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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 (OR Slope = 28, P trend = 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 ., (©2017 American Association for Cancer Research.)

We investigated the effect of weekends and school holidays on the daily frequency and severity of respiratory and other symptoms among children attending schools with (index) or without (reference) moisture damage in Spain, the Netherlands, and Finland. Throughout 1 year, parents of 419 children with a respiratory condition attending index (n=15) or reference (n=10) primary schools completed three symptom diaries. We assessed associations between lower respiratory tract, upper respiratory tract or allergy, and other symptom scores and school day, weekend, or summer holiday using mixed regression models stratified by country and moisture damage. We evaluated interactions between moisture damage and type of day. We combined country-specific estimates (incidence rate ratios [IRRs] and 95% confidence interval [CI]) in meta-analyses. Symptom scores were lower during weekends and holiday. Lower respiratory tract symptoms were statistically significantly less common during holiday with strongest effect in index schools (IRR=0.7; CI=0.6-0.8). Reporting of other symptoms was more reduced during holiday in index (IRR=0.6; CI=0.4-0.9) than in reference (IRR=0.95; CI=0.8-1.2) schools (interaction P<.01). In conclusion, symptoms were less frequent and/or severe during summer holiday and weekends. This pattern was stronger among children attending moisture-damaged schools, suggesting potential improvement in moisture damage-related symptoms during school breaks., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A high prevalence of contact dermatitis (CD) and respiratory symptoms has been observed in the construction industry, probably due to widespread exposure to irritants and allergens. It is unknown whether carriers of loss-of-function mutations in the gene encoding filaggrin (FLG), a known risk gene for eczema and asthma, are at increased risk., Objectives: To investigate associations of FLG mutations with CD and respiratory symptoms in Dutch construction workers., Methods: A questionnaire including items on dermal and respiratory symptoms such as wheeze, shortness of breath and asthma was administered to construction workers. Total and specific serum IgE was analysed by enzyme immunoassays. Four FLG loss-of-function mutations were genotyped. CD was diagnosed by a team of a dermatologist and a clinical occupational medicine specialist using photographs of the subjects' hands and self-reported questionnaire data., Results: Of the 506 participating workers, 6·3% carried at least one FLG mutation. Mild CD was diagnosed by the specialists in 34·0%, and severe CD in an additional 24·3%. CD was considered work related in 282 of 295 subjects (95·6%). Carriers of FLG variants had an increased risk of CD compared with subjects carrying wild-type alleles [mild CD: odds ratio (OR) 5·71, 95% confidence interval (CI) 1·63-20·06; severe CD: OR 8·26, 95% CI 2·32-29·39]. FLG variants and the presence of CD were not associated with respiratory symptoms and atopy., Conclusions: Contact dermatitis prevalence in construction workers is high. FLG loss-of-function mutations increase the risk of CD even further. FLG mutations were not associated with respiratory symptoms or atopy., (© 2015 British Association of Dermatologists.)

Background: Allergies arise from aberrant Th2 responses to allergens. The processes involved in the genesis of allergic sensitization remain elusive. Some allergens such as derived from house dust mites have proteolytic activity which can induce oxidative stress in vivo. A reduced capacity of the host to control oxidative stress might prime for allergic sensitization., Methods: Two different strains of mice were compared for their antioxidant and immune response to HDM. Protease activity of the HDM extract was reduced to investigate its role in oxidative stress induction in the airways and whether this induction could determine allergic sensitization and inflammation. The role of oxidative stress in allergic sensitization was also investigated in humans. An occupational cohort of animal workers was followed for the development of sensitization to rodent urinary proteins. Levels of oxidative stress in serum and antioxidant responses by PBMCs were determined., Results: Susceptibility to allergic sensitization to mite allergens in mice was highly dependent on host genetic background and was associated with oxidative stress in the lungs before allergen exposure and poor antioxidant response after allergen exposure. Reduction in mite protease activity limited its capacity to induce oxidative stress and allergic inflammation in mice. We showed that also in human subjects, oxidative stress before allergen exposure and poor antioxidant responses were associated with predisposition to occupational allergy., Conclusion: Our study indicates that oxidative stress condition before allergen exposure due to an inadequate antioxidant response may prime for allergic Th2 responses., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Indoor exposure to microbial agents is known to influence respiratory health. Besides home exposure, exposure in schools can affect respiratory health. In this study, we measured endotoxin in settled dust in primary schools in three European countries from three different geographical regions with different climates. Our aim was to characterize endotoxin levels in primary schools and evaluate associations with potential determinants. Endotoxin levels were repeatedly assessed in 23 schools in Spain (n = 7), the Netherlands (n = 10), and Finland (n = 6) using electrostatic dustfall collectors. In total, 645 measurements were taken in 237 classrooms. Endotoxin levels differed significantly between countries; Dutch schools had the highest levels, while Finnish schools showed the lowest levels. In each country, differences in endotoxin levels were observed between schools and over the sampling periods. Estimates improved after adjustment for sampling period. Factors affecting endotoxin levels in a school differed per country. In general, endotoxin levels were higher in lower grades and in classrooms with higher occupancy. School endotoxin levels may contribute significantly to total endotoxin exposure in children and teachers. As the correlation between the repeated measurements is reasonable, single endotoxin measurements form a reasonable basis for estimating annual endotoxin levels in schools., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 β-(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 β-(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 β-(1,3)-glucans were also approximately two times higher in schools than in homes., Conclusion: Exposure levels of several allergens and β-(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.

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.

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.

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., (Copyright © 2012. Published by Elsevier B.V.)

Unlabelled: The aim of this study was to assess occurrence of dampness and mold in school buildings in three European countries (the Netherlands, Spain, and Finland), representing different climatic regions. An assessment was performed utilizing both questionnaires and on-site building investigations, and the agreement between these two methods was evaluated for validation purposes. On the basis of questionnaire data from a representative sample of schools, different types of moisture problems were reported in 24-47% of all school buildings at the time of the study. Most commonly reported was dampness in the Netherlands, moisture/water damage in Spain, and mold odor in Finland. Subsequently, 20-24 schools per country were selected for on-site inspections by trained staff. The overall agreement between the questionnaire and inspection data was good (kappa-value 0.62), however, with large differences (0.39-0.91) between countries. Extrapolating from the inspection data, the minimum estimates for prevalence of moisture problems in school buildings are 20% in the Netherlands, 41% in Spain, and 24% in Finland. In conclusion, moisture problems (such as moisture damage, dampness, and mold) are relatively common in schools. The occurrence and severity may vary across geographical areas, which can be partly explained by building characteristics., Practical Implications: On the basis of this study, the prevalence of verified moisture problems in school buildings was highest in Spain, but lower and similar in Finland and the Netherlands. Questionnaire-based surveys can be used to assess moisture problems in school buildings, but because of large variation in agreement with inspection data, the questionnaire needs to be validated by on-site inspections in a subsample of the surveyed buildings., (© 2012 John Wiley & Sons A/S.)

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.

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.", (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Associations between acute respiratory inflammatory responses, changes in bronchial hyperresponsiveness, serum pneumoprotein levels, and exposure to fire smoke were studied., Methods: The study comprised 51 firefighters. Blood samples were taken within 24 hr following exposure to fire smoke, and after a week and 3 months. Sputum was induced within 5 days post-exposure and subjects underwent spirometry and methacholine provocation one week post-exposure. Exposure was registered by a questionnaire., Results: No changes were observed following smoke exposure in bronchial hyperresponsiveness and serum pneumoprotein levels. Nevertheless, in a sizable proportion of the firefighters (44%) elevated sputum neutrophil levels (≥60%) were found. Serum IL-8 concentrations were higher 24 hr post-exposure compared to pre-exposure. Elevated neutrophil levels in sputum were associated with elevated serum IL-8 (β = 0.010, P = 0.004) and TNFα (β = 0.005, P = 0.034) levels within 24 hr post-exposure and IL-8 elevation lasted up to 3 months., Conclusions: Acute exposure to fire smoke induces acute neutrophilic airway and long-lasting systemic inflammation in healthy firefighters in the absence of bronchial hyperresponsiveness., (Copyright © 2011 Wiley Periodicals, Inc.)

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.

Background: The modified Th2 response, defined as an IgG4 response in the absence of IgE, is suggested to protect against the development of allergic sensitization. However, studies suggesting this protective effect all had a cross-sectional design, making it impossible to study the development of both responses., Aim of the Study: We aimed to study the dynamics in IgG4 antibodies in relation to allergic sensitization in an occupational cohort of starting laboratory animal workers. Moreover, we studied the relation between exposure, antibody responses, atopy and self reported allergic symptoms., Methods: A total of 110 starting animal workers were followed for 2 years. IgG4 antibodies against rats and mice were assessed. Workers were tested for allergic sensitization and exposure to animal allergens was estimated. Symptom status was assessed using questionnaires., Results: Rat and mouse specific IgG4 antibodies were present before the development of allergy and did not significantly change over time. Allergic sensitization was related to exposure and atopic status but high levels of IgG4 showed no protective effect. In contrary, workers that developed mouse specific sensitization during follow up had higher levels of mouse specific IgG4. Symptoms were related to allergic sensitization and IgG4 levels did not influence that relationship., Conclusions: IgG4 antibodies are present before IgE antibodies develop and IgG4 levels are stable over time. In our occupational cohort, the modified Th2 response had no protective effect on development of sensitization or allergic symptoms., (© 2010 John Wiley & Sons A/S.)

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.

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 (

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.

Not everyone exposed to endotoxin develops respiratory symptoms, even at very high exposure levels. The aim was to investigate whether ex vivo lipopolysaccharide (LPS)-induced cytokine release may be predictive of individual sensitivity to occupational endotoxin exposure. In 412 agricultural workers, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-10 release was measured in supernatants from LPS-stimulated whole blood, lung function was measured, and respiratory symptoms were assessed by questionnaire. For each cytokine, the population was dichotomised into low and high responders according to median cytokine concentrations. Endotoxin exposure levels were determined based on 249 personal exposure measurements. High IL-10 responders had a higher prevalence of airway symptoms than low IL-10 responders (odds ratios between 2.03 and 5.10; p<0.05). TNF-alpha response was positively, but not significantly, associated with symptoms, whereas no relationship was found between IL-1beta response and symptoms. For all three cytokines, subjects with above-median responses showed significant positive dose-response relationships between endotoxin exposure and asthma symptoms, and significant associations between endotoxin exposure and a lower forced expiratory volume in 1 s (p<0.05). In contrast, exposure-response relationships were weak and statistically nonsignificant for low responders. The ex vivo inflammatory response to LPS reflects, to a large extent, whether individuals are susceptible to adverse respiratory effects induced by high occupational endotoxin exposure.

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.

Background: Family members of laboratory animal workers are at risk of developing allergy to laboratory animals. Little is known about the spreading of laboratory animal allergens outside the animal facilities., Objective: To assess the presence of laboratory animal allergens in dust collected from mattresses of laboratory animal workers and unexposed controls., Methods: Mouse and rat urinary proteins were measured in samples of mattress dust collected by laboratory animal workers and unexposed controls. In addition, rat and mouse allergens were determined in extracts of hair-covering caps, used during laboratory animal work, to estimate spreading of allergen through dust captured on hair. Allergen concentrations on hair caps were compared with exposure measured by personal airborne dust sampling., Results: Levels of rat urinary allergens (RUA) and mouse urinary allergens (MUA) and mouse urinary protein (MUP) 8, a specific pheromone-binding mouse allergen, were significantly higher in mattress samples of laboratory animal workers than in those of controls. Hair-covering caps used in animal facilities harboured large amounts of RUA and MUA, which correlated significantly with exposure measured by the personal sampling technique in the animal facility., Conclusions: Occupational laboratory animal allergens are detectable in mattress dust of laboratory animal workers. Transfer of allergens via uncovered hair of animal workers is likely contributing to this phenomenon. This study stresses the importance of using hair caps to prevent spreading of occupational allergens.

Background: Recombinant allergens are preferred over natural allergen extracts in measuring antibodies. We tested the use of recombinant variants of the major mouse allergen Mus m 1 in detection of mouse-specific antibodies in sera of laboratory animal workers and children., Methods: Six recombinant major urinary proteins (MUPs) were produced and antibody-binding capacity was compared to natural Mus m 1 and to mouse urine extract. In a specific subset, cross-reactivity of MUP with Mus m 1 and between the different recombinant MUPs was determined., Results: For IgE antibodies, MUP8 showed high cross-reactivity with Mus m 1. MUP8-specific IgE was found in 55% of the mouse urine IgE-positive sera. Specific IgG and IgG4 antibodies against natural Mus m 1 correlated strongly with antibodies against recombinant MUP8 and were cross-reactive. IgG4 levels against MUP8 and mouse urine extract correlated, but detection of mouse urine-specific IgG4 in the absence of MUP-specific IgG4 was not uncommon. Cross-reactivity of IgG antibodies between MUP8 and Mus m 1 as well as between the different MUPs was high and inhibition varied between 54 and 99%., Conclusion: The mouse allergen Mus m 1 can be replaced in antibody testing by recombinant MUP8. Other MUPs, except MUP4, are interchangeable with MUP8. However, mouse urine extract showed better detection of both mouse-specific IgE and IgG4 levels. Other components in the mouse urine, like mouse albumin and other yet unidentified components, also induce IgE and IgG4 antibodies., (Copyright 2007 S. Karger AG, Basel.)

Background: High serum levels of cat-specific IgG and IgG4 are associated with protection against allergic sensitization to cat, but whether this association applies to other animal allergens remains unclear., Objective: To determine if high levels of mouse-specific IgG and IgG4 are associated with a decreased risk of mouse skin test sensitivity., Methods: Two hundred and sixty workers of a mouse facility underwent skin prick testing and completed a questionnaire. Serum levels of mouse-specific IgG and IgG4 were quantified by solid-phase antigen binding assays. Room air samples were collected and airborne Mus m 1 was quantified by ELISA., Results: Forty-nine participants had a positive skin prick test to mouse. Mouse-specific IgG was detected in 219 (84%) participants and IgG4 was detected in 72 (28%) participants. A detectable mouse-specific IgG4 level was associated with an increased risk of mouse skin test sensitivity (odds ratios (OR) 6.4, 95% confidence intervals (CI) 3.3-12.4). Mouse-specific IgG and IgG4 were both positively correlated with mouse allergen exposure (r(s)=0.31, P=0.0001, and r(s)=0.27, P=0.0006, respectively). The odds of skin test sensitivity peaked at moderate levels of IgG4, but decreased at the highest levels of mouse-specific IgG4. In contrast, the odds of skin test sensitivity increased monotonically with IgG levels., Conclusions: A detectable level of mouse-specific IgG4 is associated with an increased risk of skin test sensitivity to mouse. However, the highest IgG4 levels appear to be associated with an attenuated risk of mouse skin test sensitivity, suggesting that induction of high levels of IgG4 through natural exposure may protect against the development of allergic sensitization.

Background: Production of both antigen-specific immunoglobulin (Ig)E and IgG4 antibodies is dependent on stimulation of B cells by T helper 2 cell-derived cytokines. However, there is controversy as to their interaction. In this study, we investigated the interdependency of IgE and IgG4 antibody responses to a relatively high range of airway exposure to animal-derived proteins in an occupational setting. Moreover, associations with self-reported airway symptoms and bronchial hyperresponsiveness were established., Methods: In a cross-sectional design, employees of an animal plasma spray-drying factory were questioned about airway symptoms, exposure was measured with personal sampling technique, and serology was performed. In a selection of subjects from this population, serology was repeated 15 months later, and bronchial hyperresponsiveness was measured., Results: IgE and IgG4 antibodies were detected in 17 and 57% of all employees and were both associated with degree of exposure. Only IgE antibodies showed an independent association with self-reported airway symptoms and bronchial hyperresponsiveness. The presence of IgE antibodies was limited to employees with high levels of IgG4. Employees with IgE and symptoms appeared to have less IgG4 than asymptomatic IgE-positive individuals. The level of specific IgG4 antibodies was stable over a 15-month period., Conclusions: In high-range airway exposure, development of IgE and IgG4 antibodies depended on the level of exposure. The threshold for development of IgG4 antibodies appeared to be less than that for IgE antibodies, and IgG4 antibodies may protect against the development of symptoms., (Copyright (c) 2006 S. Karger AG, Basel.)

Background: High levels of allergen-specific IgG have been associated with clinical efficacy in immunotherapy studies, but whether this antibody isotype is associated with clinical tolerance in the setting of environmental exposure remains unclear., Objective: To determine if mouse allergen-specific IgG (mIgG) and IgG4 (mIgG4) levels are associated with mouse-related symptoms among IgE-sensitized laboratory workers., Methods: Fifty-eight workers with either skin test or serologic evidence of IgE-mediated mouse sensitization were studied. Symptom data were obtained by a questionnaire. Serum levels of mouse-specific IgG, IgG4, and IgE were quantified by a solid-phase antigen-binding assay (IgG) and RAST (IgG4 and IgE), and the relationships between mouse-specific serologic responses and mouse-related symptoms were analysed., Results: Twenty-three (39.7%) participants reported mouse-related symptoms. Mouse-specific IgG and IgG4 levels were not associated with mouse-related symptoms among the study population as a whole. Among the 29 (50%) participants with detectable mouse-specific IgE (mIgE), higher mouse-specific IgG and IgG4 levels were associated with a decreased risk of symptoms, after adjusting for mIgE level (odds ratio (OR) 0.3, 95% confidence interval (CI): 0.1-1.4, and OR 0.3, 95% CI: 0.04-2.6, respectively). Higher levels of mIgG and mIgG4 remained associated with a decreased risk of symptoms after additional adjustment for sex and handling of mice (OR 0.1, 95% CI: 0.02-0.7, and OR 0.2, 95% CI: 0.02-2.1, respectively). Higher mIgG : IgE and mIgG4 : IgE ratios were also associated with a decreased risk of symptoms after adjusting for these confounders (OR 0.1, 95% CI: 0.02-0.7, and OR 0.2, 95% CI: 0.02-0.92, respectively)., Conclusion: Among workers with detectable mIgE, higher mIgG and mIgG4 levels are associated with a decreased risk of mouse-related symptoms. High serum levels of mIgG or mIgG4 may be markers for clinical tolerance among laboratory mouse workers with detectable mIgE, but these findings need to be confirmed in larger, prospective studies.

Background: There is evidence that surfactant protein (SP)-D is important in the innate, as well as in the adaptive pulmonary immune response. Serum concentrations of SP-D have been proposed as parameter of the integrity of the blood-airspace barrier in interstitial lung diseases. We hypothesized that serum SP-D concentrations are affected in allergic patients and correlate with changes in allergic airway inflammation., Objective: To determine levels of serum SP-D in allergic patients compared with non-allergic controls. Furthermore, to investigate associations between serum SP-D concentrations on the one hand and changes in commonly used markers of bronchial inflammation in allergic airways disease on the other hand., Materials and Methods: Fifty allergic patients were studied and bronchial allergen challenge was used as a model to increase bronchial allergic inflammation in these patients. Serum SP-D concentrations, inflammatory parameters in induced sputum and bronchial hyper-responsiveness (BHR) were determined before and after allergen challenge. Twenty-five non-allergic volunteers served as controls., Results: Baseline serum SP-D was significantly higher in allergic patients as compared with controls (mean serum SP-D concentration (95% confidence interval): 62.7 (55.5, 70.0) in allergic patients vs. 49.5 (36.7, 62.3) ng/mL in non-allergic controls, P=0.006). In addition, baseline serum SP-D appeared to be an independent predictor for the magnitude of the late asthmatic response after allergen challenge. Furthermore, serum SP-D was predictive for the sputum eosinophil cationic protein concentration after allergen challenge., Conclusion: We propose that serum SP-D concentrations are associated with allergic bronchial inflammation and may give additional information, beside BHR and sputum eosinophils, about the degree of bronchial inflammation in allergic patients.

Background: Although there is evidence that contact with mice is associated with IgE-mediated mouse sensitization and mouse specific antibody responses, the exposure-response relationships remain unclear., Objective: To determine whether IgE-mediated mouse sensitization and mouse specific IgG (mIgG) and mIgG4 levels increase with increasing Mus m 1 exposure., Methods: One hundred fifty-one workers at a mouse research and production facility were studied. Exposure assignments were made by linking participants to airborne Mus m 1 concentrations in their respective work areas. Cumulative exposure was estimated by multiplying airborne Mus m 1 concentration by duration of employment. Serum mIgG and mIgG4 levels were quantified by antigen-binding assays, and IgE-mediated mouse sensitization was evaluated by skin prick testing (SPT)., Results: Prevalence rates of mouse SPT sensitivity and of high levels of mIgG and mIgG4 were increasingly higher by quintiles of increasing cumulative exposure (P < .01 for SPT, mIgG, and mIgG4). After adjusting for age, sex, and atopy, the log odds ratio (OR) of having positive mouse SPT results was linearly related to cumulative exposure (r2 = 0.87), as was the log OR of having a high mIgG level (r2 = 0.86). Quintile of cumulative exposure was an independent predictor of both SPT sensitivity (OR, 1.7; 95% confidence interval, 1.2-2.5) and a high mIgG level (OR, 1.7; 95% confidence interval, 1.2-2.4)., Conclusions: IgE-mediated mouse sensitization and mIgG and mIgG4 levels were related to cumulative exposure in a dose-dependent manner. Thus, strategies to prevent allergy to mice should remain focused on reducing mouse allergen exposure.