Macrophages (Mφ) play a central role as effector cells in immunity to intracellular pathogens such as Mycobacterium. Paradoxically, they also provide a habitat for intracellular bacterial survival. ...This paradoxical role of Mφ remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mφ: Whereas Mφ-1 polarized in the presence of granulocyte-Mφ colony-stimulating factor promoted type 1 immunity, Mφ-2 polarized with Mφ colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mφ-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated Mφ-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mφ-1 required IFN-γ as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion. Activated dendritic cells produced both IL-12 and IL-23, but unlike Mφ-1 they slightly reduced their IL-23 secretion after addition of IFN-γ. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mφ subsets, but more efficiently by Mφ-2 than Mφ-1. Whereas Mφ-1 efficiently stimulated type 1 helper cells, Mφ-2 only poorly supported type 1 helper function. Accordingly, activated Mφ-2 but not Mφ-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mφ-1 and Mφ-2 play opposing roles in cellular immunity and (ii) IL-23 rather than IL-12 is the primary type 1 cytokine produced by activated proinflammatory Mφ-1. Mφ heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In ...the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn's disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.
The nucleotide oligomerization domain 2 (NOD2) 3020insC (NOD2fs) mutation increases susceptibility to Crohn’s disease (CD), but the mechanism remains controversial. Loss‐of‐function and ...gain‐of‐function phenotypes have been described as a result of NOD2fs. Here, we show that dendritic cells (DC) derived from CD patients homozygous for this mutation respond normally to purified Toll‐like receptor (TLR) ligands but fail to up‐regulate the costimulatory molecules CD80 and CD86 in response to the NOD2 ligand muramyl dipeptide (MDP). Moreover, they lack MDP‐induced enhancement of TLR‐mediated tumor necrosis factor α, interleukin (IL)‐12, and IL‐10 production, which is observed in control DC with intact NOD2. These data indicate that the NOD2fs mutation results in a loss‐of‐function phenotype in human myeloid DC and imply decreased immune regulation by IL‐10 as a possible mechanism for this mutation in CD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective:
The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold ...storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD).
Background:
HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT).
Methods:
Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI), length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD).
Results:
Demographics were equally distributed between both groups donor age: 72 (IQR: 59–78) years, recipient age: 62 (IQR: 55–65) years, labMELD: 15 (IQR: 9–25), 38 male and 8 female recipients. HOPE resulted in a 47% decrease in serum peak ALT 418 (IQR: 221–828) vs 796 (IQR: 477–1195) IU/L,
P
= 0.030, a significant reduction in 90-day complications 44% vs 74% CD grade ≥3,
P
= 0.036; 32 (IQR: 12–56) vs 52 (IQR: 35–98) CCI,
P
= 0.021, and shorter ICU- and hospital-stays 5 (IQR: 4–8) vs 8 (IQR: 5–18) days,
P
= 0.045; 20 (IQR: 16–27) vs 36 (IQR: 23–62) days,
P
= 0.002 compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%;
P
= 0.314).
Conclusion:
This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.
Regional weather forecasting models like the Weather Research and Forecasting (WRF) model allow for nested domains to save computational effort and provide detailed results for mesoscale weather ...phenomena. The sudden resolution change by nesting may cause artefacts in the model results. On the contrary, the novel global Model for Prediction Across Scales (MPAS) runs on Voronoi meshes that allow for smooth resolution transition towards the desired high resolution in the region of interest. This minimises the resolution-related artefacts, while still saving computational effort. We evaluate the MPAS model over Europe focussing on three mesoscale weather events: a synoptic gale over the North Sea, a föhn effect in Switzerland, and a case of organised convection with hail over the Netherlands. We use four different MPAS meshes (60 km global refined to-3 km (60– 3 km), analogous 30–3 km, 15–3 km, global 3 km) and compare their results to routine observations and a WRF setup with a single domain of 3 km grid spacing. We also discuss the computational requirements for the different MPAS meshes and the operational WRF setup. In general, the MPAS 3 km and WRF model results correspond to the observations. However, a global model at 3 km resolution as a replacement for WRF is not feasible for operational use. More importantly, all variable-resolution meshes employed in this study show comparable skills in short-term forecasting within the high-resolution area at considerably lower computational costs.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
Coxsackie B viruses (CVB) and Echoviruses (EV) form a single species; Human enterovirus B (HeV‐B), within the genus Enterovirus. Although HeV‐B infections are usually mild or asymptomatic, ...they can cause serious acute illnesses. In addition, HeV‐B infections have been associated with chronic immune disorders, such as type 1 diabetes mellitus and chronic myocarditis/dilated cardiomyopathy. It has therefore been suggested that these viruses may trigger an autoimmune process. Here, we demonstrate that human dendritic cells (DCs), which play an essential role in orchestration of the immune response, are productively infected by EV, but not CVB strains, in vitro. Infection does not result in DC activation or the induction of antiviral immune responses. Instead, EV infection rapidly impedes Toll‐like receptor‐mediated production of cytokines and upregulation of maturation markers, and ultimately causes loss of DC viability. These results describe for the first time the effect of EV on the function and viability of human DCs and suggest that infection of DCs in vivo can impede regulation of immune responses.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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