57 research outputs found
Multiple sclerosis risk variants influence the peripheral B-cell compartment early in life in the general population
Background and purpose: Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population. Methods: Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (nĀ =Ā 1261) as well as naive and memory subsets (nĀ =Ā 675). Results: After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (nĀ =Ā 26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (pĀ =Ā 1.03 Ć 10ā4 and pĀ =Ā 0.82, respectively), and higher frequencies and absolute numbers of CD27+ memory B cells (pĀ =Ā 8.83 Ć 10ā4 and pĀ =Ā 4.89 Ć 10ā3, respectively). These associations remained significant after adjustment for EpsteināBarr virus seropositivity and the HLA-DRB1*15:01 genotype. Conclusions: The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS.</p
Impact of coding risk variant <i>IFNGR2 </i>on the B cell-intrinsic IFN-Ī³ signaling pathway in multiple sclerosis
B cells of people with multiple sclerosis (MS) are more responsive to IFN-Ī³, corresponding to their brain-homing potential. We studied how a coding single nucleotide polymorphism (SNP) in IFNGR2 (rs9808753) co-operates with Epstein-Barr virus (EBV) infection as MS risk factors to affect the IFN-Ī³ signaling pathway in human B cells. In both cell lines and primary cells, EBV infection positively associated with IFN-Ī³ receptor expression and STAT1 phosphorylation. The IFNGR2 risk SNP selectively promoted downstream signaling via STAT1, particularly in transitional B cells. Altogether, EBV and the IFNGR2 risk SNP independently amplify IFN-Ī³ signaling, potentially driving B cells to enter the MS brain.</p
Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4<sup>+</sup> T cells with brain-homing capacity
Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the bloodācentral nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet ā enrichment in cerebrospinal fluid samples of treatment-naĆÆve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 ā/dim). Previously published CD28 ā CD4 T cells were characterized by a Runx3 +Eomes āT-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the bloodābrain barrier in vitro. This was only found for other subsets including CD28 ā cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the bloodābrain barrier as a possible early event in MS.</p
Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4<sup>+</sup> T cells with brain-homing capacity
Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the bloodācentral nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet ā enrichment in cerebrospinal fluid samples of treatment-naĆÆve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 ā/dim). Previously published CD28 ā CD4 T cells were characterized by a Runx3 +Eomes āT-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the bloodābrain barrier in vitro. This was only found for other subsets including CD28 ā cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the bloodābrain barrier as a possible early event in MS.</p
Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation
Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1Ī², IL-6, TNF-Ī±, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by the TLR7/8-L R848 (20ā30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides. To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24Ā h followed by addition of CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation
Warming Can Boost Denitrification Disproportionately Due to Altered Oxygen Dynamics
Background: Global warming and the alteration of the global nitrogen cycle are major anthropogenic threats to the environment. Denitrification, the biological conversion of nitrate to gaseous nitrogen, removes a substantial fraction of the nitrogen from aquatic ecosystems, and can therefore help to reduce eutrophication effects. However, potential responses of denitrification to warming are poorly understood. Although several studies have reported increased denitrification rates with rising temperature, the impact of temperature on denitrification seems to vary widely between systems. Methodology/Principal Findings: We explored the effects of warming on denitrification rates using microcosm experiments, field measurements and a simple model approach. Our results suggest that a three degree temperature rise will double denitrification rates. By performing experiments at fixed oxygen concentrations as well as with oxygen concentrations varying freely with temperature, we demonstrate that this strong temperature dependence of denitrification can be explained by a systematic decrease of oxygen concentrations with rising temperature. Warming decreases oxygen concentrations due to reduced solubility, and more importantly, because respiration rates rise more steeply with temperature than photosynthesis. Conclusions/Significance: Our results show that denitrification rates in aquatic ecosystems are strongly temperature dependent, and that this is amplified by the temperature dependencies of photosynthesis and respiration. Our result
Comparison of denitrification rates in lake sediments obtained by the N2 flux method, the 15N isotope pairing technique and the mass balance approach.
Comparison of denitrification rates in lake sediments obtained by the N2 flux method, the 15N isotope pairing technique and the mass balance approach.
Nitrogen fluxes and processes in sandy and muddy sediments from a shallow eutrophic lake
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