Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity

Socioeconomic position across life and body composition in early old age: findings from a British birth cohort study.

Background Previous studies have reported associations between lower lifetime socioeconomic position (SEP) and higher body mass index in adulthood, but few have examined associations with direct measures of fat and lean mass which are likely to have independent roles in health and physical functioning. Methods We examined associations of SEP across life with dual-energy X-ray absorptiometry measures of fat and lean mass at 60–64 years using data from a total of 1558 men and women participating in the Medical Research Council (MRC) National Survey of Health and Development. We also examined whether associations of childhood SEP with fat and lean mass were explained by preadulthood weight gain (birth weight, 0–7 and 7–20 years) and adult SEP. Results Lower SEP across life was associated with higher fat mass and higher android to gynoid fat mass ratio. For example, the mean difference in fat mass index comparing the lowest with the highest paternal occupational class at 4 years (slope index of inequality) was 1.04 kg/m1.2 in men (95% CI 0.09 to 1.99) and 2.61 in women (1.34 to 3.89), equivalent to a 8.6% and 16.1% difference, respectively. After adjustment for fat mass, lower SEP across life was associated with lower lean mass in women, while only contemporaneous household income was associated in men. Associations between childhood SEP and outcomes were partly explained by preadulthood weight gain and adult SEP. Conclusions This study identified lifetime socioeconomic patterning of fat and lean mass in early old age. This is likely to have important implications and may partly explain socioeconomic inequalities in health and physical functioning

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Effect of 4-trifluoromethyl derivatives of salicylate on nuclear factor κB-dependent transcription in human astrocytoma cells

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro-inflammatory activities the regulation of which is associated to the transcription factor NF-κB, was assayed in the human astrocytoma cell line 1321N1. 2. Tumour necrosis factor-α (TNF-α) activated NF-κB as judged from both the appearance of κB-binding activity in the nuclear extracts, the degradation of IκB proteins in the cell lysates, and the activation of IκB kinases using an immunocomplex kinase assay with glutathione S-transferase (GST)-IκB proteins as substrates. 3. HTB up to 3 mM did not inhibit the nuclear translocation of NK-κB/Rel proteins as judged from electrophoretic mobility-shift assays; however, HTB inhibited the degradation of IκBβ without significantly affecting the degradation of both IκBα and IκBε. 4. In keeping with their inhibitory effect on IκBβ degradation in the cell lysates, both HTB and triflusal inhibited the phosphorylation of GST-IκBβ elicited by TNF-α, without affecting the phosphorylation of GST-IκBα. 5. The effect of both HTB and triflusal on κB-dependent trans-activation was studied by assaying the expression of both cyclo-oxygenase-2 (COX-2) and vascular cell adhesion molecule-1 (VCAM-1). HTB and triflusal inhibited in a dose-dependent manner the expression of COX-2 and VCAM-1 mRNA and the induction of COX-2 protein at therapeutically relevant concentrations. 6. These findings show the complexity of the biochemical mechanisms underlying the activation of NF-κB in the different cell types and extend the anti-inflammatory effects of HTB and triflusal to neural cells