Heterogeneity and plasticity of the CD4 T cell compartment in viral infections

Project #1: Long-lived Tfh cells The CD4 memory compartment has been subdivided into 3 distinct subsets that have different functions: inflammatory T effector memory (Tem), T central memory (Tcm), and tissue resident memory (Trm) cells. Whether T follicular helper (Tfh) cells that orchestrate the humoral response persist after the pathogen is cleared is controversial. We were able to show that Tfh cells are long-lived but extremely susceptible to NAD induced cell death (NICD) and therefore have previously been overlooked. Further characterization of Tfh cells revealed that folate receptor 4 (FR4) is a superior marker to CXCR5 in identifying Tfh memory cells. Surprisingly, Tfh memory cells maintain an anabolic state characterized by increased glucose uptake and mTORc1 activity yet retain full developmental plasticity. Furthermore, we identified a previously unknown functional role of Tfh memory cells in contributing to the maintenance of the humoral immune response beyond effector time points. Project #2: GP61 variants Upon a viral infection, naïve CD4 T cells differentiate into inflammatory T helper 1 (Th1) cells and Tfh cells which shape the antibody response. The role of the T cell receptor (TCR) signal strength on Th1 vs Tfh cell differentiation in a viral infection model is incompletely understood. Here, we developed a new tool that allows us to address this question in both acute and chronic viral infections. We generated LCMV strains with point mutations in the GP61 epitope, which is part of the LCMV glycoprotein and is recognized by TCR transgenic SMARTA cells. In acute infections, TCR signal strength positively correlated with Th1 induction. In contrast, chronic infections preferentially induced Tfh cells with increasing TCR signal strength and led to acquisition of surface markers associated with chronic T cell stimulation. Thus, depending on the immune context, TCR signals exerts opposite effects on the Th1 versus Tfh generation

Annoyance due to air pollution in Europe

Background Annoyance due to air pollution is a subjective score of air quality, which has been incorporated into the National Environmental monitoring of some countries. The objectives of this study are to describe the variations in annoyance due to air pollution in Europe and its individual and environmental determinants. Methods This study took place in the context of the European Community Respiratory Health Survey II (ECRHS II) that was conducted during 1999-2001. It included 25 centres in 12 countries and 7867 randomly selected adults from the general population. Annoyance due to air pollution was self-reported on an 11-point scale. Annual mean mass concentration of fine particles (PM2.5) and its sulphur (S) content were measured in 21 centres as a surrogate of urban air pollution. Results Forty-three per cent of participants reported moderate annoyance (1-5 on the scale) and 14% high annoyance (≥6) with large differences across centres (2-40% of high annoyance). Participants in the Northern European countries reported less annoyance. Female gender, nocturnal dyspnoea, phlegm and rhinitis, self-reported car and heavy vehicle traffic in front of the home, high education, non-smoking and exposure to environmental tobacco smoke were associated with higher annoyance levels. At the centre level, adjusted means of annoyance scores were moderately associated with sulphur urban levels (slope 1.43 μg m−3, standard error 0.40, r = 0.61). Conclusions Annoyance due to air pollution is frequent in Europe. Individuals' annoyance may be a useful measure of perceived ambient quality and could be considered a complementary tool for health surveillanc

Air pollution and diabetes association : modification by type 2 diabetes genetic risk score

Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma case-control study design. AP was estimated as 10-year mean residential particulate matter <10μm (PM10). We computed count-GRS and weighted-GRS, and applied PM10 interaction terms in mixed logistic regressions, on odds of diabetes. Analyses were stratified by pathways of diabetes pathology and by asthma status. Diabetes prevalence was 4.6% and mean exposure to PM10 was 22μg/m(3). Odds of diabetes increased by 8% (95% confidence interval: 2, 14%) per T2D risk allele and by 35% (-8, 97%) per 10μg/m(3) exposure to PM10. We observed a positive interaction between PM10 and count-GRS on diabetes [ORinteraction=1.10 (1.01, 1.20)], associations being strongest among participants at the highest quartile of count-GRS [OR: 1.97 (1.00, 3.87)]. Stronger interactions were observed with variants of the GRS involved in insulin resistance [(ORinteraction=1.22 (1.00, 1.50)] than with variants related to beta-cell function. Interactions with count-GRS were stronger among asthma cases. We observed similar results with weighted-GRS. Five single variants near GRB14, UBE2E2, PTPRD, VPS26A and KCNQ1 showed nominally significant interactions with PM10 (P<0.05). Our results suggest that genetic risk for T2D may modify susceptibility to air pollution through alterations in insulin sensitivity. These results need confirmation in diabetes cohort consortia

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity

CD4; +; memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (T; cm; ) cells, whereas the existence and functional significance of long-lived T follicular helper (T; fh; ) cells are controversial. Here, we show that T; fh; cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant T; fh; cells with high expression of hallmark T; fh; markers to at least 400 days after infection, by which time T; cm; cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived T; fh; cells are transcriptionally distinct from T; cm; cells, maintain stemness and self-renewal gene expression, and, in contrast to T; cm; cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived T; fh; cells from T; cm; cells. Unexpectedly, long-lived T; fh; cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to T; fh; cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of T; fh; and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish T; fh; cells as an attractive target for the induction of durable adaptive immunity

Factors associated with cessation of smoking among Swiss adults between 1991 and 2011: results from the SAPALDIA cohort

Smoking is still the most preventable cause of disease and premature death in Switzerland, as elsewhere. We aimed to assess the main determinants of smoking cessation in the population-based cohort of SAPALDIA (Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults).; The SAPALDIA study was initiated in 1991 with 9651 participants aged 18 to 60 years from eight areas (S1). Follow-up assessments were conducted in 2002 (S2; 8047 participants) and 2010/11 (S3; 6088 participants). At each survey, detailed information on health and potential health-related factors was collected and lung function measured. Using logistic regression, we assessed predictors of smoking cessation between S1 and S2 and between S2 and S3.; In both periods, highest educational level (summary odds ratio [OR] 1.49, 95% confidence interval [CI] 1.08-2.06; ref. lowest level), FEV1/FVC <0.5 (OR 6.19, 95% CI 2.44-15.7, ref. FEV1/FVC ≥0.7), higher age in men (OR 1.02, 95% CI 1.01-1.03, per year) and overweight (OR 1.38, 95% CI 1.16-1.64) were significant predictors of smoking cessation. Nicotine dependence (OR 0.97, 95% CI 0.96-0.98, per cigarette smoked a day) and female sex between age 45 and 60 (e.g., OR 0.74, 95% CI 0.61-0.91, at age 50) were negatively associated with smoking cessation. Moreover, smokers at S2 reporting a diagnosis of depression were less likely to quit smoking by S3 (OR 0.53, 95% CI 0.30-0.93).; Prospective tobacco control policies in Switzerland should be addressed to women, younger persons and persons of lower education

Transportation Noise and Blood Pressure in a Population-Based Sample of Adults

Background: There is some evidence for an association between traffic noise and ischemic heart disease; however, associations with blood pressure have been inconsistent, and little is known about health effects of railway noise

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991-2003: methods and characterization of participants

Summary.: Objectives: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution. Methods: The health assessment at recruitment (1991) and at the first reassessment (2001-3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates. Results: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6528 individuals (70%) agreed to the health examination and 5973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5kg in 11years and 28% of smokers in 1991 had quit by the time of the reassessmen

Reasons for prehospital delay in acute ischemic stroke

Background Prehospital delay reduces the proportion of patients with stroke treated with recanalization therapies. We aimed to identify novel and modifiable risk factors for prehospital delay. Methods and Results We included patients with an ischemic stroke confirmed by diffusion-weighted magnetic resonance imaging, symptom onset within 24 hours and hospitalized in the Stroke Center of the University Hospital Basel, Switzerland. Trained study nurses interviewed patients and proxies along a standardized questionnaire. Prehospital delay was defined as >4.5 hours between stroke onset-or time point of wake-up-and admission. Overall, 336 patients were enrolled. Prehospital delay was observed in 140 patients (42%). The first healthcare professionals to be alarmed were family doctors for 29% of patients (97/336), and a quarter of these patients had a baseline National Institute of Health Stroke Scale score of 4 or higher. The main modifiable risk factor for prehospital delay was a face-to-face visit to the family doctor (adjusted odds ratio, 4.19; 95% CI, 1.85-9.46). Despite transport by emergency medical services being associated with less prehospital delay (adjusted odds ratio, 0.41; 95% CI, 0.24-0.71), a minority of patients (39%) who first called their family doctor were transported by emergency medical services to the hospital. The second risk factor was lack of awareness of stroke symptoms (adjusted odds ratio, 4.14; 95% CI, 2.36-7.24). Conclusions Almost 1 in 3 patients with a diffusion-weighted magnetic resonance imaging-confirmed ischemic stroke first called the family doctor practice. Face-to-face visits to the family doctor quadrupled the odds of prehospital delay. Efforts to reduce prehospital delay should address family doctors and their staffs as important partners in the prehospital pathway. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02798770

Der (sub-)disziplinäre Status der AVT

Der vorliegende Artikel befasst sich mit der wissenschaftstheoretischen Verortung der AVT. Er gibt zunächst einen Überblick über ihre Entwicklungslinien außerhalb und innerhalb der Translationswissenschaft, die sich auch in verschiedenen Benennungen widerspiegeln, sowie die verschiedenen Translationstypen. Anschließend wird die fachliche Einordnung der AVT am Beispiel von drei Disziplinen, die zumindest Teilbereiche der AVT auch in ihrer disziplinären Zuständigkeit verankert sehen, diskutiert

Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score

Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma case-control study design. AP was estimated as 10-year mean residential particulate matter <10μm (PM10). We computed count-GRS and weighted-GRS, and applied PM10 interaction terms in mixed logistic regressions, on odds of diabetes. Analyses were stratified by pathways of diabetes pathology and by asthma status. Diabetes prevalence was 4.6% and mean exposure to PM10 was 22μg/m(3). Odds of diabetes increased by 8% (95% confidence interval: 2, 14%) per T2D risk allele and by 35% (-8, 97%) per 10μg/m(3) exposure to PM10. We observed a positive interaction between PM10 and count-GRS on diabetes [ORinteraction=1.10 (1.01, 1.20)], associations being strongest among participants at the highest quartile of count-GRS [OR: 1.97 (1.00, 3.87)]. Stronger interactions were observed with variants of the GRS involved in insulin resistance [(ORinteraction=1.22 (1.00, 1.50)] than with variants related to beta-cell function. Interactions with count-GRS were stronger among asthma cases. We observed similar results with weighted-GRS. Five single variants near GRB14, UBE2E2, PTPRD, VPS26A and KCNQ1 showed nominally significant interactions with PM10 (P<0.05). Our results suggest that genetic risk for T2D may modify susceptibility to air pollution through alterations in insulin sensitivity. These results need confirmation in diabetes cohort consortia