B Cell-Derived IL-10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr Mice

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2011; 188(2):678-85. DOI: 10.4049/jimmunol.1102456
Source: PubMed


B cells contribute to the pathogenesis of chronic autoimmune disorders, like systemic lupus erythematosus (SLE), via multiple effector functions. However, B cells are also implicated in regulating SLE and other autoimmune syndromes via release of IL-10. B cells secreting IL-10 were termed "Bregs" and were proposed as a separate subset of cells, a concept that remains controversial. The balance between pro- and anti-inflammatory effects could determine the success of B cell-targeted therapies for autoimmune disorders; therefore, it is pivotal to understand the significance of B cell-secreted IL-10 in spontaneous autoimmunity. By lineage-specific deletion of Il10 from B cells, we demonstrated that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B and T cells during lupus. Correspondingly, severity of organ disease and survival rates in mice harboring Il10-deficient B cells are unaltered. Genetic marking of cells that transcribe Il10 illustrated that the pool of IL-10-competent cells is dominated by CD4 T cells and macrophages. IL-10-competent cells of the B lineage are rare in vivo and, among them, short-lived plasmablasts have the highest frequency, suggesting an activation-driven, rather than lineage-driven, phenotype. Putative Breg phenotypic subsets, such as CD1d(hi)CD5(+) and CD21(hi)CD23(hi) B cells, are not enriched in Il10 transcription. These genetic studies demonstrated that, in a spontaneous model of murine lupus, IL-10-dependent B cell regulation does not restrain disease and, thus, the pathogenic effects of B cells are not detectably counterbalanced by their IL-10-dependent regulatory functions.

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    • "While B cell-mediated immunosuppression by secretion of the anti-inflammatory cytokine interleukin-10 (IL-10) has received much recent attention, there are several reports of suppressive effects of B cells independent of IL-10, including in mouse models of type 1 diabetes and multiple sclerosis [5], [9]–[11]. Additionally, it was recently shown that selective deletion of IL-10 in B cells did not affect disease parameters in a mouse model of lupus, suggesting that the in vivo effects of endogenous regulation by IL-10-producing B cells may be more subtle than previously thought [12]. Therefore, understanding the full repertoire of immunosuppressive mechanisms employed by B cells is crucial for appreciating their role in maintaining self-tolerance [13]. "
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    ABSTRACT: Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis-inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL(+) killer B cells, showing they are enriched in the IgM(high)CD5(+)CD1d(high) B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL(+) B cells, but most FasL(+) B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL(+) B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL(+) cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4(+) T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL(+) B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders.
    PLoS ONE 08/2013; 8(8):e70131. DOI:10.1371/journal.pone.0070131 · 3.23 Impact Factor
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    • "In this study, however, only the IL-10 secreted by endogenous B10 cells was absent. IL-10 is typically produced by other B-cell subsets as well [47], and the progenitor B10 cells, which are a main source of IL-10 [17], [51], were not deleted in this study. Thus, insufficient data is available to solidly conclude that B10 cells do not limit disease in MRL/lpr mice [47]. "
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    ABSTRACT: T follicular helper (Tfh) cells can mediate humoral immune responses and augment autoimmunity, whereas the role of Tfh cells on regulatory B (B10) cells in autoimmunity diseases is not clear. Here, we investigated the percentages of Tfh cells and B10 cells in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the effects and mechanism of Tfh cell-derived interleukin-21 (IL-21) on IL-10 production during the differentiation of B10 cells. Both Tfh cells and B10 cells were expanded in spleens of MRL/lpr mice. In addition, a positive correlation between the proportions of Tfh cells and B10 cells was observed. Tfh cell-derived IL-21 from MRL/lpr mice could promote IL-10 production during the differentiation of B10 cells. Importantly, neutralization of IL-21 inhibited IL-10 production and expansion of B10 cells both in vitro and in vivo. IL-21 induced IL-10 production via activation of phosphorylated signal transduction and activator of transcription 3 (p-STAT3). Inhibition of p-STAT3 effectively blocked IL-10 production during the differentiation of B10 cells. Moreover, IL-21-induced IL-10 exerted a regulatory function by inhibiting the proliferation of T cells. These data suggest that Tfh cells not only mediate humoral immune responses and augment autoimmunity but also play a broader role in immune regulatory actions via the induction of IL-10 production.
    PLoS ONE 05/2013; 8(4):e62855. DOI:10.1371/journal.pone.0062855 · 3.23 Impact Factor
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    • "In the MRL.Fas(lpr) mouse lupus model, B cell-derived IL-10 does not regulate spontaneous autoimmunity [89]. B cell-specific deletion of IL-10 in MRL.Fas(lpr) mice indicates that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B cells and T cells during lupus. "
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    ABSTRACT: B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.
    Arthritis research & therapy 02/2013; 15 Suppl 1(Suppl 1):S1. DOI:10.1186/ar3907 · 3.75 Impact Factor
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