Chemokine gene expression in lung CD8 T cells correlates with protective immunity in mice immunized intra-nasally with Adenovirus-85A

<p>Abstract</p> <p>Background</p> <p>Immunization of BALB/c mice with a recombinant adenovirus expressing <it>Mycobacterium tuberculosis </it>(<it>M. tuberculosis</it>) antigen 85A (Ad85A) protects against aerosol challenge with <it>M. tuberculosis </it>only when it is administered intra-nasally (i.n.). Immunization with Ad85A induces a lung-resident population of activated CD8 T cells that is antigen dependent, highly activated and mediates protection by early inhibition of <it>M. tuberculosis </it>growth. In order to determine why the i.n. route is so effective compared to parenteral immunization, we used microarray analysis to compare gene expression profiles of pulmonary and splenic CD8 T cells after i.n. or intra-dermal (i.d.) immunization.</p> <p>Method</p> <p>Total RNA from CD8 T cells was isolated from lungs or spleens of mice immunized with Ad85A by the i.n. or i.d. route. The gene profiles generated from each condition were compared. Statistically significant (p ≤ 0.05) differentially expressed genes were analyzed to determine if they mapped to particular molecular functions, biological processes or pathways using Gene Ontology and Panther DB mapping tools.</p> <p>Results</p> <p>CD8 T cells from lungs of i.n. immunized mice expressed a large number of chemokines chemotactic for resting and activated T cells as well as activation and survival genes. Lung lymphocytes from i.n. immunized mice also express the chemokine receptor gene <it>Cxcr6</it>, which is thought to aid long-term retention of antigen-responding T cells in the lungs. Expression of CXCR6 on CD8 T cells was confirmed by flow cytometry.</p> <p>Conclusions</p> <p>Our microarray analysis represents the first <it>ex vivo </it>study comparing gene expression profiles of CD8 T cells isolated from distinct sites after immunization with an adenoviral vector by different routes. It confirms earlier phenotypic data indicating that lung i.n. cells are more activated than lung i.d. CD8 T cells. The sustained expression of chemokines and activation genes enables CD8 T cells to remain in the lungs for extended periods after i.n. immunization. This may account for the early inhibition of <it>M. tuberculosis </it>growth observed in Ad85A i.n. immunized mice and explain the effectiveness of i.n. compared to parenteral immunization with this viral vector.</p

Parental knowledge of alcohol consumption : a cross sectional survey of 11-17 year old schoolchildren and their parents

Background: Developing timely and effective strategies for preventing alcohol misuse in young people is required in order to prevent related harms since, worldwide, alcohol consumption was associated with 320,000 deaths amongst 15–29 year olds in 2004. Providing guidance and advice to parents is essential if alcohol misuse is to be reduced. However, prevention of risky behaviours is hampered if parents are unaware of the risks involved. Methods: A cross-sectional school-based survey of parent–child dyads, simultaneously questioning 935 children aged 11–17 years old and their parent(s). Univariate and multivariate associations are reported between demography, alcohol behaviours and parental knowledge of their child’s alcohol consumption. Results: 41.1% (n = 384) of children reported drinking alcohol. Of these, 79.9% of their parents were aware of their child’s alcohol consumption. Children aged 11–14 years had over a twofold greater odds of consuming alcohol without parental knowledge compared with 15–17 year olds (AOR: 2.7, 95% CI: 1.3-5.7). Of parent–child dyads where the child reported consuming alcohol, 92.7% of parents reported that they had spoken to their child about alcohol at least once in the past three months, whereas 57.3% of their children reported that this had occurred. Children who consumed alcohol and whose parents did not know they drank alcohol were less likely to report having a parental discussion about alcohol in the last three months (AOR: 0.4, 95% CI: 0.1-1.0) or report lifetime receipt of at least one other parenting protective measure (AOR: 0.5, 95% CI: 0.2-0.9) compared with those children who drank alcohol with parental knowledge. Conclusions: Whilst only small numbers of young adolescents in our sample were drinking alcohol compared with older adolescents, those who did were more likely to do so without their parents’ knowledge. These two factors combined (drinking earlier and drinking without parental knowledge) could place children at risk of immediate harm. Further research is essential to identify whether public health strategies should be developed which could support parents to employ lifestyle parenting techniques even before the parent believes the child to be at risk

Altered Activation of Innate Immunity Associates with White Matter Volume and Diffusion in First-Episode Psychosis

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1-and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFa, CXCL1, CCL7, IFN-alpha 2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum lan association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.evel of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstratePeer reviewe