(D) Mean + SD number of IgM or IgG antibodysecreting B cells per spleen from control and treated NZB/W F1 mice

(D) Mean + SD number of IgM or IgG antibodysecreting B cells per spleen from control and treated NZB/W F1 mice. IgG antidouble-stranded DNA response. Furthermore, both reagents inhibited the T cellindependent marginal zone B cell response to particulate antigen delivered i.v., but not the B1 B cell response to the same antigen delivered i.p. In contrast, blockade of both BAFF and APRIL, Ginsenoside Rg3 but not blockade Ginsenoside Rg3 of BAFF alone, reduced the serum levels of IgM antibodies, decreased the frequency of plasma cells in the spleen, and inhibited the IgM response to a T celldependent antigen. The differences between selective and nonselective BAFF blockade are relevant to the choice of a BAFF blocking agent for Ginsenoside Rg3 the treatment of autoimmune and malignant diseases. == Introduction == It is increasingly acknowledged that B cells have multiple functions that contribute to the pathogenesis of autoimmunity. They produce autoantibodies that mediate tissue injury, they function as antigen-presenting cells that present epitopes of self antigen to autoreactive T cells, and they produce soluble mediators involved in the business of lymphoid tissues and in the initiation and perpetuation of inflammatory processes (1). In some autoimmune diseases, B cells migrate to inflamed sites, where they act as local effector cells (2,3). The TNF-like molecule B cellactivating factor of the TNF family (BAFF; Mouse monoclonal to Fibulin 5 TNFSF13b) is usually a key B cell survival factor, and its 3 receptors (transmembrane activator and calcium modulator ligand interactor [TACI; TNFRSF13b], B cell maturation antigen [BCMA; TNFRSF17], and BAFF receptor [BAFF-R; TNFRSF13c]) are variably expressed on B cells during their differentiation (4). A proliferation-inducing ligand (APRIL; TNFSF13a), a molecule homologous to BAFF, binds only to TACI and BCMA and shares many functions in common with BAFF, although it cannot facilitate survival of transitional B cells, a function that depends on the conversation of BAFF with BAFF-R (5). Serum levels of BAFF and APRIL are increased in autoimmune diseases, including SLE and rheumatoid arthritis (6,7), and blockade of BAFF and APRIL using soluble fusion proteins of BAFF receptors prevents autoimmunity in animal models of disease (811). A number of different BAFF antagonists are in early clinical trials for human autoimmune diseases. Some, such as BAFF-RIg and anti-BAFF, selectively block only BAFF, whereas others, such as TACI-Ig, block both BAFF and APRIL (12). Since plasma cells predominantly express BCMA and TACI that bind to both BAFF and APRIL (13,14), these Ginsenoside Rg3 differences may be physiologically important. Furthermore, the mechanism of action of these therapeutic reagents Ginsenoside Rg3 needs to be explored in the setting of autoimmunity because intrinsic B cell hyperreactivity, the provision of extra T cell help, and the presence of inflammatory mediators may alter the normal dependence of B cells on BAFF or APRIL and thus the response to blockade. Our goal in this study was to examine the immunologic effects of selective and nonselective BAFF blockade in a murine model of SLE. Our results show that although both BAFF-RIg and TACI-Ig prevented the onset of SLE in this model, there were significant differences in the effects of the 2 2 reagents around the survival of plasma cells in the spleen and bone marrow. These differences may affect the type of disease that will be responsive to these reagents as well as their immunosuppressive potential. == Results == == Expression of BAFF-RIg and TACI-Ig fusion proteins. == Fully murine BAFF-RIg and TACI-Ig were expressed using recombinant adenoviruses. BAFF-RIg is usually a monomer on SDS-PAGE, whereas TACI-Ig is usually a covalently linked dimer (Physique1A). (15). There is little difference between TACI-Ig and BAFF-RIg with respect to half-life (data not shown), relative affinity for BAFF, or the ability.