Toll-like receptor 9 activation induces expression of membrane-bound B-cell activating factor (BAFF) on human B cells and leads to increased proliferation in response to both soluble and membrane-bound BAFF

摘要

Objectives: Activation of TLR7 and TLR9 and high serum levels of BAFF have been implicated in the pathogenesis of SLE. However, little is known about the effects of TLR9 activation on BAFF expression by human B cells. We investigated the effect of the TLR9 agonist, CpG-ODN 2006, on the expression of BAFF and its receptors BAFF-R, TACI and BCMA, in isolated B cells from healthy donors. Methods: We used RT-PCR, flow cytometry and ELISA to investigate the expression of BAFF, and flow cytometry for BAFF-R, TACI and BCMA. Functional assays assessed the responses of resting and CpG-ODN-activated B cells to exogenous soluble and membrane-bound BAFF. Results: CpG-ODN did not induce BAFF secretion, but increased expression of membrane-bound BAFF on B cells. CpG-ODN also induced the expression of TACI and BCMA, but did not up-regulate BAFF-R expression. In functional studies, CpG-ODN sensitized human B cells to proliferate in response to exogenous BAFF. This effect was inhibited by a blocking antibody against BAFF-R, but was not inhibited by anti-TACI or anti-BCMA antibodies. Membrane-bound BAFF, induced by CpG-ODN, co-stimulated the proliferation of B cells stimulated with anti-IgM in a manner that was dependent on the expression of surface BAFF on the CpG-ODN-treated B cells. Conclusion: TLR9 activation induces expression of membrane-bound BAFF on human B cells and leads to increased proliferation in response to both soluble and membrane-bound BAFF. These data extend our understanding of the role of TLR9 activation on human B cells and provide insights into the mechanisms by which TLR9 may participate in the pathogenesis of SLE.