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2.  Seven Steps to the Diagnosis of NSAIDs Hypersensitivity: How to Apply a New Classification in Real Practice? 
Frequent use of non-steroidal anti-inflammatory drugs (NSAIDs) has been paralleled by increasing occurrence of adverse reactions, which vary from mild local skin rashes or gastric irritation to severe, generalized symptoms and even life-threatening anaphylaxis. NSAID-induced hypersensitivity reactions may involve both immunological and non-immunological mechanisms and should be differentiated from type A adverse reactions. Clinical diagnosis and effective management of a hypersensitive patient cannot be achieved without identifying the underlying mechanism. In this review, we discuss the current classification of NSAID-induced adverse reactions and propose a practical diagnostic algorithm that involves 7 steps leading to the determination of the type of NSAID-induced hypersensitivity and allows for proper patient management.
PMCID: PMC4446629  PMID: 25749768
Nonsteroidal anti-inflammatory drugs; NSAID-induced hypersensitivity; aspirin hypersensitivity; aspirin; drug allergy
3.  Local Immunoglobulin E in the Nasal Mucosa: Clinical Implications 
Immunoglobulin E (IgE) can be highly elevated in the airway mucosa independently of IgE serum levels and atopic status. Mostly, systemic markers are assessed to investigate inflammation in airway disease for research or clinical practice. A more accurate but more cumbersome approach to determine inflammation at the target organ would be to evaluate markers locally. We review evidence for local production of IgE in allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Diagnostic and therapeutic consequences in clinical practice are discussed. We describe that the airway mucosa has the intrinsic capability to produce IgE. Moreover, not only do IgE-positive B cells reside within the mucosa, but all tools are present locally for affinity maturation by somatic hypermutation (SHM), clonal expansion, and class switch recombination to IgE. Recognizing local IgE in the absence of systemic IgE has diagnostic and therapeutic consequences. Therefore, we emphasize the importance of local IgE in patients with a history of AR or CRSwNP.
PMCID: PMC4446630  PMID: 25749769
local IgE; allergic rhinitis; local allergic rhinitis; chronic rhinosinusitis with nasal polyps; diagnostics; treatment
4.  Diagnostic Decision Points of Specific IgE Concentrations in Korean Children With Egg and Cow's Milk Allergies 
The purpose of this study was to evaluate the utility of specific IgE (sIgE) concentrations for the diagnosis of immediate-type egg and cow's milk (CM) allergies in Korean children and to determine the optimal cutoff levels.
In this prospective study, children ≥12 months of age with suspected egg or CM allergy were enrolled. Food allergy was diagnosed by an open oral food challenge (OFC) or through the presence of a convincing history after ingestion of egg or CM. The cutoff levels of sIgE for egg white (EW) and CM were determined by analyzing the receiver operating characteristic curves.
Out of 273 children, 52 (19.0%) were confirmed to have egg allergy. CM allergy was found in 52 (23.1%) of 225 children. The EW-sIgE concentration indicating a positive predictive value (PPV) of >90% was 28.1 kU/L in children <24 months of age and 22.9 kU/L in those ≥24 months of age. For CM-sIgE, the concentration of 31.4 kU/L in children <24 months of age and 10.1 kU/L in those ≥24 months of age indicated a >90% PPV. EW-sIgE levels of 3.45 kU/L presented a negative predictive value (NPV) of 93.6% in children <24 months of age, while 1.80 kU/L in those ≥24 months of age presented a NPV of 99.2%. The CM-sIgE levels of 0.59 kU/L in children <24 months of age and 0.94 kU/L in those ≥24 months of age showed NPVs of 100% and 96.9%.
Our results indicate that different diagnostic decision points (DDPs) of sIgE levels should be used for the diagnosis of egg or CM allergy in Korean children. The data also suggest that DDPs with high PPV and high NPV are useful for determining whether OFC is required in children with suspected egg or CM allergy.
PMCID: PMC4446631  PMID: 25749781
Egg allergy; food allergy; milk allergy; specific IgE
5.  The Association of Lung Function, Bronchial Hyperresponsiveness, and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children 
Although many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA.
One hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5'-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured.
The AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only.
These findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR.
PMCID: PMC4446632  PMID: 25749776
Asthma; atopy; child; lung function, bronchial hyperresponsiveness; exhaled nitric oxide
6.  Distinct Inflammatory Profiles in Atopic and Nonatopic Patients With Chronic Rhinosinustis Accompanied by Nasal Polyps in Western China 
The role of systemic sensitization in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) remains elusive. This study sought to characterize the pattern of cytokines in polyp tissues from atopic and nonatopic patients with CRSwNP.
Atopic and nonatopic polyp and normal tissues were collected from 70 CRSwNP patients and 26 control subjects, respectively. The distribution of inflammatory cells (eosinophils, neutrophils, mast cells, etc.) were examined using immunohistochemistry, the mRNA levels of the transcription factors GATA-3, T-bet, RORc, and FOXP3 were determined using quantitative real-time polymerase chain reaction. The levels of inflammatory mediators (IFN-γ, IL-5, IL-17A, etc.) in tissue homogenates were measured using enzyme-linked immunosorbent assay (ELISA). Moreover, the levels of inflammatory mediators in the supernatant of anti-IgE stimulated polyp tissues were measured using ELISA.
Atopic CRSwNP patients were characterized by increased eosinophil accumulation, enhanced eosinophilic inflammation (elevated IL-5, ECP, and total IgE), and significantly increased GATA-3 mRNA levels (P<0.05), whereas both atopic and non-atopic CRSwNP patients showed decreased FOXP3 mRNA expression (P<0.05). After addition of anti-IgE stimulation, atopic CRSwNP patients produced more IL-5, IL-2, IL-10, IL-17A, and PGD2 in the supernatant of stimulated polyp tissues than nonatopic CRSwNP patients did.
Atopic and nonatopic CRSwNP patients may possess the patterns of inflammatory response in polyp tissues.
PMCID: PMC4446633  PMID: 25936910
Nasal polyps; chronic rhinosinusitis; atopy; cytokine; eosinophil; IgE
7.  Effect of Traffic-Related Air Pollution on Allergic Disease: Results of the Children's Health and Environmental Research 
This study evaluated the relationship of living near to main roads to allergic diseases, airway hyperresponsiveness (AHR), allergic sensitization, and lung function in Korean children.
A total of 5,443 children aged 6-14 years from 33 elementary schools in 10 cities during 2005-2006 were included in a baseline survey of the Children's Health and Environmental Research. We assessed association of traffic-related air pollution (TAP) exposure with the distance to the nearest main road, total road length of main roads and the proportion of the main road area within the 200-m home area.
Positive exposure-response relationships were found between the length of the main road within the 200-m home area and lifetime wheeze (adjusted prevalence ratio [PR] for comparison of the longest to the shortest length categories=1.24; 95% CIs, 1.04-1.47; P for trend=0.022) and diagnosed asthma (PR=1.42; 95% CIs, 1.08-1.86; P for trend=0.011). Living less than 75 m from the main road was significantly associated with lifetime allergic rhinitis (AR), past-year AR symptoms, diagnosed AR, and treated AR. The distance to the main road (P for trend=0.001), the length of the main road (P for trend=0.041), and the proportion of the main road area (P for trend=0.006) had an exposure-response relationship with allergic sensitization. A strong inverse association was observed between residential proximity to the main load and lung function, especially FEV1, FEV1/FVC, and FEF25-75. The length of the main road and the proportion of the main road area were associated with reduced FEV1 in schoolchildren.
The results of this study suggest that exposure to traffic-related air pollution may be associated with increased risk of asthma, AR, and allergic sensitization, and with reduced lung function in schoolchildren.
PMCID: PMC4446634  PMID: 25936911
Air pollution; asthma; allergic rhinitis; respiratory function tests; bronchial hyperreactivity; child
8.  TMEM16A-Mediated Mucin Secretion in IL-13-Induced Nasal Epithelial Cells From Chronic Rhinosinusitis Patients 
Chronic rhinosinusitis with nasal polyps (CRSwNP), a mainly Th2 cytokine-mediated disease, often involves mucus secretion. Recent evidence suggests that transmembrane protein 16A (TMEM16A), a calcium-activated Cl- channel (CaCC), can regulate mucus secretion from airway epithelium by transepithelial electrolyte transport and hydration. However, the role of TMEM16A in mucin production/secretion in the airway epithelium is not clear. This study was conducted to determine the role of TMEM16A in mediating mucin secretion in human nasal polyp epithelial cells (HNPECs) induced by IL-13.
Human sinonasal mucosa tissue and dissociated sinonasal epithelium from control subjects and patients with CRSwNP were assessed for the expression of TMEM16A and the secretion of human mucin 5AC (MUC5AC) by immunohistochemistry, Western blot analysis, and enzyme-linked immuno-sorbent assay (ELISA). A model of the Th2 inflammatory environment was created by exposure of primary air-liquid interface (ALI)-cultured HNPECs to interleukin-13 (IL-13) for 14 days, with subsequent assessment of TMEM16A expression in cell lysates by Western blotting and MUC5AC secretion in apical washings of cells by ELISA.
The expressions of TMEM16A and MUC5AC were increased in human nasal polyp tissue and dissociated nasal polyp epithelium. TMEM16A was detected in IL-13-treated HNPECs, specifically in MUC5AC-positive cells but not in ciliated cells. IL-13 treatment increased percentages of TMEM16A-positive cells, MUC5AC-positive cells, and cells coexpressing TMEM16A/MUC5AC, the expression of TMEM16A protein, and the secretion of MUC5AC. T16Ainh-A01, a TMEM16A inhibitor, attenuated these IL-13-induced effects.
The expression of TMEM16A and MUC5AC are increased in CRSwNP, which might be a direct effect of Th2 cytokines present in the sinonasal mucosa in CRSwNP. Down-regulation of TMEM16A expression and MUC5AC secretion in HNPECs by T16Ainh-A01 indicates that TMEM16A might play an important role in mucin secretion in upper airway inflammatory diseases.
PMCID: PMC4446635  PMID: 25749771
Chronic rhinosinusitis with nasal polyps; MUC5AC; mucin secretion; nasal epithelial cells; TMEM16A
9.  IgE-Binding Epitope Mapping and Tissue Localization of the Major American Cockroach Allergen Per a 2 
Cockroaches are the second leading allergen in Taiwan. Sensitization to Per a 2, the major American cockroach allergen, correlates with clinical severity among patients with airway allergy, but there is limited information on IgE epitopes and tissue localization of Per a 2. This study aimed to identify Per a 2 linear IgE-binding epitopes and its distribution in the body of a cockroach.
The cDNA of Per a 2 was used as a template and combined with oligonucleotide primers specific to the target areas with appropriate restriction enzyme sites. Eleven overlapping fragments of Per a 2 covering the whole allergen molecule, except 20 residues of signal peptide, were generated by PCR. Mature Per a 2 and overlapping deletion mutants were affinity-purified and assayed for IgE reactivity by immunoblotting. Three synthetic peptides comprising the B cell epitopes were evaluated by direct binding ELISA. Rabbit anti-Per a 2 antibody was used for immunohistochemistry.
Human linear IgE-binding epitopes of Per a 2 were located at the amino acid sequences 57-86, 200-211, and 299-309. There was positive IgE binding to 10 tested Per a 2-allergic sera in 3 synthetic peptides, but none in the controls. Immunostaining revealed that Per a 2 was localized partly in the mouth and midgut of the cockroach, with the most intense staining observed in the hindgut, suggesting that the Per a 2 allergen might be excreted through the feces.
Information on the IgE-binding epitope of Per a 2 may be used for designing more specific diagnostic and therapeutic approaches to cockroach allergy.
PMCID: PMC4446636  PMID: 25749772
Cockroach allergy; IgE-binding epitope; synthetic peptide; specific immunotherapy; Per a 2
10.  IgE Reactivity of the Dog Lipocalin Allergen Can f 4 and the Development of a Sandwich ELISA for Its Quantification 
Divergent results on the IgE reactivity of dog-allergic subjects to Can f 4 have been reported. The aim of this study was to evaluate the significance of Can f 4 in dog allergy and to develop an immunochemical method for measuring Can f 4 content in environmental samples.
We purified the natural dog allergen Can f 4 from a dog dander extract by monoclonal antibody-based affinity chromatography and generated its variant in a recombinant form. Sixty-three dog-allergic patients and 12 nonallergic control subjects were recruited in the study. The IgE-binding capacity of natural Can f 4 and its recombinant variant was assessed by ELISA, immunoblotting, and skin prick tests (SPT).
Eighty-one percent of the dog-allergic patients showed a positive result to the immunoaffinity-purified natural Can f 4 in IgE ELISA, but only 46% in IgE immunoblotting. Respective results with the recombinant Can f 4 variant were 54% and 49%. SPT results reflected those obtained in ELISA and immunoblotting. The overall IgE reactivity of the immunoaffinity-purified natural Can f 4 was found to depend strongly on the integrity of the allergen's conformation. A sandwich ELISA based on monoclonal antibodies was found to be functional for measuring Can f 4 in environmental samples.
Can f 4 is a major allergen of dog together with Can f 1 and Can f 5. In combination with other dog allergens, it improves the reliability of allergy tests in dog allergy.
PMCID: PMC4446637  PMID: 25749774
Allergen; Can f 4; Canis familiaris; dog; IgE; lipocalin
11.  Der p2 Internalization by Epithelium Synergistically Augments Toll-like Receptor-Mediated Proinflammatory Signaling 
House-dust-mite (HDM) major allergen Der p2 shares homology and function with Toll-like receptor (TLR) signaling protein myeloid differentiation-2 (MD2) and may lead to airway inflammation. Should Der p2 be internalized by human airway epithelium, it has the theoretical propensity to potentiate epithelium activation. This study aimed to demonstrate the internalization of Der p2 by airway epithelium and to investigate the effects of Der p2 on MD2 expression and epithelium activation.
Internalization of recombinant, enhanced green fluorescent protein-labelled Der p2 (rDer p2-EGFP) into human airway epithelium (BEAS-2B) was tracked by laser confocal microscopy and confirmed by immunoblotting. Reverse-transcription polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical staining were used to determine the effect of Der p2 on MD2 expression in vitro and ex vivo. Expression of messenger RNA (mRNA) encoding receptors/cytokines was measured by RT-PCR. Secretion of interleukin-6/interleukin-8 (IL-6/IL-8) was measured by enzyme-linked immunosorbent assay (ELISA).
Internalization of Der p2 by BEAS-2B was confirmed by confocal microscopy and immunoblotting using rDer p2-EGFP and rDer p2, respectively. Expression of MD2 protein was increased in BEAS-2B and human nasal polyp airway epithelium cultured with rDer p2. Recombinant Der p2-cultured BEAS-2B caused little spontaneous IL-6/IL-8 secretion but significantly augmented by TLR ligand LPS. IL-6 secretion was up-regulated after MD2 transfection. Internalization of Der p2 was reduced by TLR2 RNA knockdown. Dexamethasone, calcitriol, anti-MD2/anti-TLR2 antibodies, and signalling inhibitors significantly reduced LPS+Der p2-induced IL-6/IL-8 secretion.
Human airway epithelium may internalize Der p2, which potentiates the response to environmental proinflammatory stimuli through MD2 and TLRs. This study highlights a novel mechanism and alleviates IL-6/IL-8 secretion in mite-induced airway inflammation.
PMCID: PMC4446638  PMID: 25749775
Internalization; Der p2; human airway epithelium; Toll-like receptor 2; inflammation; calcitriol
12.  Fractional Exhaled Nitric Oxide: Comparison Between Portable Devices and Correlation With Sputum Eosinophils 
This study was performed to compare the 2 different portable devices measuring fractional exhaled nitric oxide (FeNO) and to see the correlation between FeNO and induced sputum eosinophil count (ISE). Forty consecutive subjects clinically suspected to have asthma underwent FeNO measurement by NIOX-MINO® and NObreath® concurrently. All also had induced sputum analysis, methacholine provocation test or bronchodilator response test, and spin prick test. Agreement between the 2 devices was evaluated. The correlation between FeNO and ISE was assessed, as well as the cut-off level of FeNO to identify ISE ≥3%. The intraclass correlation coefficient (ICC) between FeNO levels measured by NIOX-MINO® (FeNONIOX-MINO) and NObreath® (FeNONObreath) was 0.972 with 95% confidence interval of 0.948-0.985. The 95% limits of agreement were -28.9 to 19.9 ppb. The correlation coefficient between ISE and FeNONIOX-MINO was 0.733 (P<0.001), and 0.751 between ISE and FeNONObreath (P<0.001). The ROC curve found that the FeNONIOXMINO of 37.5 ppb and the FeNONObreath of 36.5 ppb identified ISE ≥3% with 90% sensitivity and 81% specificity. Age, sex, body mass index, smoking history, atopy, and the presence of asthma did not affect the FeNO level and its correlation with ISE. The NIOX-MINO ® and NObreath® agree with each other to a high degree. Both devices showed close correlation with ISE with similar cut-off value in identifying ISE ≥3%.
PMCID: PMC4446639  PMID: 25749783
Asthma; nitric oxide; electrochemical technique; eosinophils; sputum
13.  Immunomodulatory Effects of Lactobacillus salivarius LS01 and Bifidobacterium breve BR03, Alone and in Combination, on Peripheral Blood Mononuclear Cells of Allergic Asthmatics 
The aim of this study was to evaluate probiotic characteristics of Lactobacillus salivarius LS01 and Bifidobacterium breve BR03 alone and in combination and their immunomodulatory activity in asthmatic subjects. Subjects affected by allergic asthma were recruited. Initially, LS01 and BR03 were analyzed for their growth compatibility by a broth compatibility assay. To study the antimicrobial activity of probiotic strains, an agar diffusion assay was performed. Finally, cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with LS01 and BR03 was determined by means of specific quantitative enzyme-linked immunosorbent assay (ELISA). The growth of some clinical pathogens were slightly inhibited by LS01 and LS01-BR03 co-culture supernatant not neutralized to pH 6.5, while only the growth of E. coli and S. aureus was inhibited by the supernatant of LS01 and LS01-BR03 neutralized to pH 6.5. Furthermore, LS01 and BR03 combination was able to decrease the secretion of proinflammatory cytokines by PBMCs, leading to an intense increase in IL-10 production. L. salivarius LS01 and B. breve BR03 showed promising probiotic properties and beneficial immunomodulatory activity that are increased when the 2 strains are used in combination in the same formulation.
PMCID: PMC4446640  PMID: 25749784
Asthma; probiotics; immune system
14.  Basophil Activation Tests Based on CD193 Marker in Dipyrone Allergy 
PMCID: PMC4446641  PMID: 25749766
16.  Is Your Cough Getting Better? 
PMCID: PMC4397359  PMID: 25840709
17.  Mold Allergens in Respiratory Allergy: From Structure to Therapy 
Allergic reactions to fungi were described 300 years ago, but the importance of allergy to fungi has been underestimated for a long time. Allergens from fungi mainly cause respiratory and skin symptoms in sensitized patients. In this review, we will focus on fungi and fungal allergens involved in respiratory forms of allergy, such as allergic rhinitis and asthma. Fungi can act as indoor and outdoor respiratory allergen sources, and depending on climate conditions, the rates of sensitization in individuals attending allergy clinics range from 5% to 20%. Due to the poor quality of natural fungal allergen extracts, diagnosis of fungal allergy is hampered, and allergen-specific immunotherapy is rarely given. Several factors are responsible for the poor quality of natural fungal extracts, among which the influence of culture conditions on allergen contents. However, molecular cloning techniques have allowed us to isolate DNAs coding for fungal allergens and to produce a continuously growing panel of recombinant allergens for the diagnosis of fungal allergy. Moreover, technologies are now available for the preparation of recombinant and synthetic fungal allergen derivatives which can be used to develop safe vaccines for the treatment of fungal allergy.
PMCID: PMC4397360  PMID: 25840710
Fungal allergy; allergen structure; specific immunotherapy; recombinant allergens
18.  Specific Immunotherapy in Atopic Dermatitis 
Allergen specific immunotherapy (SIT) using house dust mite (HDM) extracts has been performed mainly with patients of asthma and allergic rhinitis. In the meanwhile, there has been a long debate on the efficacy of SIT in atopic dermatitis (AD) with only a few double-blind placebo-controlled trials. However, several randomized controlled trials of SIT in AD revealed significant improvement of clinical symptoms and also, positive result was shown by a following meta-analysis study of these trials. In order to predict and evaluate the treatment outcome, finding a biomarker that can predict treatment responses and treatment end-points is critical but it is very challenging at the same time due to the complexity of causes and mechanisms of AD. Other considerations including standardization of the easiest and safest treatment protocol and optimizing the treatment preparations should be studied as well. This review summarizes the basics of SIT in AD including the brief mechanisms, treatment methods and schedules, and also highlights the clinical efficacy of SIT in AD along with mild, controllable adverse reactions. Immunologic effects and studies of various biomarkers are also introduced and finally, future considerations with upcoming studies on SIT were discussed.
PMCID: PMC4397361  PMID: 25749758
Specific immunotherapy; subcutaneous immunotherapy; atopic dermatitis; clinical efficacy; biomarker
19.  Reliability and Validity of a Korean Version of the Leicester Cough Questionnaire 
There are no specific tools for measurement of the severity of chronic cough in Korea. We developed a Korean version of the Leicester Cough Questionnaire (LCQ) and tested its scaling and clinical properties.
The LCQ was adapted for Korean conditions following a forward-backward translation procedure. All patients referred to chronic cough clinics at 5 university hospitals between May 2011 and October 2013 completed 2 questionnaires, the LCQ and the Short-Form 36 (SF-36), upon presentation and completed the LCQ and the Global Rating of Change (GRC) upon follow-up visits after 2 or 4 weeks. Concurrent validation, internal consistency, repeatability, and responsiveness were determined.
For the concurrent validation, the correlation coefficients (n=202 patients) between the LCQ and SF-36 varied between 0.42 and 0.58. The internal consistency of the LCQ (n=207) was high for each of the domains with a Cronbach's alpha coefficient of 0.82-0.94. The repeatability of the LCQ in patients with no change in cough (n=23) was high, with intra-class correlation coefficients of 0.66-0.81. Patients who reported an improvement in cough (n=30) on follow-up visits demonstrated significant improvement in each of the domains of the LCQ.
The Korean version of the LCQ is a valid and reliable questionnaire for measurement of the severity of cough in patients with chronic cough.
PMCID: PMC4397362  PMID: 25749761
Cough; questionnaires; quality of life; chronic disease
20.  Novel Risk Factors for Allergic Rhinitis in Korean Elementary School Children: ARCO-kids Phase II in a Community 
Allergic rhinitis (AR) is a multifactorial disease whose genetic and environmental risk factors have been studied for decades. Many pediatric studies have pointed out the familial history of allergy, hygiene hypothesis, breast-feeding, pet ownership, and diets as risk factors of AR. However, most of factors are still up for debate. This preliminary report aimed to confirm the known risk factors and find the novel risk factors for AR in the Korean pediatric population.
A bi-seasonal, winter and summer, study in 2 elementary schools included all students whose parents completed the questionnaire of medical and social histories, quality of life, infant and early-childhood history, and the living styles. Skin prick tests and endoscopic examinations were conducted on all participants.
Among total 1,020 children, 338 participants had AR. The multivariate logistic regression analysis highlighted 6 factors: male gender (OR, 2.10; 95% CI, 1.32-3.33), older age (1.65; 1.03-2.65), previous history of allergic conjunctivitis (14.25; 4.99-40.74), asthma (2.73; 0.96-7.76) and pneumonia (0.39; 0.19-0.82), and an hour increase in daily playing time (0.90; 0.80-1.00).
Lack of pneumonia in early childhood and short playing time are newly found risk factors for Korean pediatric AR in this study confirming male gender, older age and previous history of allergic conjunctivitis and asthma as the risk factors.
PMCID: PMC4397363  PMID: 25749770
Allergic rhinitis; risk factors; play; pneumonia
21.  Interactions Between Innate Immunity Genes and Early-Life Risk Factors in Allergic Rhinitis 
Allergic rhinitis (AR) is a common chronic disease. Many factors could affect the development of AR. We investigated early-life factors, such as delivery mode, feeding method, and use of antibiotics during infancy, which could affect the development of AR. In addition, how interactions between these factors and innate gene polymorphisms influence the development of AR was investigated.
A cross-sectional study of 1,828 children aged 9-12 years was conducted. Three early-life factors and AR were assessed by a questionnaire. Skin prick tests were done. Polymorphisms of TLR4 (rs1927911) and CD14 (rs2569190) were genotyped.
Use of antibiotics during infancy increased the risk of AR (aOR [95% CI] 1.511 [1.222-2.037]) and atopic AR (aOR [95% CI], 1.565 [1.078-2.272]). There were synergistic interactions between caesarean delivery, formula feeding, and use of antibiotics in the rate of atopic AR (aOR [95% CI], 3.038 [1.256-7.347]). Additional analyses revealed that the risk for the development of AR or atopic AR subjects with the TLR4 CC genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.127 [1.265-20.780] for AR; 6.078 [1.499-24.649] for atopic AR). In addition, the risk for the development of AR or atopic AR in subjects with the CD14 TT genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.960 [1.421-15.002] for AR; 6.714 [1.440-31.312] for atopic AR).
Delivery mode, feeding method, and use of antibiotics during infancy appeared to have synergistic interactions in the development of AR. Gene-environment interactions between polymorphism of innate genes and early- life risk factors might affect the development of AR.
PMCID: PMC4397364  PMID: 25840711
Obstetric delivery; infant food; antibiotics; gene-environment interaction, allergic rhinitis
22.  Association of Single Nucleotide Polymorphisms in the MD-2 Gene Promoter Region With Der p 2 Allergy 
Sensitization to house dust mite (Dermatophagoides pteronyssinus) is a considerable risk factor for the progression of allergic disease. The group 2 allergen from Dermatophagoides pteronyssinus, Der p 2, is considered a major one in patients with specific immunoglobulin E (IgE) to Der p 2. Der p 2 has structural homology with myeloid differentiation 2 (MD-2), which is involved in the lipopolysaccharide-binding component of the Toll-like receptor 4 signaling pathway and the development of inflammation. The aim of this study was to examine the genetic association of single nucleotide polymorphisms (SNPs) in the promoter region of MD-2 with Der p 2-sensitive allergy.
We investigated associations between cohort's characteristics, including 280 allergic and 80 healthy subjects by examining total IgE, eosinophils, D. pteronyssinus-specific IgE, Der p 2-specific IgE, the number of IgE-producing B cells induced by Der p 2, and the odds ratio of allergic symptoms.
Based on the 1,000 genome project data, the minor allele frequencies of the rs1809441 and rs1809442 are 0.467 and 0.474, respectively. However, the correlation of linkage disequilibrium (LD) between these 2 SNPs is D'=1, the genotype frequencies of the 2 MD-2 (LY96) SNPs (rs1809441 and rs1809442) that are located nearby were significantly different between allergic and health subjects: the TT genotype of rs1809441 and the GG genotype of rs1809442 were more frequent in allergic subjects than in healthy subjects (16.1% vs 2.5% in both genotypes). The allergic patients with these genotypes exhibited significantly higher levels of D. pteronyssinus-specific IgE and Der p 2-specific Ig E, and a larger number of Der p 2-activated B cells. In addition, these 2 SNPs in the MD-2 promoter region were significantly associated with the prevalence of nasal, skin, and asthmatic allergic symptoms.
Our results indicated that 2 SNPs in the MD-2 promoter region were significantly associated with Der p 2-specific Ig E, and thereby suggest that these SNPs may play a major role in susceptibility to Der p 2-triggered immune responses in a Taiwanese population.
PMCID: PMC4397365  PMID: 25749780
Dermatophagoides pteronyssinus; myeloid differentiation-2 (MD-2); Der p 2; single nucleotide polymorphisms (SNPs); mite allergy
23.  Antiallergic Function of KR62980, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in a Mouse Allergic Rhinitis Model 
Peroxisome proliferator-activated receptor γ (PPAR-γ) has been shown to play an important role in the control of inflammatory responses acting on macrophages, mast cells, T cells and eosinophils. A novel PPAR-γ ligand, KR62980 have been recently focused on due to the lower undesirable effects than other PPAR-γ ligands such as rosiglitazone and pioglitazone. The present study was aimed to investigate the effects of KR62980 on nasal symptoms and immunopathological profiles in allergic nasal mucosa in murine allergic rhinitis model.
BALB/c mice were sensitized and challenged intranasally with ovalbumin (OVA). KR62980 was administered intraperitoneally or orally 3 hours before each intranasal OVA challenge.
Administration of KR62980 significantly decreased the number of nasal rubbing, nasal sneezing, ova-specific IgE and total IgE in serum, secretion of Interleukin (IL)-4, IL-5, and IL-17 from the spleen and eosinophilic infiltration in the nasal mucosa. KR62980 decreased the expression of IL-4, IL-5 and IL-10 mRNAs in the nasal mucosal tissue, while, it elevated the level of IL-10 and IFN-γ in splenocyte culture. KR62980 seemed to decrease IL-17 level in local and systemic level even though it did not reach to statistical significance. The anti-inflammatory effect was more definite when the KR62980 was administered intraorally than intraperitoneally.
A novel PPAR-γ ligand, KR62980 can attenuate OVA-induced allergic inflammation in mice mainly through modulation of Th2 cytokines. This finding suggests that PPAR-γ might have a role in the treatment of allergic rhinitis.
PMCID: PMC4397366  PMID: 25749778
Allergic rhinitis; PPAR gamma; T-Lymphocytes; regulatory; Interleukin-10; Interleukin-17
24.  Copy Number Variation Burden on Asthma Subgenome in Normal Cohorts Identifies Susceptibility Markers 
Asthma is a complex disease caused by interplay of genes and environment on the genome of an individual. Copy number variations (CNVs) are more common compared to the other variations that disrupt genome organization. The effect of CNVs on asthma subgenome has been less studied compared to studies on the other variations. We report the assessments of CNV burden in asthma genes of normal cohorts carried out in different geographical areas of the world and discuss the relevance of the observation with respect to asthma pathogenesis.
CNV analysis was performed using Affymerix high-resolution arrays, and various bioinformatics tools were used to understand the influence of genes on asthma pathogenesis.
This study identified 61 genes associated with asthma and provided various mechanisms and pathways underlying asthma pathogenesis. CCL3L1, ADAM8, and MUC5B were the most prevalent asthma genes. Among them, CCL3L1 was found across all 12 populations in varying copy number states. This study also identified the inheritance of asthma-CNVs from parents to offspring creating the latent period for manifestation of asthma.
This study revealed CNV burden with varying copy number states and identified susceptibility towards the disease manifestation. It can be hypothesized that primary CNVs may not be the initiating event in the pathogenesis of asthma and additional preceding mutations or CNVs may be required. The initiator or primary CNVs sensitize normal cohorts leading to an increased probability of accumulating mutations or exposure to allergic stimulating agents that can augment the development of asthma.
PMCID: PMC4397367  PMID: 25749760
Asthma; DNA copy number variation; inheritance pattern; CCL3L1; genetic markers
25.  Inhibitory Effect of Delphinidin on Extracellular Matrix Production via the MAPK/NF-κB Pathway in Nasal Polyp-Derived Fibroblasts 
Nasal polyps are associated with chronic inflammation of the mucous membranes in the nose and paranasal sinuses and involved in extracellular matrix (ECM) accumulation. Delphinidin promotes ECM degradation in hepatitis and cardiac fibrosis. The aims of this study were to examine the inhibitory effect of delphinidin on TGF-β1-induced myofibroblast differentiation and ECM accumulation, and to determine the underlying mechanisms in nasal polyp-derived fibroblasts (NPDFs).
NPDFs were stimulated with TGF-β1, with or without delphinidin, and the expression levels of α-SMA, fibronectin, and collagen type I were determined by RT-PCR, Western blot analysis, and collagen assay. The expression of α-SMA protein was measured by immunocytochemical staining. Mitogen-activated protein kinase and NF-κB activation induced by TGF-β1 were determined by Western blot analysis. The transcriptional activity of NF-κB was measured by luciferase assay.
The expression levels of α-SMA, fibronectin, and collagen type I increased in TGF-β1-stimulated NPDFs. In TGF-β1-induced NPDFs, delphinidin inhibited the expression of α-SMA, fibronectin, and collagen. Inhibitors of MAPK and NF-κB blocked the expression of α-SMA, fibronectin, and collagen type I. Delphinidin suppressed the activation of MAPK and NF-κB induced by TGF-β1 stimulation.
These results suggest that delphinidin may inhibit TGF-β1-induced myofibroblast differentiation and ECM production through the MAPK/NF-κB signaling pathway in NPDFs.
PMCID: PMC4397368  PMID: 25749779
Chronic rhinosinusitis; nasal polyposis; TGF-β1; extracellular matrix; myofibroblast; delphinidin; MAPK; NF-κB

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