Byoung-Ju Kim

Asthma Prevention by Lactobacillus Rhamnosus in a Mouse Model is Associated With CD4+CD25+Foxp3+ T Cells

Purpose Probiotic bacteria can induce immune regulation or immune tolerance in allergic diseases. The underlying mechanisms have been recently investigated, but are still unclear. The aim of this study was to evaluate the protective effects of the probiotic Lactobacillus rhamnosus (Lcr35) in a mouse model of asthma and to identify its mechanism of action. Methods Lcr35 was administered daily by the oral route at a dosage of 1×109 CFU/mouse in BALB/c mice for 7 days before the first sensitization. Clinical parameters and regulatory T (Treg) cells were examined. The role of CD4+CD25+Foxp3+ Treg cells was analyzed using a Treg cell-depleting anti-CD25 monoclonal antibody (mAb). Results Airway hyperresponsiveness, total IgE production, pulmonary eosinophilic inflammation, and splenic lymphocyte proliferation were suppressed after Lcr35 treatment. Th1 (IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines in the serum were suppressed, and the percentage of CD4+CD25+Foxp3+ Treg cells in the spleen was significantly increased in the Lcr35 treatment group. Anti-CD25 mAb administration abolished the protective effects of Lcr35, indicating that CD4+ CD25+Foxp3+ Treg cells are essential in mediating the activity of Lcr35. Conclusions Oral administration of Lcr35 attenuated the features of allergic asthma in a mouse model and induced immune regulation by a CD4+CD25+Foxp3+ Treg cell-mediated mechanism.

Association of ozone exposure with asthma, allergic rhinitis, and allergic sensitization

BACKGROUND Children are vulnerable to air pollution, which is known to be related to the recent increasing trend of allergic disease. OBJECTIVE To investigate the effects of air pollution on respiratory allergic diseases in school children. METHODS A prospective survey of parental responses to International Study of Asthma and Allergies in Childhood questionnaires, together with allergy evaluation, was conducted in 1743 school children selected from metropolitan cities and industrial areas during a 2-year period. Individual exposure to air pollution was estimated by using a geometric information system with the 5-year mean concentration of air pollutants. RESULTS A total of 1,340 children (male:female ratio, 51.4:48.6) with a mean (SD) age of 6.84 (0.51) years were included in the analysis. Each child underwent allergy evaluation at the time of enrollment and at a 2-year follow-up. After 2 years, the 12-month prevalence of wheezing was significantly decreased, whereas the lifetime prevalence of allergic rhinitis showed a significant increase. Ozone exposure was significantly associated with the 12-month prevalence of wheeze (odds ratio per 5 ppb, 1.372; 95% confidence interval, 1.016-1.852). Ozone was also associated with allergic rhinitis in children who reside in industrial areas. In addition, significant positive associations between ozone and the rate of newly developed sensitization to outdoor allergen were found (P for trend = .007). CONCLUSION Exposure to ozone was associated with current wheeze and allergic rhinitis. An increased rate of newly developed sensitization to outdoor allergen by ozone may explain the association.

The Effects of Lactobacillus rhamnosus on the Prevention of Asthma in a Murine Model

Purpose Lactobacilli are probiotic bacteria that are effective in the management of allergic diseases or gastroenteritis. It is hypothesized that such probiotics have immunoregulatory properties and promote mucosal tolerance. Our goal was to investigate whether Lactobacillus casei rhamnosus Lcr35 could inhibit airway inflammation in an ovalbumin (OVA)-induced murine model of asthma. Methods BALB/c mice aged 6 weeks were used in the present study. Lactobacillus casei rhamnosus Lcr35 was administered daily, starting 1 week prior to the first OVA sensitization (group 1) and 2 days before the first 1% OVA airway challenge (group 2). Mice that received only saline at both sensitization and airway challenge time points were used as negative controls (group 3), and those that had OVA-induced asthma were used as positive controls (group 4). Airway responsiveness to methacholine was assessed, and bronchoalveolar lavage (BAL) was performed. At the endpoint of the study, total IgE as well as OVA-specific IgE, IgG1 and IgG2a in serum was measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. Results Airway hyperresponsiveness, total cell counts and the proportion of eosinophils in BAL fluid were significantly decreased in group 1 compared with group 4 (P<0.05). Total serum IgE levels were also significantly decreased in group 1 compared with group 4. Serum levels of OVA-specific IgE, IgG1 and IgG2a were not significantly influenced by treatment with Lcr35. There was significantly less peribronchial and perivascular infiltration of inflammatory cells in group 1 compared with group 4; however, there were no significant differences in methacholine challenge, BAL, serology or histology between groups 2 and 4. Conclusions Oral treatment with Lcr35 prior to sensitization can attenuate airway inflammation and hyperreactivity in a mouse model of allergic airway inflammation. These results suggest that Lcr35 may have potential for preventing asthma.

Interaction between IL13 genotype and environmental factors in the risk for allergic rhinitis in Korean children

BACKGROUND The prevalence of allergic rhinitis (AR) is increasing worldwide. Allergic diseases develop in susceptible subjects when they are exposed to specific environmental factors. OBJECTIVE We analyzed changes in the prevalence of AR and identified genetic and environmental factors in early childhood that affect risk. METHODS We used the International Study of Asthma and Allergies in Childhood questionnaire to collect data on AR, allergies, and environmental exposures from 4554 elementary school students from 5 areas of Seoul, Korea, in 2008. We also obtained DNA from 1050 subjects from 1 area of Seoul for genotype analysis of IL13. RESULTS We identified genetic and environmental factors during infancy and early childhood that increased the risk for current AR (resulting in a diagnosis of AR and AR symptoms in the past 12 months) in elementary school-aged children. These included allergic disease in parents and antibiotic use in infants, allergic disease in parents and exposure of infants to mold, and allergic disease in parents and moving an infant to a newly built house. The risk of current AR also increased in subjects with GA or AA at nucleotide 2044 in IL13 who had been exposed to mold in the home during infancy (adjusted odds ratio, 3.27; 95% CI, 1.75-6.11) compared with subjects who had GG at this position and had not been exposed to mold (adjusted odds ratio, 3.27; 95% CI, 1.75-6.11). CONCLUSION The prevalence of AR is increasing in Korean children. Children with a family history of allergic disease and exposure to specific environmental risk factors during infancy are more likely to have AR. Children with GA or AA at IL13(+2044) are at increased risk for AR when exposed to mold in the home during the first year of life.

Association of IL-13 polymorphisms with leukotriene receptor antagonist drug responsiveness in Korean children with exercise-induced bronchoconstriction.

Background IL-13 is a pivotal cytokine in allergic inflammation and bronchial hyperresponsiveness, and is known to influence leukotriene levels. Objective We investigated whether IL-13 polymorphisms may be associated with clinical phenotypes and drug responsiveness to the leukotriene receptor antagonist (LTRA) in Korean asthmatic children with exercise-induced bronchoconstriction (EIB). Methods We enrolled 242 normal controls and 374 patients with asthma. Of the asthmatic patients, 100 performed exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks and included 80 subjects in drug responsiveness analysis. We assessed IL-13 polymorphisms (−1512A/C, −1112C/T, +2044G/A) through PCR–restriction fragment length polymorphism analysis. Results Significantly higher total IgE levels and maximum percent fall in forced expiratory volume in 1 s (FEV1) (%) after exercise challenge test were found in asthmatic patients carrying one or two copies of the IL-13 +2044A versus those homozygous for +2044G (P=0.011 and 0.040, respectively). We further noted a correlation of total IgE with maximum percent fall in FEV1 (%) in asthmatic patients, as well as a reverse correlation with improvement of maximum percent fall in FEV1 (%) after exercise challenge tests. Finally, we observed a significant association between responsiveness to montelukast and IL-13 −1112C/T polymorphism and the haplotype of IL-13 polymorphisms. Conclusion The IL-13 +2044G/A polymorphism may be associated with atopy and EIB severity in Korean children with EIB, and thus could potentially be considered as a disease-modifying gene. Moreover, the IL-13 −1112C/T polymorphism and the haplotype of IL-13 polymorphisms seem to be associated with LTRA drug responsiveness, and thus might prove useful as a target for modulation of LTRA drug responsiveness.

Inhalation Toxicity of Humidifier Disinfectants as a Risk Factor of Children's Interstitial Lung Disease in Korea: A Case-Control Study

Background The occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD. Methods This retrospective, 1∶3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire. Results The median age of the affected children (43.8% male) was 26 months (18.25–36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.41–5.90, P = 0.00) were independently associated with an increased risk. Conclusions This study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals.

Exposure to Gene-Environment Interactions before 1 Year of Age May Favor the Development of Atopic Dermatitis

Background: The aims of this study were to determine (1) the prevalence of atopic dermatitis (AD) in Seoul, Korea, and (2) the influence of environmental and genetic factors on disease risk. Methods: A questionnaire survey was conducted in 5,036 primary school children and 4,607 middle school children in 2008. For each child, a modified version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and a questionnaire assessing exposure to environmental variables were completed. Results: In primary school children, the lifetime prevalence of itchy eczema was 24.3%, the 12-month prevalence of itchy flexural eczema was 18.0%, the lifetime prevalence of AD diagnosis was 31.3%, and the 12-month prevalence of AD treatment was 14.5%. In middle school children, the corresponding rates were 16.0, 10.8, 22.1, and 8.3%, respectively. These rates are significantly higher than those reported in similar studies conducted in 1995 and 2000. In both primary and middle school children, a parental history of allergic disease and a history of having moved into a newly built house before 1 year of age were independently associated with a risk for current AD. For current AD, the prevalence odds ratio was higher in the subgroup with both a genetic and a specific environmental risk factor than in the subgroup with no risk factor or subgroups with only one risk factor. Conclusions: The prevalence of AD in primary and middle school children in Seoul has increased. Its development may be influenced by gene-environment interactions, particularly before 1 year of age.

Polymorphisms in GSDMA and GSDMB are associated with asthma susceptibility, atopy and BHR.

The gasdermin A (GSDMA) and gasdermin B (GSDMB) genes are located at 17q21.2. The GSDM family genes have been studied in the gastrointestinal tract but recent reports suggest that GSDMB is associated with childhood asthma in several populations. We investigated the association of the GSDMA and GSDMB variants with asthma in Korean children, and to assess the effect of these variants on intermediate phenotypes of asthma. Asthmatic (n = 778) and normal (n = 522) children were enrolled and genotypes were determined using PCR‐RFLP. Asthma susceptibility was associated with GG of the GSDMA (rs7212938) and TT of GSDMB (rs7216389). And a combination of risk alleles of two polymorphisms was associated with asthma susceptibility and a frequency of those was higher in asthmatic children with increased levels of total IgE (aOR 1.77, 95% CI 1.15–2.72) and BHR (aOR 1.54, 95% CI 0.99–2.40) compared to normal. Also, we observed a significant association between haplotype of two polymorphisms and asthma susceptibility. The region including the GSDMA and GSDMB polymorphisms may be associated with asthma susceptibility and intermediate phenotypes of asthma, such as elevated IgE and BHR, in Korean children with asthma. These results strongly support an important role for the GSDMA and GSDMB in the development of childhood asthma. Pediatr. Pulmonol. 2011; 46:701–708.

Ambient air pollution and allergic diseases in children

The prevalence of allergic diseases has increased worldwide, a phenomenon that can be largely attributed to environmental effects. Among environmental factors, air pollution due to traffic is thought to be a major threat to childhood health. Residing near busy roadways is associated with increased asthma hospitalization, decreased lung function, and increased prevalence and severity of wheezing and allergic rhinitis. Recently, prospective cohort studies using more accurate measurements of individual exposure to air pollution have been conducted and have provided definitive evidence of the impact of air pollution on allergic diseases. Particulate matter and ground-level ozone are the most frequent air pollutants that cause harmful effects, and the mechanisms underlying these effects may be related to oxidative stress. The reactive oxidative species produced in response to air pollutants can overwhelm the redox system and damage the cell wall, lipids, proteins, and DNA, leading to airway inflammation and hyper-reactivity. Pollutants may also cause harmful effects via epigenetic mechanisms, which control the expression of genes without changing the DNA sequence itself. These mechanisms are likely to be a target for the prevention of allergies. Further studies are necessary to identify children at risk and understand how these mechanisms regulate gene-environment interactions. This review provides an update of the current understanding on the impact of air pollution on allergic diseases in children and facilitates the integration of issues regarding air pollution and allergies into pediatric practices, with the goal of improving pediatric health.

The CCR5 (−2135C/T) Polymorphism may be Associated with the Development of Kawasaki Disease in Korean Children

BackgroundKawasaki disease (KD) is an acute vasculitis syndrome of unknown etiology that frequently affects small to medium size arteries. C-C chemokine receptor 5 (CCR5) is a chemokine receptor that binds C-C chemokines. This study investigated the association of the CCR5 (−2135C/T) polymorphism with KD in Korean children.MethodsThe study population consisted 189 Korean children with KD and 194 Korean children with congenital heart disease (CHD). CCR5 (−2135C/T) polymorphism genotypes were determined using the single-base extension method.ResultsThe allele frequencies of the CCR5 (−2135C/T) polymorphism differed significantly between CHD children and KD children (−2135T/T, 16.75% vs. 30.05%, aOR 2.14, 95% CI 1.31–3.51). The tested laboratory parameters differed significantly between the KD and CHD groups. The development of coronary artery aneurysm in KD patients was not associated with the CCR5 polymorphism.ConclusionsOur findings suggest that the T allele at the CCR5 (−2135C/T) polymorphism might be associated with the development of KD in Korean children but does not appear to be associated with the development of coronary artery aneurysm.