Activation of Marginal Zone B Cells from Lupus Mice with Type A(D) CpG-Oligodeoxynucleotides

Abstract

Several types of CpG-oligodeoxynucleotides (ODN) have been recently characterized. In mice, type A(D) CpG-ODNs primarily stimulate macrophages and dendritic cells, but fail to stimulate B cells. On the contrary, type B(K) CpG-ODNs are excellent B cell activators. Type C CpG-ODNs combine features of both types A(D) and B(K) CpG-ODNs. Despite cell type preferences, all CpG-ODNs require the presence of TLR9 for activation. In this study, we show that a subset of B cells from lupus mice responds to type A(D) CpG-ODN stimulation vigorously and directly with increased CD25 and CD86 expression and IL-10 secretion. Furthermore, these CpG-ODNs induce high surface IgM expression and promote 50- to 100-fold higher IgM and IgG3 secretion in lupus B cells than in controls. This response is similar to that seen with bacterial DNA stimulation of B cells. Type A(D)-responsive cells are enriched within lupus B cells with the marginal zone (MZ) phenotype. These cells are at least twice more numerous in lupus mice than in controls. The ability of lupus B cells to respond to type A(D) CpG-ODN stimulation is not due to differential TLR9 expression. Therefore, type A(D) CpG-ODNs may contribute to the lupus pathogenesis by inducing MZ-B cell activation, costimulatory molecule expression, and polyclonal Ig secretion. Through increased IL-10 secretion, MZ-B cells may also modify the activity of other cell types, particularly dendritic cells and macrophages.

A Case for Regulatory B Cells

“…B cells also produce IL-10 following in vitro activation with LPS (29), CpG (37,38), or heat shock protein 60 (50). These inflammationinduced IL-10-producing Bregs inhibit the progression of inflammation and/or hasten the recovery from the experimental inflammatory conditions such as IBD (23,29), EAE (13), arthritis (36), and lupus (37,38). Such IL-10-producing B cells have also been identified in humans (51).…”

“…Notably, B cells produce IL-10, the regulatory cytokine that can suppress harmful immune responses by regulating Th1/Th2 balance and directly dampening innate cell-mediated inflammatory responses (43)(44)(45)(46). Activated murine B cells capable of producing large amounts of IL-10 have now been detected in vivo under a variety of experimental inflammatory conditions, including IBD (22,29), EAE (13,47), arthritis (36), lupus (37,38), UV irradiation, and infection with Schistosoma mansoni (48) and Brugia pahangi (49). B cells also produce IL-10 following in vitro activation with LPS (29), CpG (37,38), or heat shock protein 60 (50).…”

“…Activated murine B cells capable of producing large amounts of IL-10 have now been detected in vivo under a variety of experimental inflammatory conditions, including IBD (22,29), EAE (13,47), arthritis (36), lupus (37,38), UV irradiation, and infection with Schistosoma mansoni (48) and Brugia pahangi (49). B cells also produce IL-10 following in vitro activation with LPS (29), CpG (37,38), or heat shock protein 60 (50). These inflammationinduced IL-10-producing Bregs inhibit the progression of inflammation and/or hasten the recovery from the experimental inflammatory conditions such as IBD (23,29), EAE (13), arthritis (36), and lupus (37,38).…”

“…In EAE and RA, both of which are mainly mediated by T cell-mediated acquired responses, Bregs suppress inflammation by restoring the Th1/Th2 balance (13,36). Bregs also dampen immune responses that are mediated by dendritic cells (DC) in lupus mice (37,53).…”

“…Interestingly, regulatory B cells (Bregs) may also be present in diseases such as lupus and experimental rheumatoid arthritis (RA) (10,(35)(36)(37)(38), where B cell-producing autoantibodies have a pathogenic role (9,10,39) (Table I).…”