCs from lupus patients and healthy donors. There can be multiple reasons for this discrepancy. Firstly, different aspects of B cell activation, such as proliferation, antibody production, cytokine secretion and expression of co-stimulatory molecules, may be differentially regulated by TLR signals in SLE patients. Secondly, PBMCs versus purified B cells were used in some of the studies, which raise the possibility that the altered B cell response may actually be a secondary effect. Lastly, the discrepancy may result from the considerable variations in the subjects under investigation, including sample size, clinical features and medical treatment. Using purified B cell from a relative large cohort, the present study demonstrates that SLE B cells mount a largely normal, if not diminished, response to TLR7 and TLR9 signaling in terms of cell proliferation and antibody production. In addition to single treatment with the TLR7 or TLR9 agonist, we examined the responses of SLE B cell to simultaneous stimulation of TLR and BCR. Possibly through upregulating TLR9 expression. In contrast, continuous BCR signaling has a profound inhibitory effect in the formation of antibody-secreting cells nduced by TLR9 engagement. We confirmed the synergistic effect of BCR and TLR9 signals in the proliferation of B cells, whereas no obvious synergism was seen between TLR7 and BCR signals. As much as the antibody response is concerned, BCR crosslinking indeed resulted in the suppression of TLR9-induced generation of IgG-secreting cells from normal B cells. Notably, such an inhibitory effect was lost in SLE B cells. This result is reminiscent of several previous reports in which B cells from lupusprone mice or SLE patients were found to be resistant to antiBCR-mediated inhibition of either LPS-induced IgM production or PWM-induced activation. The pathological relevance of the seemingly general loss of the antagonism mediated by BCR in SLE B cells certainly warrants further investigation. TLR signaling is tightly controlled by a number of negative regulators, including SIGIRR.