Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure

Background

Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.

Methods and Findings

We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.

Conclusions

We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.     

Nasal epithelium integrity, environmental stressors, and allergic sensitization: a biomarker study in adolescents

Changes in the airways epithelium caused by environmental insults might play a role in the development of allergic rhinitis. We measured albumin and Clara cell protein (CC16) in the nasal lavage fluid (NALF) from 474 adolescents (263 girls and 211 boys). The NALF CC16/albumin ratio, integrating the permeability and cellular integrity of the nasal epithelium, decreased mostly with time spent in chlorinated pools. In boys, a lower CC16/albumin ratio in NALF was associated with an increased risk of house dust mite sensitization. The results suggest that the CC16/albumin ratio in NALF can be used to detect nasal epithelium alterations linked to allergic sensitization.     

IFN-gamma-inducing factor (IL-18) increases allergic sensitization, serum IgE, Th2 cytokines, and airway eosinophilia in a mouse model of allergic asthma

We investigated the effects of IFN-gamma-inducing factor (IL-18) in a ragweed (RW) mouse model of allergic asthma. Administration of IL-18 in conjunction with allergic sensitization and challenge in wild-type, but not IFN-gamma -/- mice, inhibited the bronchoalveolar lavage (BAL) eosinophilia induced by RW challenge, and increased serum levels of RW-specific IgG2a and production of IFN-gamma from splenocytes cultured with RW, indicating a critical role for IFN-gamma in mediating these effects. Paradoxically, the same treatment schedule in WT mice increased serum levels of RW-specific IgE and IgG1, and production of IL-4 and IL-5 from splenocytes cultured with RW. When the effects of the same IL-18 treatment schedule were allowed to mature for 3 wk, the inhibition of lung eosinophil recruitment was replaced by augmentation of lung eosinophil recruitment. In another experiment, IL-18 administered only with allergic sensitization increased BAL eosinophilia and lung expression of IL-5 and IFN-gamma, while IL-18 administered only with RW challenge decreased BAL eosinophilia and increased lung IFN-gamma expression, while lung expression of IL-5 remained unchanged. IL-18 administered without RW or adjuvant to naive mice increased total serum IgE levels. Finally, intrapulmonary administrations of IL-18 plus RW in naive mice dramatically increased Th2 cytokine production, IgE levels, eosinophil recruitment, and airway mucus, demonstrating induction of allergic sensitization. This is the first report demonstrating that IL-18 promotes a Th2 phenotype in vivo, and potently induces allergic sensitization. These results suggest that IL-18 may contribute to the pathogenesis of allergic asthma.     

Social development of bonnet macaques from six months to three years of age: A longitudinal study

Observations of age-sex class associations of three young female and five young male bonnet macaques born in the spring, 1975, were taken semiannually over three years beginning in the fall, 1975. Analysis reveals several patterns: (1) both males and females show continuous decline in association with age mates; (2) solitary time of females peaks at 1.5 years after which they begin to associate with adult females; (3) solitary time of males peaks at 2.5 years after which they associate predominantly with sub-adult males; (4) both males and females showed higher association with juveniles of the same sex than of opposite sex; and (5) both males and females showed annual cycles of association with some age-sex classes. These results are best understood with reference to the natural breeding cycle of the animals and the different life histories of male and female macaques in the wild.     

Nasal epithelium integrity,environmental stressors,and allergic sensitization: A biomarker study in adolescents

Changes in the airways epithelium caused by environmental insults might play a role in the development of allergic rhinitis. We measured albumin and Clara cell protein (CC16) in the nasal lavage fluid (NALF) from 474 adolescents (263 girls and 211 boys). The NALF CC16/albumin ratio, integrating the permeability and cellular integrity of the nasal epithelium, decreased mostly with time spent in chlorinated pools. In boys, a lower CC16/albumin ratio in NALF was associated with an increased risk of house dust mite sensitization. The results suggest that the CC16/albumin ratio in NALF can be used to detect nasal epithelium alterations linked to allergic sensitization.     

Anthropometric data, proportion and form in children 2 to 5 years old--a longitudinal study

A longitudinal anthropometric study with integrated picture documentation was made in the German administrative district of Potsdam-Mittelmark from April 2002 until April 2003. During that time 183 children aged between 2 to 5 years were measured. The results of the study show, that with the help of the calculation method for pictures, presented here for the first time, additional information about the changes of proportions and body shape can be gained and made measurable. The aim of the study is to make use of the measureable individual changes in body shape for an objective estimation of the biological age. Being able to calculate the age of a child may be useful when investigating a crime, e. g. in case of an abused child, whose chronological age is unknown at the time of the incident, and the only possibility for an age-estimation depends on a picture.     

Subjective duration of every three-year period for 3 to 18 years of age, estimated by students

Results indicated that both subjective time durations, one day and three years, are well described by the normal distribution if the time scale is logarithmic rather than linear. A remarkable finding obtained here is that in reference to the mean subjective time duration of the junior high school (three years), the mean subjective time durations for each of the three-year periods before elementary school were significantly longer than unity (about 1.2), and the subjective duration of the three year period of the senior high school is significantly shorter (about 0.8). When subjects transferred to other elementary schools at 6 to 11 years of age, the mean subjective time duration of the periods below 11 years of age was much longer, more than 1.3.     

A metabolomic,geographic, and seasonal analysis of the contribution of pollen-derived adenosine to allergic sensitization

Background

Studies on ragweed and birch pollen extracts suggested that the adenosine content is an important factor in allergic sensitization. However, exposure levels from other pollens and considerations of geographic and seasonal factors have not been evaluated.

Objective

This study compared the metabolite profile of pollen species important for allergic disease, specifically measured the adenosine content, and evaluated exposure to pollen-derived adenosine.

Methods

An NMR metabolomics approach was used to measure metabolite concentrations in 26 pollen extracts. Pollen count data was analyzed from five cities to model exposure.

Results

A principal component analysis of the various metabolites identified by NMR showed that pollen extracts could be differentiated primarily by sugar content: glucose, fructose, sucrose, and myo-inositol. In extracts of 10 mg of pollen/ml, the adenosine was highest for grasses (45 µM) followed by trees (23 µM) and weeds (19 µM). Pollen count data showed that tree pollen was typically 5–10 times the amount of other pollens. At the daily peaks of tree, grass, and weed season the pollen-derived adenosine exposure per day is likely to be only 1.1, 0.11, and 0.12 µg, respectively. Seasonal models of pollen exposure and respiration suggest that it would be a rare event limited to tree pollen season for concentrations of pollen-derived adenosine to approach physiological levels.

Conclusion

Sugar content and other metabolites may be useful in classifying pollens. Unless other factors create localized exposures that are very different from these models, pollen-derived adenosine is unlikely to be a major factor in allergic sensitization.

     

Evidence for linkage of a new region (11p14) to eczema and allergic diseases

Asthma, allergic rhinitis (AR) and atopic dermatitis also called eczema are allergic co-morbidites, which are likely to depend on pleiotropic genetic effects as well as on specific genetic factors. After a previous genome-wide linkage screen conducted for asthma and AR in a sample of 295 French EGEA families ascertained through asthmatic subjects, the aim here was to search for genetic factors involved in eczema and more particularly the ones shared by the three allergic diseases using the same EGEA data. In this sake, eczema and phenotypes of “allergic disease” accounting for the joint information on the presence/absence of the three diseases were examined by linkage analyses using the maximum likelihood binomial method. A fine mapping was carried out in regions detected for potential linkage, followed by association studies using the family-based association test (FBAT). Evidence for linkage to 11p14 region was shown for “allergic disease” and eczema. Linkage was also indicated between eczema and 5q13 and between “allergic disease” and both 5p15 and 17q21 regions. Fine mapping supported the evidence of linkage to 11p14 and FBAT analyses showed the association between “allergic disease” and a marker located at the linkage peak on 11p14. Further investigations in this region will allow identifying genetic factor(s) which could have pleiotropic effect in the three allergic diseases.     

Prenatal influenza vaccination and allergic and autoimmune diseases in childhood: A longitudinal,population-based linked cohort study

BackgroundFew studies have evaluated the effect of maternal influenza vaccination on the development of allergic and autoimmune diseases in children beyond 6 months of age. We aimed to investigate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and subsequent diagnosis of allergic and autoimmune diseases.Methods and findingsThis longitudinal, population-based linked cohort study included 124,760 singleton, live-born children from 106,206 mothers in Western Australia (WA) born between April 2012 and July 2016, with up to 5 years of follow-up from birth. In our study cohort, 64,169 (51.4%) were male, 6,566 (5.3%) were Aboriginal and/or Torres Strait Islander children, and the mean age at the end of follow-up was 3.0 (standard deviation, 1.3) years. The exposure was receipt of seasonal IIV during pregnancy. The outcomes were diagnosis of an allergic or autoimmune disease, including asthma and anaphylaxis, identified from hospital and/or emergency department (ED) records. Inverse probability of treatment weights (IPTWs) accounted for baseline probability of vaccination by maternal age, Aboriginal and/or Torres Strait Islander status, socioeconomic status, body mass index, parity, medical conditions, pregnancy complications, prenatal smoking, and prenatal care. The models additionally adjusted for the Aboriginal and/or Torres Strait Islander status of the child. There were 14,396 (11.5%) maternally vaccinated children; 913 (6.3%) maternally vaccinated and 7,655 (6.9%) maternally unvaccinated children had a diagnosis of allergic or autoimmune disease, respectively. Overall, maternal influenza vaccination was not associated with diagnosis of an allergic or autoimmune disease (adjusted hazard ratio [aHR], 1.02; 95% confidence interval [CI], 0.95 to 1.09). In trimester-specific analyses, we identified a negative association between third trimester influenza vaccination and the diagnosis of asthma (n = 40; aHR, 0.70; 95% CI, 0.50 to 0.97) and anaphylaxis (n = 36; aHR, 0.67; 95% CI, 0.47 to 0.95).We did not capture outcomes diagnosed in a primary care setting; therefore, our findings are only generalizable to more severe events requiring hospitalization or presentation to the ED. Due to small cell sizes (i.e., <5), estimates could not be determined for all outcomes after stratification.ConclusionsIn this study, we observed no association between in utero exposure to influenza vaccine and diagnosis of allergic or autoimmune diseases. Although we identified a negative association of asthma and anaphylaxis diagnosis when seasonal IIV was administered later in pregnancy, additional studies are needed to confirm this. Overall, our findings support the safety of seasonal inactivated influenza vaccine during pregnancy in relation to allergic and autoimmune diseases in early childhood and support the continuation of current global maternal vaccine programs and policies.

Damien Foo and colleagues evaluate the association between prenatal influenza vaccination and diagnosis of allergic and autoimmune diseases in childhood.     

Gender-specific growth patterns for stature,sitting height and limbs length in Croatian children and youth (3 to 18 years of age)

In a cross-sectional study of growth, 5,155 children (2,591 females, 2,564 males) from the town of Zagreb (Croatia) were measured. Four traits of linear dimensionality (stature, sitting height, arm and leg lengths) were studied in the age span of 3 to 18 years. A significant average annual increase of all four anthropometric parameters were observed up to 14 and 15 years of age in girls and 16 years of age in boys, showing that girls had a shorter growing period. In the prepubertal period until 9 years of age, gender differences were negligible. At the age of 10, boys were overgrown by girls in all parameters due to the earlier onset of puberty in girls. The growth gains for girls, when compared with those for boys, show a different pattern across variables. The female growth advantage remained in a two years period for the limbs length, but in a three year period for stature and the longest, for 4 years, for sitting height. The male predominance in size had an onset at the age of 13 for the limbs and in the age of 14 for stature and sitting height. The patterns of sexual dimorphism in stature and sitting height during growing years are similar to those observed in other populations of Europe. Growth of Croatian children and youth is very similar to that of the tallest European populations.     

Greater severity of new onset asthma in allergic subjects who smoke: a 10-year longitudinal study

Background

Little is known about the association between cigarette smoking and asthma severity. We assessed smoking as a determinant of disease severity and control in a cohort of clinic-referred allergic subjects who developed new onset asthma.

Methods

Allergic rhinitis subjects with no asthma (n = 371) were followed-up for 10 years and routinely examined for asthma diagnosis. In those who developed asthma (n = 152), clinical severity and levels of asthma control were determined. Among these subjects, 74 (48.7%) were current smokers, 17 (11.2%) former smokers, and 61 (40.1%) never smokers.

Results

When comparing current or past smokers to never smokers they had a higher risk of severe asthma in the univariate analysis, which became non-significant in the multivariate analysis. On the other hand, the categories of pack-years were significantly related to severe asthma in a dose response relationship in both the univariate and multivariate analysis: compared to 0 pack years, those who smoked 1-10 pack-years had an OR(95% CI) of 1.47(0.46-4.68), those who smoked 11-20 pack-years had an OR of 2.85(1.09-7.46) and those who smoked more than 20 pack-years had an OR of 5.59(1.44-21.67) to develop more severe asthma. Smokers with asthma were also more likely to have uncontrolled disease. A significant dose-response relationship was observed for pack-years and uncontrolled asthma. Compared to 0 pack years, those who smoked 1-10 pack-years had an OR of 5.51(1.73-17.54) and those who smoked more than 10 pack-years had an OR of 13.38(4.57-39.19) to have uncontrolled asthma.

Conclusions

The current findings support the hypothesis that cigarette smoking is an important predictor of asthma severity and poor asthma control.     

Longitudinal study of anthropometric,skinfold, work,and motor characteristics of boys and girls,three to six years of age

Groups of preschool children were followed longitudinally: boys, n = 36, from 3.48 up to 6.02 years and girls, n = 22, from 3.53 up to 6.03 years. Anthropometric dimensions, skinfold thicknesses, reaction of the cardiovascular system to a work load (modified step test), motor performance, and hand grip strength were measured. Boys had greater values for height, weight, length, and circumferential measures, with the exception of the thigh. Boys had also smaller skinfolds and better performances in 20 meter dash, broad jump, cricket ball throw, and grip strength compared to girls. All anthropometric dimensions increased with age, but these increase did not have the same character. Children became more linear in spite of relatively greater increase in total body weight. Chest and abdomen circumferences increased more in boys during the last year of the study. Skinfold thicknesses decreased significantly in boys, and stayed the same in girls. Motor performance and muscle strength also increased during the experimental period. Pulse rate at rest, during modified step test and recovery period decreased with age, and the economy of cardiac work improved significantly as indicated by step test index and/or cardiac efficiency index. The changes derived from longitudinal observations corresponded to previous results of cross-sectional data.