Intraindividual Long-term Immune Marker Stability in Plasma Samples Collected in Median 9.4 Years Apart in 304 Adult Cancer-free Individuals.

BACKGROUND: Changes in immune marker levels in the blood could be used to improve the early detection of tumor-associated inflammatory processes. To increase predictiveness and utility in cancer detection, intraindividual long-term stability in cancer-free individuals is critical for biomarker candidates as to facilitate the detection of deviation from the norm. METHODS: We assessed intraindividual long-term stability for 19 immune markers (IL10, IL13, TNFα, CXCL13, MCP-3, MIP-1α, MIP-1ß, fractalkine, VEGF, FGF-2, TGFα, sIL2Rα, sIL6R, sVEGF-R2, sTNF-R1, sTNF-R2, sCD23, sCD27, and sCD30) in 304 cancer-free individuals. Repeated blood samples were collected up to 20 years apart. Intraindividual reproducibility was assessed by calculating intraclass correlation coefficients (ICC) using a linear mixed model. RESULTS: ICCs indicated fair to good reproducibility (ICCs ≥ 0.40 and < 0.75) for 17 of 19 investigated immune markers, including IL10, IL13, TNFα, CXCL13, MCP-3, MIP-1α, MIP-1ß, fractalkine, VEGF, FGF-2, TGFα, sIL2Rα, sIL6R, sTNF-R1, sTNF-R2, sCD27, and sCD30. Reproducibility was strong (ICC ≥ 0.75) for sCD23, while reproducibility was poor (ICC < 0.40) for sVEGF-R2. Using a more stringent criterion for reproducibility (ICC ≥ 0.55), we observed either acceptable or better reproducibility for IL10, IL13, CXCL13, MCP-3, MIP-1α, MIP-1ß, VEGF, FGF-2, sTNF-R1, sCD23, sCD27, and sCD30. CONCLUSIONS: IL10, IL13, CXCL13, MCP-3, MIP-1α, MIP-1ß, VEGF, FGF-2, sTNF-R1, sCD23, sCD27, and sCD30 displayed ICCs consistent with intraindividual long-term stability in cancer-free individuals. IMPACT: Our data support using these markers in prospective longitudinal studies seeking early cancer detection biomarkers.

Pesticide Exposure of Residents Living Close to Agricultural Fields in the Netherlands: Protocol for an Observational Study.

BACKGROUND: Application of pesticides in the vicinity of homes has caused concern regarding possible health effects in residents living nearby. However, the high spatiotemporal variation of pesticide levels and lack of knowledge regarding the contribution of exposure routes greatly complicates exposure assessment approaches. OBJECTIVE: The objective of this paper was to describe the study protocol of a large exposure survey in the Netherlands assessing pesticide exposure of residents living close (<250 m) to agricultural fields; to better understand possible routes of exposure; to develop an integrative exposure model for residential exposure; and to describe lessons learned. METHODS: We performed an observational study involving residents living in the vicinity of agricultural fields and residents living more than 500 m away from any agricultural fields (control subjects). Residential exposures were measured both during a pesticide use period after a specific application and during the nonuse period for 7 and 2 days, respectively. We collected environmental samples (outdoor and indoor air, dust, and garden and field soils) and personal samples (urine and hand wipes). We also collected data on spraying applications as well as on home characteristics, participants' demographics, and food habits via questionnaires and diaries. Environmental samples were analyzed for 46 prioritized pesticides. Urine samples were analyzed for biomarkers of a subset of 5 pesticides. Alongside the field study, and by taking spray events and environmental data into account, we developed a modeling framework to estimate environmental exposure of residents to pesticides. RESULTS: Our study was conducted between 2016 and 2019. We assessed 96 homes and 192 participants, including 7 growers and 28 control subjects. We followed 14 pesticide applications, applying 20 active ingredients. We collected 4416 samples: 1018 air, 445 dust (224 vacuumed floor, 221 doormat), 265 soil (238 garden, 27 fields), 2485 urine, 112 hand wipes, and 91 tank mixtures. CONCLUSIONS: To our knowledge, this is the first study on residents' exposure to pesticides addressing all major nondietary exposure sources and routes (air, soil, dust). Our protocol provides insights on used sampling techniques, the wealth of data collected, developed methods, modeling framework, and lessons learned. Resources and data are open for future collaborations on this important topic. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/27883.

Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated pre-diagnostic blood samples.

Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor-alpha (TGF-α). In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. The first and repeated samples from myeloma cases were donated at a median 13 and 4 years, respectively, before the myeloma was diagnosed. Known risk factors for progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, and TGF-α in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were noted for TGF-α (P=2.5 × 10-4) indicating progression to MM. Investigating this, we found that low levels of TGF-α assessed at the time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P=0.003). TGF-α can potentially improve early detection of MM.

Residential proximity to livestock farms is associated with a lower prevalence of atopy.

OBJECTIVES: Exposure to farm environments during childhood and adult life seems to reduce the risk of atopic sensitisation. Most studies have been conducted among farmers, but people living in rural areas may have similar protective effects for atopy. This study aims to investigate the association between residential proximity to livestock farms and atopy among non-farming adults living in a rural area in the Netherlands. METHODS: We conducted a cross-sectional study among 2443 adults (20-72 years). Atopy was defined as specific IgE to common allergens and/or total IgE ≥100 IU/mL. Residential proximity to livestock farms was assessed as 1) distance to the nearest pig, poultry, cattle or any farm, 2) number of farms within 500 m and 1000 m, and 3) modelled annual average fine dust emissions from farms within 500 m and 1000 m. Data were analysed with multiple logistic regression and generalised additive models. RESULTS: The prevalence of atopy was 29.8%. Subjects living at short distances from farms (<327 m, first tertile) had a lower odds for atopy compared with subjects living further away (>527 m, third tertile) (OR 0.79, 95% CI 0.63 to 0.98). Significant associations in the same direction were found with distance to the nearest pig or cattle farm. The associations between atopy and livestock farm exposure were somewhat stronger in subjects who grew up on a farm. CONCLUSIONS: Living in close proximity to livestock farms seems to protect against atopy. This study provides evidence that protective effects of early-life and adult farm exposures may extend beyond farming populations.

Occupational endotoxin exposure in association with atopic sensitization and respiratory health in adults: Results of a 5-year follow-up.

The objective of the present longitudinal study was to investigate the effects of occupational endotoxin exposure on respiratory health and atopic sensitization in adults. Health outcomes and personal endotoxin exposure estimates were determined for 234 farmers and agricultural workers both at baseline and 5 years later. A questionnaire was used to assess respiratory symptoms, spirometry tests were performed and total and specific IgE levels were measured in serum. A twofold increase in personal endotoxin exposure was associated with less hay fever (OR 0.68, 95%CI 0.54-0.87) and grass IgE positivity (OR 0.81, 95%CI 0.68-0.97) at both time points ("persistent" versus "never"). Although not statistically significant, a consistent protective pattern was observed for an increased loss of hay fever symptoms (OR 2.19, 95%CI 0.96-4.99) and grass IgE positivity (OR 1.24, 95%CI 0.76-2.02), and for less new-onset of hay fever (OR 0.87, 95%CI 0.65-1.17), grass IgE positivity (OR 0.83, 95%CI 0.61-1.12) and atopic sensitization (OR 0.75, 95%CI 0.55-1.02). Endotoxin exposure was not associated with changes in lung function. We showed that occupational endotoxin exposure is associated with a long-term protective effect on hay fever and grass IgE positivity. Results on longitudinal changes in hay fever, atopy and grass IgE positivity in adulthood were consistent with a protective effect of endotoxin exposure, but results need to be confirmed in larger cohorts. An effect of endotoxin exposure on lung function decline was not found.

Contact dermatitis is an unrecognized problem in the construction industry: Comparison of four different assessment methods.

BACKGROUND: A high contact dermatitis symptoms prevalence has been observed in Dutch construction workers. METHODS: Contact dermatitis was diagnosed by an expert panel using questionnaire data and photographs of 751 subjects' hands. A subset was evaluated by two occupational physicians. Their diagnoses were compared to those of the expert panel. In addition, two self-reported questionnaire-based assessment methods were compared to the expert panel evaluation. Associations between contact dermatitis and determinants were assessed using log-binomial regression analysis. RESULTS: Contact dermatitis prevalence was high: 61.4% (expert panel's diagnosis) and 32.9% (self-reported). Agreement between occupational physicians and the expert panel was low but increased after training. Washing hands with solvents and performing job-related tasks at home were related to contact dermatitis. CONCLUSIONS: Contact dermatitis prevalence among construction workers is high. Recognition of contact dermatitis by occupational physicians is poor but can be improved by training. Awareness of skin disorders should be raised.

Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis.

The B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker-disease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 × 10-10). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. Cancer Res; 77(6); 1408-15. ©2017 AACR.

Allergens and ß-glucans in dutch homes and schools: characterizing airborne levels.

BACKGROUND: Indoor air quality has an effect on respiratory health. Children are more vulnerable to a decreased indoor air quality as their lungs are still developing. We measured levels of allergens and ß-(1,3)-glucans in 19 school buildings and determined whether measured levels could be reproduced. School levels were compared to those in 169 homes and the effect of building characteristics on both home and school exposure was explored. METHODS: Electrostatic Dust fall Collectors were placed in school buildings for 8 weeks and in homes for 2 weeks to collect settled airborne dust. Cat, dog, and mouse allergen levels, domestic mite antigen levels and ß-(1,3)-glucans were measured in the extracts from the collectors. Results were corrected for sampling duration. Using questionnaire data, relations between measured levels and building and classroom characteristics were explored. RESULTS: In schools, exposure levels were highest in classrooms and were influenced by the socioeconomic status of the children, the season measurements were performed, moisture status of the building and pet ownership. Repeated measurements in different seasons and over the years showed significantly different levels. Home exposure was influenced by socioeconomic status, occupancy and pet ownership. Domestic mite antigen was found in higher levels in extracts from homes compared to schools while pet allergen levels were 13 times higher in schools compared to homes without pets. For mouse allergen overall levels of exposure were low but still two times higher in schools compared to homes. Levels of ß-(1,3)-glucans were also approximately two times higher in schools than in homes. CONCLUSION: Exposure levels of several allergens and ß-(1,3)-glucans in schools differ over time and are higher than in homes. For children, exposure levels measured at school could contribute to their total exposure as especially animal allergen levels can be much higher in schools compared to homes.

Dampness and mould in schools and respiratory symptoms in children: the HITEA study.

BACKGROUND: The adverse respiratory health effects of dampness and mould in the home have been extensively reported, but few studies have evaluated the health effects of such exposures in schools. OBJECTIVES: To assess the associations between dampness and mould in school buildings and respiratory symptoms among 6-12-year-old pupils in three European countries with different climates. METHODS: Based on information from self-reports and observations, we selected 29 primary schools with and 27 without moisture damage in Spain, the Netherlands and Finland. Information on respiratory symptoms and potential determinants was obtained using a parent-administered questionnaire among 6-12-year-old pupils. Country-specific associations between moisture damage and respiratory symptoms were evaluated using multivariable multilevel mixed effects logistic regression analysis. RESULTS: Data from 9271 children were obtained. Nocturnal dry cough was consistently associated with moisture damage at school in each of the three countries: OR 1.15; 95% CI 1.00 to 1.30 with p for heterogeneity 0.54. Finnish children attending a moisture damaged school more often had wheeze (OR 1.36; CI 1.04 to 1.78), nasal symptoms (OR 1.34; CI 1.05 to 1.71) and respiratory-related school absence (OR 1.50; CI 1.10 to 2.03). No associations with these symptoms were found in the Netherlands or Spain (p for heterogeneity <0.05). CONCLUSIONS: Moisture damage in schools may have adverse respiratory health effects in pupils. Finnish school children seem to be at higher risk, possibly due to quantitative and/or qualitative differences in exposure.

Endotoxin levels in homes and classrooms of Dutch school children and respiratory health.

Several studies describe indoor pollutant exposure in homes and to a lesser extent in schools. Population studies that include both environments are sparse. This study aims to assess endotoxin levels in primary schools and homes of children. Endotoxin was also studied in relation to asthma and sensitisation. 10 schools with (index) and without (reference) dampness were selected, based on reports and inspections. Cases and controls were selected from 169 homes based on the presence or absence of asthma-like symptoms of children. Classroom and bedroom airborne settled dust was sampled using electrostatic dust fall collectors. Average endotoxin levels in schools ranged from 2178 to 6914 endotoxin units (EU)·m(-2) per week compared with 462-1285 EU·m(-2) per week in homes. After mutual adjustment for home and school endotoxin, school endotoxin was positively associated with nonatopic asthma (OR 1.11, 95% CI 0.97-1.27), while no associations with endotoxin were found at home. The high endotoxin levels in schools compared with homes indicate that exposure at school can contribute considerably to environmental endotoxin exposure of children and teachers. Our results also suggest that endotoxin in schools may be associated with nonatopic asthmatic symptoms in pupils, although the results require reproduction because of the modest sample size.

A multi-center ring trial of allergen analysis using fluorescent multiplex array technology.

BACKGROUND: Consistent performance of allergen assays is essential to ensure reproducibility of exposure assessments for investigations of asthma and occupational allergic disease. This study evaluated intra- and inter-laboratory reproducibility of a fluorescent multiplex array, which simultaneously measures eight indoor allergens in a single reaction well. METHODS: A multi-center study was performed in nine laboratories in the US and Europe to determine the inter-laboratory variability of an 8-plex array for dust mite, cat, dog, rat, mouse and cockroach allergens. Aliquots of 151 dust extract samples were sent to participating centers and analyzed by each laboratory on three separate occasions. Agreement within and between laboratories was calculated by the concordance correlation coefficient (CCC). RESULTS: Results were obtained for over 32,000 individual allergen measurements. Levels covered a wide range for all allergens from below the lower limit of detection (LLOD = 0.1-9.8 ng/ml) to higher than 6800 ng/ml for all allergens except Mus m 1, which was up to 1700 ng/ml. Results were reproducible within as well as between laboratories. Within laboratories, 94% of CCC were ≥ 0.90, and 80% of intra-laboratory results fell within a 10% coefficient of variance (CV%). Results between laboratories also showed highly significant positive correlations for all allergens (~0.95, p<0.001). Overall means of results were comparable, and inter-laboratory CV% for all allergens except Rat n 1 ranged between 17.6% and 26.6%. CONCLUSION: The data indicate that performance criteria for fluorescent multiplex array technology are reproducible within and between laboratories. Multiplex technology provides standardized and consistent allergen measurements that will streamline environmental exposure assessments in allergic disease.

Swimming pool attendance and respiratory symptoms and allergies among Dutch children.

OBJECTIVES: To describe associations among swimming, respiratory health, allergen sensitisation and Clara cell protein 16 (CC16) levels in Dutch schoolchildren. Trichloramine levels in swimming pool air were determined to assess potential exposure levels. METHODS: Respiratory health and pool attendance information was collected from 2359 children, aged 6-13 years. Serum from 419 children was tested for allergen sensitisation and CC16 levels. Trichloramine levels were assessed in nine swimming facilities. RESULTS: Trichloramine levels ranged from 0.03 to 0.78 mg/m3 (average 0.21 mg/m3). Reported swimming pool attendance and trichloramine exposure were both not associated with asthma, wheezing, rhinitis or CC16 levels. Birch and house dust mite sensitisation were associated with recent indoor swimming (OR>1.86), but not after considering recent swimming frequency multiplied by trichloramine levels. Sensitisation to house dust mites was associated with frequent baby swimming (ORs=1.75; 95% CI 1.09 to 2.79). Furthermore, sensitisation was associated with lower serum CC16 levels. CC16 levels were associated with average trichloramine concentrations in pools; however, not after considering swimming frequency multiplied by trichloramine levels. CONCLUSIONS: Measured trichloramine levels were comparable with other studies but lower than in an earlier Dutch study. Swimming pool attendance was not associated with respiratory symptoms. The association between sensitisation and swimming during the first 2 years of life suggests that early-life exposures might be important, although this needs further study. The interpretation of transient and chronic changes of CC16 and other inflammatory markers in relation to the pool environment and health impacts warrants further investigation. Detailed comparisons with other studies are limited as few studies have measured trichloramine levels.

Can f 1 levels in hair and homes of different dog breeds: lack of evidence to describe any dog breed as hypoallergenic.

BACKGROUND: Certain dog breeds are described and marketed as being "hypoallergenic" on the basis of anecdotal reports that these dogs are better tolerated by patients allergic to dogs. OBJECTIVE: These observations were investigated by comparing Can f 1 (major dog [Canis familiaris] allergen) levels in hair and coat samples and in the home environment of various hypoallergenic (Labradoodle, Poodle, Spanish Waterdog, and Airedale terrier) and non-hypoallergenic dogs (Labrador retriever and a control group). METHODS: Hair and coat samples were obtained from dogs, and settled floor and airborne dust samples were taken from the dogs' homes. Can f 1 concentrations were measured by using ELISA, and results were analyzed by using multiple linear regression analyses. RESULTS: Significantly higher Can f 1 concentrations were found in hair and coat samples of hypoallergenic dogs (n = 196, geometric mean [GM], 2.26 µg/g, geometric standard deviation [GSD], 0.73, and GM, 27.04 µg/g, GSD, 0.57, respectively) than of non-hypoallergenic dogs (n = 160, GM, 0.77 µg/g, GSD, 0.71, and GM, 12.98 µg/g, GSD, 0.76, respectively). Differences between breeds were small, relative to the variability within a breed. Can f 1 levels in settled floor dust samples were lower for Labradoodles, but no differences were found between the other groups. No differences in airborne levels were found between breeds. CONCLUSION: So-called hypoallergenic dogs had higher Can f 1 levels in hair and coat samples than did control breeds. These differences did not lead to higher levels of environmental exposure to dog allergens. There is no evidence for the classification of certain dog breeds as being "hypoallergenic."

Searching for early breast cancer biomarkers by serum protein profiling of pre-diagnostic serum; a nested case-control study.

BACKGROUND: Serum protein profiles have been investigated frequently to discover early biomarkers for breast cancer. So far, these studies used biological samples collected at or after diagnosis. This may limit these studies' value in the search for cancer biomarkers because of the often advanced tumor stage, and consequently risk of reverse causality. We present for the first time pre-diagnostic serum protein profiles in relation to breast cancer, using the Prospect-EPIC (European Prospective Investigation into Cancer and nutrition) cohort. METHODS: In a nested case-control design we compared 68 women diagnosed with breast cancer within three years after enrollment, with 68 matched controls for differences in serum protein profiles. All samples were analyzed with SELDI-TOF MS (surface enhanced laser desorption/ionization time-of-flight mass spectrometry). In a subset of 20 case-control pairs, the serum proteome was identified and relatively quantified using isobaric Tags for Relative and Absolute Quantification (iTRAQ) and online two-dimensional nano-liquid chromatography coupled with tandem MS (2D-nanoLC-MS/MS). RESULTS: Two SELDI-TOF MS peaks with m/z 3323 and 8939, which probably represent doubly charged apolipoprotein C-I and C3a des-arginine anaphylatoxin (C3adesArg), were higher in pre-diagnostic breast cancer serum (p = 0.02 and p = 0.06, respectively). With 2D-nanoLC-MS/MS, afamin, apolipoprotein E and isoform 1 of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4) were found to be higher in pre-diagnostic breast cancer (p < 0.05), while alpha-2-macroglobulin and ceruloplasmin were lower (p < 0.05). C3a(desArg) and ITIH4 have previously been related to the presence of symptomatic and/or mammographically detectable breast cancer. CONCLUSIONS: We show that serum protein profiles are already altered up to three years before breast cancer detection.

Allergen and endotoxin exposure in a companion animal hospital.

BACKGROUND: Exposure to allergens, both in general and occupational environments, is known to result in sensitisation and exacerbation of allergic diseases, while endotoxin exposure might protect against allergic diseases. This may be important for veterinarians and co-workers. However, exposure levels are mostly unknown. OBJECTIVE: We investigated the allergen and endotoxin exposure levels of veterinary medicine students and workers in a companion animal hospital. METHODS: Airborne and surface dust was collected using various sampling methods at different locations. Allergen levels in extracts were measured with sandwich ELISAs and/or the multiplex array for indoor allergens (MARIA). Endotoxin was determined by limulus amebocyte lysate (LAL) assay. RESULTS: Fel d 1 (Felis domesticus), Can f 1 (Canus familiaris) and endotoxin were detected in all except stationary samples. The geometric mean (GM) level of personal inhalable dust samples for Fel d 1 was 0.3 ng/m(3) (range: below lower limit of detection (

Plasma cytokines and future risk of non-Hodgkin lymphoma (NHL): a case-control study nested in the Italian European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Recently, biological markers related to the immune system such as cytokines have been studied to further understand the etiology of non-Hodgkin Lymphoma (NHL). However, to date, there are no studies that have studied cytokine levels prospectively in relation to NHL risk in the general population. METHODS: Using bead-based immunoassays, plasma levels of 11 cytokines, 4 chemokines, and 1 adhesion molecules were measured in prediagnostic blood samples of 86 NHL cases and 86 matched controls (average time between blood collection and diagnosis, 4.5 y). Conditional logistic regression adjusted for body mass index and alcohol consumption was used to analyze the association between individual plasma cytokine levels and the risk of developing NHL. RESULTS: In multivariate models, excluding cases diagnosed within 2 years after inclusion, we observed a significant association for interleukin 2 (IL2; P trend = 0.004), interferon (IFN)-gamma (P trend = 0.05), and intercellular adhesion molecule (ICAM) (P trend = 0.04). Subanalyses of B-cell NHL patients showed a significant association with IL2 (P trend = 0.003), tumor necrosis factor-alpha (TNF-alpha; P trend = 0.03), and ICAM (P trend = 0.04) and a borderline association with IL5 (P trend = 0.07) and IFN-gamma (P trend = 0.08). CONCLUSIONS: The results of this study suggest, in a prospective setting, a possible association between plasma levels of IL2, ICAM, IFN-gamma, and TNF-alpha with NHL risk and provide some evidence that risk of NHL might be related to a downregulation of T helper 1 cytokines. IMPACT: Identification of subtle changes in immune response regulation quantified by plasma cytokine levels possibly provides new insights in the etiology of NHL.

Dynamics in cytokine responses during the development of occupational sensitization to rats.

BACKGROUND: Occupational allergy forms an attractive model to study the development of allergic responses, as in some occupations it has a high incidence and develops quickly. In a cohort of starting laboratory animal workers, we previously found 20% sensitization to animal allergens within 2 years. METHODS: We compared cellular responses of incident laboratory animal workers who developed rat-specific sensitization (cases, n = 18) during 2 years of follow-up to control animal workers matched for atopic status but without sensitization after follow-up (controls, n = 18). Practically, this is a case-control study, nested within the cohort. Rat-specific IgE antibodies were measured in sera, and allergen-specific and nonspecific cytokine responses were measured in whole blood and in isolated peripheral blood mononuclear cells. RESULTS: Self-reported allergic symptoms were related to the presence of rat-specific IgE (P ≤ 0.01). Cases developed a rat allergen-specific interleukin (IL)-4 response during sensitization, while controls did not show an increased IL-4 response (at visit D: 33 vs 5 IL-4 producing cells/10(6) cells, P < 0.001). The IL-4 response was related to the levels of rat-specific IgE in cases (visit D: rho = 0.706, P < 0.001). By contrast, allergen-specific IL-10 and interferon γ (IFNγ) responses as well as nonspecific cytokine responses were comparable between cases and controls. CONCLUSION: This study is the first to show the development of an allergen-specific IL-4 response in adult human subjects during allergen-specific sensitization. This IL-4 response was quantitatively associated with the development of the specific IgE antibodies. Allergen-specific or nonspecific IL-10 and IFNγ responses showed no protective effect on the development of allergic sensitization.

Stability and reproducibility of simultaneously detected plasma and serum cytokine levels in asymptomatic subjects.

Blood levels of cyto- and chemokines might reflect immune deregulations which might be related to lymphomagenesis. Potential utility of stored blood samples of a prospective cohort was evaluated by the effect of different blood sample types and freeze-thaw cycles on analyte levels. Bead-based immunoassays were performed on two fresh samples (serum, citrate and heparin plasma) of 10 asymptomatic adults collected 14 days apart and on aliquots of the first samples which were put through one to three freeze-thaw cycles to measure 11 cytokines, four chemokines and two adhesion molecules. Median coefficients of variation (CVs) of the measured analytes were 20%, 24% and 32% in serum, citrate and heparin plasma, respectively. Strong correlations (rank correlation coefficient 0.74-0.98) were observed between sample types, although small differences in analyte levels were observed for most analytes. Freeze-thaw cycles did not markedly change analyte levels. Our study supports the use of this assay among asymptomatic subjects in epidemiological studies.

Associations between pre-employment immunologic and airway mucosal factors and the development of occupational allergy.

BACKGROUND: Sensitization to occupational allergens is frequently found in laboratory animal workers (LAWs) and can cause serious health problems. Atopy is a major risk factor for sensitization, but it is considered insufficient to advise against working with animals. OBJECTIVE: We investigated whether immunologic measures, including serology and cytokine production profiles of blood cells, and parameters for airway inflammation are associated with the development of occupational sensitization. METHODS: In a prospective cohort study 110 starting LAWs were followed for 2 years. At inclusion, results of health questionnaires, skin test results, lung function measures, methacholine threshold levels, and nasal lavage fluid were obtained. Blood was taken for measuring total IgE and allergen-specific IgE antibodies. Cytokine production profiles were measured in whole blood. RESULTS: Twenty-two new cases of sensitization were identified during follow-up. In multivariate logistic regression analysis a model including atopy and total IgE level predicted sensitization best. This was corroborated in a separate validation cohort. Parameters for airway inflammation or cytokine production profiles did not further contribute to the prediction of sensitization. Based on these results, pre-employment counseling aimed at applicant LAWs with atopy and a total IgE level of greater than 100 IU/mL might be able to reduce occupational sensitization by up to 45% to 50% with less than 10% false-positive predictions. CONCLUSION: The combination of atopy and total IgE level offered the best model to predict development of occupational sensitization. Other immunologic parameters and parameters of airway inflammation did not contribute significantly.