B cell-derived IL-10 does not regulate spontaneous systemic autoimmunity in MRL.Fas(lpr) mice.

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
The Journal of Immunology (Impact Factor: 5.36). 12/2011; 188(2):678-85. DOI: 10.4049/jimmunol.1102456
Source: PubMed

ABSTRACT 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.


Available from: Mark Jay Shlomchik, May 30, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study tested the hypothesis that besides the spleen, LNs, peripheral blood, and thymus contain a regulatory IL-10-producing CD19(+)CD5(+)CD1d(high) B cell subset that may play a critical role in the maintenance of immune homeostasis. Indeed, this population was identified in the murine thymus, and furthermore, when cocultured with CD4(+) T cells, this population of B cells supported the maintenance of CD4(+)Foxp3(+) Tregs in vitro, in part, via the CD5-CD72 interaction. Mice homozygous for Cd19(Cre) (CD19(-/-)) express B cells with impaired signaling and humoral responses. Strikingly, CD19(-/-) mice produce fewer CD4(+)Foxp3(+) Tregs and a greater percentage of CD4(+)CD8(-) and CD4(-)CD8(+) T cells. Consistent with these results, transfer of thymic CD19(+)CD5(+)CD1d(hi) B cells into CD19(-/-) mice resulted in significantly up-regulated numbers of CD4(+)Foxp3(+) Tregs with a concomitant reduction in CD4(+)CD8(-) and CD4(-)CD8(+) T cell populations in the thymus, spleen, and LNs but not in the BM of recipient mice. In addition, thymic CD19(+)CD5(+)CD1d(hi) B cells significantly suppressed autoimmune responses in lupus-like mice via up-regulation of CD4(+)Foxp3(+) Tregs and IL-10-producing Bregs. This study suggests that thymic CD19(+)CD5(+)CD1d(hi)IL-10(+) Bregs play a critical role in the maintenance of immune homeostasis. © Society for Leukocyte Biology.
    Journal of leukocyte biology 12/2014; 97(3). DOI:10.1189/jlb.3A0414-213RR · 4.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. The Hygiene Hypothesis suggests that parasitic helminths (worms) protect against development of autoimmune disease as a serendipitous side-effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. We therefore investigated whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage, in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE).Methods. MRL/Lpr mice progressively produce high levels of autoantibodies and the resultant deposition of immune-complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria and kidney histology, as well as by determination of anti-nuclear antibody (ANA) and cytokine levels and flow cytometric analysis of relevant cellular populations.Results. ES-62 restores the disrupted effector:regulatory B cell balance in MRL/Lpr mice, acting to inhibit plasmablast differentiation with consequent reduction in ANA production and immune complex and C3a deposition in the kidneys. Moreover, by reducing IL-22 production, ES-62 may desensitise downstream effector mechanisms of kidney pathogenesis. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62-treated MRL/Lpr mice mimics the protection afforded by the helminth product. Mechanistically, this reflects downregulation of MyD88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic crosstalk amongst TLR-, C3a- and immune complex-mediated effector mechanisms.Conclusion. This study provides the first demonstration of protection against pathology by a parasitic worm-derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on ES-62 mechanism of action. This article is protected by copyright. All rights reserved.
    12/2014; 67(4). DOI:10.1002/art.39004
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immune suppression by regulatory T cells and regulatory B cells is a critical mechanism to limit excess inflammation and autoimmunity. IL-10 is considered the major mediator of B cell-induced immune suppression. We report a novel mechanism for immune suppression through adenosine generation by B cells. We identified a novel population of B cells that expresses CD73 as well as CD39, two ectoenzymes that together catalyze the extracellular dephosphorylation of adenine nucleotides to adenosine. Whereas CD39 expression is common among B cells, CD73 expression is not. Approximately 30-50% of B-1 cells (B220(+)CD23(-)) and IL-10-producing B (B10) cells (B220(+)CD5(+)CD1d(hi)) are CD73(hi), depending on mouse strain, whereas few conventional B-2 cells (B220(+)CD23(+)AA4.1(-)) express CD73. In keeping with expression of both CD73 and CD39, we found that CD73(+) B cells produce adenosine in the presence of substrate, whereas B-2 cells do not. CD73(-/-) mice were more susceptible to dextran sulfate sodium salt (DSS)-induced colitis than wild type (WT) mice were, and transfer of CD73(+) B cells ameliorated the severity of colitis, suggesting that B cell CD73/CD39/adenosine can modulate DSS-induced colitis. IL-10 production by B cells is not affected by CD73 deficiency. Interestingly, adenosine generation by IL-10(-/-) B cells is impaired because of reduced expression of CD73, indicating an unexpected connection between IL-10 and adenosine and suggesting caution in interpreting the results of studies with IL-10(-/-) cells. Our findings demonstrate a novel regulatory role of B cells on colitis through adenosine generation in an IL-10-independent manner.
    The Journal of Immunology 11/2014; 193(12). DOI:10.4049/jimmunol.1400336 · 5.36 Impact Factor