Induction of polyclonal B cell activation is a phenomenon observed in many types of infection, but its immunological relevance is unclear. In this study we show that staphylococcal protein A induces T cell–independent human B cell proliferation by enabling uptake of TLR-stimulating nucleic acids via the VH3+ BCR. We further demonstrate that Staphylococcus aureus strains with high surface protein A expression concomitantly trigger activation of human plasmacytoid dendritic cells (pDC). Sensitivity to chloroquine, cathepsin B inhibition, and a G-rich inhibitory oligodeoxynucleotide supports the involvement of TLR9 in this context. We then identify pDC as essential cellular mediators of B cell proliferation and Ig production in response to surface protein A–bearing S. aureus. The in vivo relevancy of these findings is confirmed in a human PBMC Nod/scidPrkdc/γc−/− mouse model. Finally, we demonstrate that co-operation of pDC and B cells enhances B cell–derived IL-10 production, a cytokine associated with immunosuppression and induction of IgG4, an isotype frequently dominating the IgG response to S. aureus. IL-10 release is partially dependent on TLR2-active lipoproteins, a hallmark of the Staphylococcus species. Collectively, our data suggest that S. aureus exploits pDC and TLR to establish B cell–mediated immune tolerance.
High mobility group box protein B1 (HMGB1), a nuclear protein reportedly involved in the structural organisation of DNA, is released from necrotic cells or upon cellular activation. After its release into the extracellular space, HMGB1 serves as a mediator of inflammation. In contrast to necrotic cells, apoptotic ones usually do not release HMGB1. Formation and release of membranous vesicles is a well-known feature of apoptotic cell death. Only recently, subcellular membrane vesicles, such as those released during apoptotic cell death have been identified as immune regulators and as mediators of cell to cell communication. We and others have previously detected nuclear antigens within apoptosis-released membranous vesicles and HMGB1 together with nuclear antigens has been discussed to be a key player in etiology and pathogenesis of autoimmune diseases. On this background, we analysed whether HMGB1 is included in the membranous vesicles generated by apoptosing cells. Employing immune blots we observed abundand amounts of HMGB1 in the fraction of the small membraneous particles isolated from cell culture supernatants and conclude that HMGB1 is translocated into vesicles generated during apoptosis.
Suppressory B-cell function controls immune responses and is mainly dependent on IL-10 secretion. Pharmacological manipulation of B-cell-specific IL-10 synthesis could, thus, be therapeutically useful in B-cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL-10-secreting B cells. The aim of the study was to identify the molecular events selectively driving IL-10 production in TLR9-stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9-induced B-cell-derived IL-10 transcription and secretion, while IL-6 transcription and release, B-cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9-induced IL-10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9-induced IL-6, IL-10 secretion was highly sensitive to targeting of spleen tyrosine kinase ( Eur. J. Immunol. 2014. 44: 1285-1298 [7]. However, the mechanisms underlying this suppressory B-cell function were less well understood. To date, it is well accepted that the hallmark of B-cell regulatory function is the anti-inflammatory cytokine . IL-10-producing B cells arise in different contexts, among them B-cell chronic lymphocytic leukemia (B-CLL), infections, and the immune response to apoptotic cells [9][10][11]. They can limit ongoing T-cell responses [12]. While exclusive lack of TLR adaptor MyD88 in B lymphocytes leads to development of chronic EAE or aggravation of Salmonella infection [10], loss of B-cell-specific IL-10 drives autoimmunity in TLR9-deficient mice [13].Further reports propose that formation of plasma blasts coincides with release of 14]. This highlights the possibility that in B cells IL-10 production is triggered in an Ag-specific manner and might selectively target Ag-specific T cells. This would discriminate the function of B-cell-derived IL-10 from that produced by myeloid cells. As a consequence, specific pharmacological intervention with B-cell-derived IL-10 could represent a promising strategy to protect from destructive T-cell responses to both auto-and alloantigen while preserving immunity to infection.Transcriptional regulation of IL-10 synthesis is cell type specific [15]. In B cells, IL-10 production has been investigated upon BCR activation and in leukemia. The studies suggest a role of calcium sensors and NFAT transcription factors (TF) [11,16]. However, little is known on the regulation of B-cell-derived IL-10 production and in particular in response to TLR9 stimulation. The objective of the present study was to analyze the molecular mechanisms regulating IL-10 production in B cells challenged with TLR9 agonists. Results CpG oligodeoxynucleotides (ODN) and BCR cross-linking represent potent IL-10 inducersIn this study, we were interested in the molecular mechanisms mediating B-cell-derived release of IL-10 upon stimulation of TLR9. BCR-, TLR-, and CD40-signaling have all been implicate...
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