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  1. Top of page
  2. Cover image
  3. Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis
  4. Leptin modulates adaptive immunity in a DC-dependent fashion
  5. Cuts that kill: calpains cleave pro-IL-1α to kill bacteria
  6. Post-transcriptional regulation of IL-10 via TRIF
  7. CXCR7 influences the migration of B cells during maturation
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The cover features a kidney section from a CD19Cre mouse, which was sampled four days after induction of nephrotoxic nephritis and stained with sheep IgG. The image is taken from the article by Kluger et al. (pp. 683–693) in which the authors show that B-cell-derived IL-10 does not play a role in the clinical course of glomerulonephritis. The authors show that cytokine production, leukocyte composition, proliferation, and activation are indistinguishable between wild-type mice and mice lacking B-cell-derived IL-10, while production and renal deposition of Ag-specific IgG are mildly impaired in the absence of B-cell-produced IL-10. These data suggest that although IL-10-secreting B cells may have protective effects, a relevant anti-inflammatory role for B-cell-derived IL-10 requires further study in other models of inflammatory disease.

Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis

  1. Top of page
  2. Cover image
  3. Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis
  4. Leptin modulates adaptive immunity in a DC-dependent fashion
  5. Cuts that kill: calpains cleave pro-IL-1α to kill bacteria
  6. Post-transcriptional regulation of IL-10 via TRIF
  7. CXCR7 influences the migration of B cells during maturation

10.1002/eji.201343784, (pp 752–762)

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Induction of toxin-neutralizing antibodies is considered essential for protection against B. anthracis (BA); however, an adaptive immune response may be required for bacterial clearance. In this issue, Harris et al. report that following ingestion and killing of germinating BA spores, human monocyte-derived dendritic cells (hDCs) produce IL-1β, IL-6, IL-12 and IL-23. The IL-23 response is regulated by IL-1R-mediated signaling, resulting in secretion of IL-17A and IFN-γ by autologous CD4+ T cells in a contact-dependent and antigen-specific manner. The T-cell epitopes that induce this signaling are distinct from lethal factor and protective antigen, the classical BA antigens. The T-cell response to BA spores was recapitulated by hDCs infected with germination-proficient, but not germination-deficient BA spores, implying that replicating bacilli trigger the cytokine response. These findings provide primary evidence that hDCs can generate a BA-specific Th17 response, and suggest that the IL-23/Th17 axis is involved in the immune response to anthrax in humans.

Leptin modulates adaptive immunity in a DC-dependent fashion

  1. Top of page
  2. Cover image
  3. Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis
  4. Leptin modulates adaptive immunity in a DC-dependent fashion
  5. Cuts that kill: calpains cleave pro-IL-1α to kill bacteria
  6. Post-transcriptional regulation of IL-10 via TRIF
  7. CXCR7 influences the migration of B cells during maturation

10.1002/eji.201343592, (pp 794–806)

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Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin levels are elevated in obesity and are correlated with fat mass. Leptin provides a critical link between the environment, metabolism and immune function and is considered a pro-inflammatory cytokine which induces Th1-type immune responses. In this issue, Moraes-Vieira et al. show that leptin deficiency impairs dendritic cell (DC) generation and maturation and DC-induced CD4+ T-cell proliferation in mice. These leptin-free DCs produce lower levels of IL-12, TNF and IL-6 while producing higher amounts of TGF-β. Leptin-free generated DCs also induce Th2, Treg or TH17 cells but not Th1 cells. In vivo, leptin limits TH17 and Treg cells and promotes an enhanced Th1 immune response. These data indicate the importance of leptin for DC homeostasis and implicate a central role for leptin in initiating and maintaining inflammatory and regulatory immune responses through a DC-dependent mechanism.

Cuts that kill: calpains cleave pro-IL-1α to kill bacteria

  1. Top of page
  2. Cover image
  3. Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis
  4. Leptin modulates adaptive immunity in a DC-dependent fashion
  5. Cuts that kill: calpains cleave pro-IL-1α to kill bacteria
  6. Post-transcriptional regulation of IL-10 via TRIF
  7. CXCR7 influences the migration of B cells during maturation

10.1002/eji.201343757, (pp 831–841)

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Upon bacterial infection, Toll-like receptor (TLR) signaling in host immune cells leads to the rapid production of mediators that kill bacteria. In this issue, Kumar et al. describe a key role for the calcium-dependent calpain proteases in fighting acute bacterial infections. Transgenic mice lacking calpains in innate immune cells fail to produce mature IL-1α during acute bacterial peritonitis. This leads to delayed neutrophil recruitment, diminished reactive oxygen species (ROS) production, and defects in bacterial killing. Calpains have been implicated in promoting tissue damage in severe sepsis, suggesting that calpain inhibitors might be considered as potential therapeutic approaches to limit that damage. However, the current study cautions that calpain inhibitors may also compromise the ability of our innate immune system to fight bacterial infections.

Post-transcriptional regulation of IL-10 via TRIF

  1. Top of page
  2. Cover image
  3. Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis
  4. Leptin modulates adaptive immunity in a DC-dependent fashion
  5. Cuts that kill: calpains cleave pro-IL-1α to kill bacteria
  6. Post-transcriptional regulation of IL-10 via TRIF
  7. CXCR7 influences the migration of B cells during maturation

10.1002/eji.201343734, (pp 856–866)

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The anti-inflammatory cytokine IL-10 plays a critical role in regulating the balance between pathogen clearance and immune pathology. Different mechanisms are in place to regulate the expression of IL-10, which range from chromatin remodeling to transcriptional and post-transcriptional control. Stimulation of macrophages by TLRs leads to IL-10 expression, with the involvement of different signaling cascades, including NF-kB and MAPK. In this issue, Teixeira-Coelho et al. show that, depending on the TLR activated, the post-transcriptional regulation of IL-10 in murine bone marrow-derived macrophages occurs differently: TLR2 signals are associated with IL-10 mRNA degradation, whereas TLR4 signals are associated with IL-10 mRNA stability. This is dependent on TRIF activation of p38, which sustains the half-life of the IL-10 mRNA. Consequently, activation of TLR4 leads to higher amounts of secreted IL-10. This mechanism is also observed upon bacterial activation of TLR2 or TLR4 in macrophages, contributing to IL-10 modulation in these cells in an infection setting.

CXCR7 influences the migration of B cells during maturation

  1. Top of page
  2. Cover image
  3. Remembrance of anthrax past: Th17 cells in the adaptive immune response to B. anthracis
  4. Leptin modulates adaptive immunity in a DC-dependent fashion
  5. Cuts that kill: calpains cleave pro-IL-1α to kill bacteria
  6. Post-transcriptional regulation of IL-10 via TRIF
  7. CXCR7 influences the migration of B cells during maturation

10.1002/eji.201343907, (pp 694–705)

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CXCR7, now also known as ACKR3, is an atypical chemokine receptor which binds CXCL12. In contrast to conventional chemokine receptors, ACKRs do not couple to G-proteins and do not trigger cell chemotaxis. Nevertheless, ACKRs contribute to cell migration by carving functional gradients. In this issue, Humpert et al. show that CXCR7 is transiently upregulated on intracellular Ig-rich, CD27high/CD38high/CD19+/CD138low plasmablasts during B-cell development, while CXCR5 expression is concomitantly lost. In contrast, B cells continuously express CXCR4, the functional receptor for CXCL12. To leave the germinal center (GC), plasmablasts must overcome the CXCL12-mediated retention which triggers CXCR4. Indeed, attenuation of CXCR7 enhances the chemotactic response towards CXCL12 in plasmablasts, but not in plasma cells. Upregulation of CXCR7 in plasmablasts, which has higher affinity for CXCL12 than CXCR4, reduces their responsiveness to CXCL12 and thus promotes their egress from the GC. Its disappearance in plasma cells allows them to home to CXCL12-expressing niches in the bone marrow.