Immunopathogenic mechanisms in primary Sjögren’s syndrome

Primary Sjögren’s syndrome is a systemic autoimmune disease primarily affecting salivary and lacrimal glands, but patients may also have other organ involvement. Development of Sjögren’s syndrome has been associated with genetic polymorphisms and aberrances in innate and adaptive immunity, which include abnormal B cell functions with autoantibody production, and increased activity of the interferon (IFN) system. Microbial triggers have been suspected to partake in the pathogenesis. The overall aim of this thesis was to characterize exogenous and endogenous mechanisms contributing to the immunopathology of Sjögren’s syndrome. Genetic variants associated with Sjögren’s syndrome convey low risk-increase for disease development, indicating that environmental factors must play an important role. However, at the start of the work leading up to this thesis, no environmental risk factors for Sjögren’s syndrome had been identified. Therefore, to assess the influence of smoking, we performed the largest questionnaire-based case-control study to date. We found that current and ever smoking was less frequent among patients compared to controls, however, smoking patterns were similar up until approximately 35 years before diagnosis and smoking thereafter declined in patients. We conclude that smoking does not appear to be a risk factor for development of Sjögren’s syndrome, but that early symptoms of dryness may influence behavior. Further, to define connections between previous infections and disease development, we extracted data on patients and matched controls from the Swedish National Patient Register. We found that a history of infection was associated with a higher risk of Sjögren’s syndrome, with overall stronger associations to anti- Ro/SSA and anti-La/SSB positive disease. Infections of the respiratory tract associated both with autoantibody positive and negative disease, and a dose-response relationship was present in autoantibody positive patients. Previous studies have identified CXCR5 as a susceptibility locus for Sjögren’s syndrome. We describe a novel eQTL effect for CXCR5 in B cells. Further, decreased percentages of CXCR5+ cells with lower CXCR5 surface expression in the circulation coincided with higher CXCL13 plasma protein levels, and higher numbers of CXCR5+ cells were detected in salivary glands of patients compared to controls. We conclude that CXCR5+ cells likely relocate from the blood stream to the autoimmune target tissues in patients. By transcriptomic analysis of peripheral B cells, we found prominent type I and type II IFN signatures, as well as higher expression of chemokines and chemokine receptors in patients compared to controls, while inhibitors of cytokine signaling were downregulated. Our data add to the understanding of B cells in Sjögren’s syndrome and define potential candidates for future functional studies. Activation of the IFN system is often assessed by quantifying the expression of IFN regulated genes. However, RNA samples are not always available, wherefore alternative methods are needed. We describe two novel IFN scores calculated from protein levels in serum or plasma, and from levels of DNA methylation. Responses to microbial antigens can be studied in vivo during vaccination. We therefore assessed serological and cellular responses to influenza vaccination in patients with Sjögren’s syndrome and SLE. Untreated patients with Sjögren’s syndrome and SLE patients receiving no or light treatment responded to the viral antigens with higher vaccine-specific antibody titers compared to controls. Augmented antibody responses were associated with upregulated markers of type I IFN system activation at the mRNA level in monocytes and at the protein level in the circulation before vaccination. Specific components associated with a higher serological response were identified, which warrant further study. Our data increase the comprehension of immune reactions toward microbial antigens in autoimmune disease. In conclusion, this thesis expands our current understanding of environmental factors and immunopathogenic processes in primary Sjögren’s syndrome

Road traffic noise and hypertension: results from a cross-sectional public health survey in southern Sweden

BACKGROUND: Results from studies of road traffic noise and hypertension are heterogeneous with respect to effect size, effects among males and females and with respect to effects across age groups. Our objective was to further explore these associations. METHODS: The study used cross-sectional public health survey data from southern Sweden, including 24,238 adults (18 - 80 years old). We used a geographic information system (GIS) to assess the average road noise (LAeq 24 hr) at the current residential address. Effects on self-reported hypertension were estimated by logistic regression with adjustment for age, sex, BMI, alcohol intake, exercise, education, smoking and socioeconomic status. RESULTS: Modest exposure effects (OR approximately 1.1) were generally noted in intermediate exposure categories (45 -64 dB(A)), and with no obvious trend. The effect was more pronounced at > 64 dB(A) (OR 1.45, 95% CI 1.04 - 2.02). Age modified the relative effect (p = 0.018). An effect was seen among middle-aged (40 - 59 years old) at noise levels 60 - 64 dB(A) (OR = 1.27, 95% CI 1.02 - 1.58)) and at > 64 dB(A) (OR = 1.91, 95% CI 1.19 - 3.06)). An effect was also indicated among younger adults but not among elderly. No apparent effect modification by gender, country of origin, disturbed sleep or strained economy was noted. CONCLUSION: The study supports an association between road traffic noise at high average levels and self-reported hypertension in middle-aged. Future studies should use age group -specific relative effect models to account for differences in prevalence

Area-aggregated assessments of perceived environmental attributes may overcome single-source bias in studies of green environments and health: results from a cross-sectional survey in southern Sweden

Most studies assessing health effects of neighborhood characteristics either use self-reports or objective assessments of the environment, the latter often based on Geographical Information Systems (GIS). While objective measures require detailed landscape data, self-assessments may yield confounded results. In this study we demonstrate how self-assessments of green neighborhood environments aggregated to narrow area units may serve as an appealing compromise between objective measures and individual self-assessments. Methods The study uses cross-sectional data (N = 24,847) from a public health survey conducted in the county of Scania, southern Sweden, in 2008 and validates the Scania Green Score (SGS), a new index comprising five self-reported green neighborhood qualities (Culture, Lush, Serene, Spacious and Wild). The same qualities were also assessed objectively using landscape data and GIS. A multilevel (ecometric) model was used to aggregate individual self-reports to assessments of perceived green environmental attributes for areas of 1,000 square meters. We assessed convergent and concurrent validity for self-assessments of the five items separately and for the sum score, individually and area-aggregated. Results Correlations between the index scores based on self-assessments and the corresponding objective assessments were clearly present, indicating convergent validity, but the agreement was low. The correlation was even more evident for the area-aggregated SGS. All three scores (individual SGS, area-aggregated SGS and GIS index score) were associated with neighborhood satisfaction, indicating concurrent validity. However, while individual SGS was associated with vitality, this association was not present for aggregated SGS and the GIS-index score, suggesting confounding (single-source bias) when individual SGS was used. Conclusions Perceived and objectively assessed qualities of the green neighborhood environment correlate but do not agree. An index score based on self-reports but aggregated to narrow area units can be a valid approach to assess perceived green neighborhood qualities in settings where objective assessments are not possible or feasible.

Recreational values of the natural environment in relation to neighbourhood satisfaction, physical activity, obesity and wellbeing.

OBJECTIVES: The aim of this population-based study was to investigate associations between recreational values of the close natural environment and neighbourhood satisfaction, physical activity, obesity and wellbeing. METHODS: Data from a large public health survey distributed as a mailed questionnaire in suburban and rural areas of southern Sweden were used (N = 24,819; 59% participation rate). Geocoded residential addresses and the geographical information system technique were used to assess objectively five recreational values of the close natural environment: serene, wild, lush, spacious and culture. RESULTS: On average, a citizen of the Scania region, inner city areas excluded, only had access to 0.67 recreational values within 300 metres distance from their residence. The number of recreational values near the residence was strongly associated with neighbourhood satisfaction and physical activity. The effect on satisfaction was especially marked among tenants and the presence of recreational values was associated with low or normal body mass index in this group. A less marked positive association with vitality among women was observed. No evident effect on self-rated health was detectable. CONCLUSIONS: Immediate access to natural environments with high recreational values was rare in the study population and was distributed in an inequitable manner. Moreover, such access was associated with a positive assessment of neighbourhood satisfaction and time spent on physical activity, which can be expected to reduce obesity and increase vitality by having a buffering effect on stress

Area-aggregated assessments of perceived environmental attributes may overcome single-source bias in studies of green environments and health: results from a cross-sectional survey in southern Sweden

<p>Abstract</p> <p>Background</p> <p>Most studies assessing health effects of neighborhood characteristics either use self-reports or objective assessments of the environment, the latter often based on Geographical Information Systems (GIS). While objective measures require detailed landscape data, self-assessments may yield confounded results. In this study we demonstrate how self-assessments of green neighborhood environments aggregated to narrow area units may serve as an appealing compromise between objective measures and individual self-assessments.</p> <p>Methods</p> <p>The study uses cross-sectional data (N = 24,847) from a public health survey conducted in the county of Scania, southern Sweden, in 2008 and validates the Scania Green Score (SGS), a new index comprising five self-reported green neighborhood qualities (Culture, Lush, Serene, Spacious and Wild). The same qualities were also assessed objectively using landscape data and GIS. A multilevel (ecometric) model was used to aggregate individual self-reports to assessments of perceived green environmental attributes for areas of 1,000 square meters. We assessed convergent and concurrent validity for self-assessments of the five items separately and for the sum score, individually and area-aggregated.</p> <p>Results</p> <p>Correlations between the index scores based on self-assessments and the corresponding objective assessments were clearly present, indicating convergent validity, but the agreement was low. The correlation was even more evident for the area-aggregated SGS. All three scores (individual SGS, area-aggregated SGS and GIS index score) were associated with neighborhood satisfaction, indicating concurrent validity. However, while individual SGS was associated with vitality, this association was not present for aggregated SGS and the GIS-index score, suggesting confounding (single-source bias) when individual SGS was used.</p> <p>Conclusions</p> <p>Perceived and objectively assessed qualities of the green neighborhood environment correlate but do not agree. An index score based on self-reports but aggregated to narrow area units can be a valid approach to assess perceived green neighborhood qualities in settings where objective assessments are not possible or feasible.</p

Cancer Incidence and Mortality in Swedish Sterilant Workers Exposed to Ethylene Oxide: Updated Cohort Study Findings 1972–2006

OBJECTIVES: To assess whether cancer incidence, mainly from lymphohaematopoietic tumours and breast cancer, and mortality were increased in a cohort of Swedish sterilant workers exposed to low levels of ethylene oxide (EtO), updated with 16 more years of follow up. METHODS: The mortality and cancer incidence 1972-2006 experienced by a cohort of 2,171 male and female workers employed for at least one year in two plants producing medical equipment sterilised with EtO were investigated. Individual cumulative exposure to EtO was assessed by occupational hygienists. Cause-specific standardized rate ratios were calculated using the regional general population as a comparison for mortality (SMR) and cancer incidence (SIR). Internal Poisson-regression analyses were performed for selected causes. RESULTS: The median cumulative exposure to EtO was 0.13 ppm-years. The overall cancer incidence was close to unity (SIR 0.94, 95% CI 0.82-1.08). Eighteen cases of lymphohaematopoietic cancer were observed (SIR 1.25, 95% CI 0.74-1.98). A healthy worker effect was indicated from a significantly decreased overall mortality and mortality from cardiovascular diseases. Internal analyses found significantly increased rate ratios for breast cancer for the two upper quartiles of cumulative exposure as compared to the lowest 50% of the cohort (IRR 2.76, 95% CI 1.20-6.33 and IRR 3.55, 95% CI 1.58-7.93). CONCLUSIONS: The findings from this updated study indicate limited or low risks for human cancer due to occupational exposure from ethylene oxide at the low cumulative exposure levels in this cohort. However a positive exposure-response relation with breast cancer was observed though

Survey context and question wording affects self reported annoyance due to road traffic noise: a comparison between two cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>Surveys are a common way to measure annoyance due to road traffic noise, but the method has some draw-backs. Survey context, question wording and answer alternatives could affect participation and answers and could have implications when comparing studies and/or performing pooled analyses. The aim of this study was to investigate the difference in annoyance reporting due to road traffic noise in two types of surveys of which one was introduced broadly and the other with the clearly stated aim of investigating noise and health.</p> <p>Methods</p> <p>Data was collected from two surveys carried out in the municipality of Malmö, southern Sweden in 2007 and 2008 (n = 2612 and n = 3810). The first survey stated an aim of investigating residential environmental exposure, especially noise and health. The second survey was a broad public health survey stating a broader aim. The two surveys had comparable questions regarding noise annoyance, although one used a 5-point scale and the other a 4-point scale. We used geographic information systems (GIS) to assess the average road and railway noise (L_Aeq,24h) at the participants' residential address. Logistic regression was used to calculate odds ratios for annoyance in relation to noise exposure.</p> <p>Results</p> <p>Annoyance at least once a week due to road traffic noise was significantly more prevalent in the survey investigating environment and health compared to the public health survey at levels > 45 dB(A), but not at lower exposure levels. However no differences in annoyance were found when comparing the extreme alternatives "never" and "every day". In the study investigating environment and health, "Noise sensitive" persons were more likely to readily respond to the survey and were more annoyed by road traffic noise compared to the other participants in that survey.</p> <p>Conclusions</p> <p>The differences in annoyance reporting between the two surveys were mainly due to different scales, suggesting that extreme alternatives are to prefer before dichotomization when comparing results between the two. Although some findings suggested that noise-sensitive individuals were more likely to respond to the survey investigating noise and health, we could not find convincing evidence that contextual differences affected either answers or participation.</p

Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study

BACKGROUND: Mutations altering BLM function are associated with highly elevated cancer susceptibility (Bloom syndrome). Thus, genetic variants of BLM and proteins that form complexes with BLM, such as TOP3A and RMI1, might affect cancer risk as well. METHODS: In this study we have studied 26 tagged single nucleotide polymorphisms (tagSNPs) in RMI1, TOP3A, and BLM and their associations with cancer risk in acute myeloid leukemia/myelodysplatic syndromes (AML/MDS; N = 152), malignant melanoma (N = 170), and bladder cancer (N = 61). Two population-based control groups were used (N = 119 and N = 156). RESULTS: Based on consistency in effect estimates for the three cancer forms and similar allelic frequencies of the variant alleles in the control groups, two SNPs in TOP3A (rs1563634 and rs12945597) and two SNPs in BLM (rs401549 and rs2532105) were selected for analysis in breast cancer cases (N = 200) and a control group recruited from spouses of cancer patients (N = 131). The rs12945597 in TOP3A and rs2532105 in BLM showed increased risk for breast cancer. We then combined all cases (N = 584) and controls (N = 406) respectively and found significantly increased risk for variant carriers of rs1563634 A/G (AG carriers OR = 1.7 [95%CI 1.1-2.6], AA carriers OR = 1.8 [1.2-2.8]), rs12945597 G/A (GA carriers OR = 1.5 [1.1-1.9], AA carriers OR = 1.6 [1.0-2.5]), and rs2532105 C/T (CT+TT carriers OR = 1.8 [1.4-2.5]). Gene-gene interaction analysis suggested an additive effect of carrying more than one risk allele. For the variants of TOP3A, the risk increment was more pronounced for older carriers. CONCLUSION: These results further support a role of low-penetrance genes involved in BLM-associated homologous recombination for cancer risk

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world\u27s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (−0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications