ABSTRACT
The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFß and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.Significance: This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. Cancer Res; 78(16); 4692-703. ©2018 AACR.
Subject(s)
Diacylglycerol Kinase/genetics , Immunotherapy, Adoptive , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Animals , CD28 Antigens/genetics , CD28 Antigens/immunology , CRISPR-Cas Systems/genetics , CRISPR-Cas Systems/immunology , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Cell Line, Tumor , Diacylglycerol Kinase/immunology , Gene Knockout Techniques , Humans , Ligands , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Signal Transduction , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Xenograft Model Antitumor AssaysABSTRACT
Doping two-dimensional (2D) semiconductors beyond their degenerate levels provides the opportunity to investigate extreme carrier density-driven superconductivity and phase transition in 2D systems. Chemical functionalization and the ionic gating have achieved the high doping density, but their effective ranges have been limited to â¼1 nm, which restricts the use of highly doped 2D semiconductors. Here, we report on electron diffusion from the 2D electride [Ca2N]+·e- to MoTe2 over a distance of 100 nm from the contact interface, generating an electron doping density higher than 1.6 × 1014 cm-2 and a lattice symmetry change of MoTe2 as a consequence of the extreme doping. The long-range lattice symmetry change, suggesting a length scale surpassing the depletion width of conventional metal-semiconductor junctions, was a consequence of the low work function (2.6 eV) with highly mobile anionic electron layers of [Ca2N]+·e-. The combination of 2D electrides and layered materials yields a novel material design in terms of doping and lattice engineering.
ABSTRACT
OBJECTIVES: 25-hydroxyvitamin D (25[OH]D) deficiency and genetic variants at the 17q12-21 locus are independent risk factors for respiratory tract infections (RTIs). We aimed to investigate whether the effect of 25(OH)D at birth and 1 year of age and the polymorphism at the 17q12-21 locus, or interactions between these two factors, increase susceptibility to RTIs in the first year of life. METHODS: We tested cord-blood (CB) 25(OH)D at birth and 1 year of age and genotypes of a variant at the 17q12-21 locus for associations with RTIs, particularly lower respiratory tract infections (LRTIs), and determined whether there exist interactions between 25(OH)D and 17q12-21 genotypes in a birth cohort of 473 infants. RESULTS: The levels of CB 25(OH)D inversely associate with development of RTIs and LRTIs during the first year of life. There exists an inverse association of 25(OH)D at birth, but not at 1 year, with the risk of acquiring LRTIs in early infancy (adjusted odds ratio [aOR], 2.37; 95% confidence interval [CI]: 1.23-4.60; P = 0.010 and aOR, 0.50; 95%CI: 0.23-1.12; P = 0.094). We have also found a significant interaction between CB 25(OH)D and a variant at the 17q12-21 locus with respect to the development of early LRTIs, such that associations between a variant at the 17q12-21 locus and LRTIs are restricted to infants with low CB 25(OH)D concentrations (P for interaction = 0.013). In addition, when infants with a variant at the 17q12-21 locus had been exposed to chronic 25(OH)D deficiency over the first year, their risk of LRTIs was increased. CONCLUSION: CB 25(OH)D deficiency during fetal life contribute to the development of LRTIs in genetically susceptible infants. Pediatr Pulmonol. 2016; 51:958-967. © 2016 Wiley Periodicals, Inc.
Subject(s)
Chromosomes, Human, Pair 17/genetics , Polymorphism, Single Nucleotide , Respiratory Tract Infections/complications , Respiratory Tract Infections/genetics , Vitamin D Deficiency/complications , Disease Susceptibility , Female , Fetal Blood/metabolism , Humans , Infant , Male , Odds Ratio , Prospective Studies , Risk Factors , Vitamin D/analogs & derivatives , Vitamin D/bloodABSTRACT
BACKGROUND: Recent evidence suggests that prenatal maternal distress increases the risk of allergic diseases in offspring. However, the effect of prenatal maternal depression and anxiety on atopic dermatitis (AD) risk remains poorly understood. OBJECTIVE: We investigated whether prenatal maternal distress is associated with AD risk in offspring and whether the mechanism is mediated by reactive oxygen species. METHODS: Two general population-based birth cohorts formed the study. One cohort (Cohort for Childhood Origin of Asthma and Allergic Diseases [COCOA]) consisted of 973 mother-baby dyads, and the other (Panel Study on Korean Children [PSKC]) consisted of 1531 mother-baby dyads. The association between prenatal distress and AD was assessed by using Cox proportional hazards and logistic regression models. In COCOA placental 11ß-hydroxysteroid dehydrogenase type 2 and glutathione levels and serum IgE levels in 1-year-old children were measured. RESULTS: In COCOA and PSKC AD occurred in 30.6% (lifetime prevalence) and 11.6% (1 year prevalence) of offspring, respectively. Prenatal maternal distress increased the risk of AD in offspring, both in COCOA (hazard ratio for depression, 1.31 [95% CI, 1.02-1.69]; hazard ratio for anxiety, 1.41 [95% CI, 1.06-1.89]) and PSKC (odds ratio for distress, 1.85 [95% CI, 1.06-3.25]). In COCOA both prenatal maternal depression and anxiety scores were positively related to the predicted probability of AD (P < .001 in both). Prenatal distress decreased placental glutathione to glutathione disulfide ratios (P = .037) and, especially in those who later had AD, decreased placental 11ß-hydroxysteroid dehydrogenase type 2 levels (P = .010) and increased IgE levels at 1 year of age (P = .005). CONCLUSION: Prenatal maternal depression and anxiety promote risk of AD in offspring. Maternal distress increases the predicted probability of AD. The mechanism might involve chronic stress, abnormal steroid levels, and reactive oxygen species.
Subject(s)
Dermatitis, Atopic/etiology , Dermatitis, Atopic/metabolism , Maternal Exposure , Prenatal Exposure Delayed Effects , Stress, Physiological , Stress, Psychological , Adult , Biomarkers , Child, Preschool , Comorbidity , Dermatitis, Atopic/epidemiology , Female , Humans , Infant , Male , Maternal Exposure/adverse effects , Middle Aged , Odds Ratio , Oxidative Stress , Pregnancy , Proportional Hazards Models , Risk Factors , Young AdultABSTRACT
PURPOSE: Although home renovation exposure during childhood has been identified as a risk factor for the development of allergy, there is limited information on the association between prenatal exposure to home renovation and cord blood (CB) IgE response. The aims of this study were to identify the effect of prenatal exposure to home renovation on CB IgE levels, and to investigate whether this exposure interacts with neonatal genes and whether the effect can be modified by maternal atopy. METHODS: This study included 1,002 mother-neonate pairs from the COhort for Childhood Origin of Asthma and allergic diseases (COCOA). Prenatal environmental factors were collected using a questionnaire. The levels of CB IgE were measured by the ImmunoCAP system, and DNA was extracted from CB. RESULTS: Exposure to home renovation during the prenatal period was associated with significantly higher levels of CB IgE only in neonates from atopic mothers, and the effect of renovation exposure on CB IgE levels persisted from 31 months before birth. Furthermore, prenatal exposure to home renovation increased the risk of CB IgE response interacting with polymorphisms of NRF2 and GSTP1 genes only in neonates from atopic mothers. CONCLUSIONS: Maternal atopy modified the effect of prenatal exposure to home renovation on CB serum IgE response as well as the interaction between the exposure and neonatal genes involved in the oxidative stress pathway. These findings suggest that the genetically susceptible offspring of atopic mothers may be more vulnerable to the effect of prenatal exposure to home renovation on the development of allergy.
ABSTRACT
PURPOSE: To investigate whether prenatal exposure to indoor fine particulate matter (PM2.5) and environmental tobacco smoke (ETS) affects susceptibility to respiratory tract infections (RTIs) in infancy, to compare their effects between prenatal and postnatal exposure, and to determine whether genetic factors modify these environmental effects. METHODS: The study population consisted of 307 birth cohort infants. A diagnosis of RTIs was based on parental report of a physician's diagnosis. Indoor PM2.5 and ETS levels were measured during pregnancy and infancy. TaqMan was used for genotyping of nuclear factor erythroid 2-related factor (Nrf2) (rs6726395), glutathione-S-transferase-pi (GSTP) 1 (rs1695), and glutathione-S-transferase-mu (GSTM) 1. Microarrays were used for genome-wide methylation analysis. RESULTS: Prenatal exposure to indoor PM2.5 increased the susceptibility of lower RTIs (LRTIs) in infancy (adjusted odds ratio [aOR]=2.11). In terms of combined exposure to both indoor PM2.5 and ETS, prenatal exposure to both pollutants increased susceptibility to LRTIs (aOR=6.56); however, this association was not found for postnatal exposure. The Nrf2 GG (aOR=23.69), GSTM1 null (aOR=8.18), and GSTP1 AG or GG (aOR=7.37) genotypes increased the combined LRTIs-promoting effects of prenatal exposure to the 2 indoor pollutants. Such effects of prenatal indoor PM2.5 and ETS exposure were not found for upper RTIs. CONCLUSIONS: Prenatal exposure to both indoor PM2.5 and ETS may increase susceptibility to LRTIs. This effect can be modified by polymorphisms in reactive oxygen species-related genes.
ABSTRACT
PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
ABSTRACT
PURPOSE: The complex interplay between environmental and genetic factors plays an important role in the development of asthma. Several studies have yielded conflicting results regarding the 2 asthma-related risk factors: antibiotic usage during infancy and/or a history of bronchiolitis during early life and the development of asthma. In addition to these risk factors, we also explored the effects of Toll-like receptor 4 (TLR4) polymorphism on the development of childhood asthma. METHODS: This cross-sectional study involved 7,389 middle school students who were from 8 areas of Seoul, Korea, and completed the International Study of Asthma and Allergies in Childhood questionnaire. The TLR4 polymorphism rs1927911 was genotyped in 1,395 middle school students from two areas using the TaqMan assay. RESULTS: Bronchiolitis in the first 2 years of life, antibiotic exposure during the first year of life, and parental history of asthma were independent risk factors for the development of asthma. When combined, antibiotic use and a history of bronchiolitis increased the risk of asthma (adjusted odds ratio [aOR]: 4.64, 95% confidence interval [CI]: 3.09-6.97, P value for interaction=0.02). In subjects with CC genotype of TLR4, antibiotic exposure and a history of bronchiolitis during infancy, the risk of asthma was increased, compared to subjects without these risk factors (aOR: 5.72, 95% CI: 1.74-18.87). CONCLUSIONS: Early-life antibiotic exposures and a history of bronchiolitis are risk factors for asthma in young adolescents. Polymorphisms of TLR4 modified the influence of these environmental factors. Reducing antibiotic exposure and preventing bronchiolitis during infancy may prevent the development of asthma, especially in genetically susceptible subjects.
Subject(s)
Claudin-1/genetics , Dermatitis, Atopic/genetics , Fungi/immunology , Immunoglobulin E/biosynthesis , Keratinocytes/immunology , Skin/immunology , Animals , Claudin-1/immunology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/microbiology , Dermatitis, Atopic/pathology , Genes, Reporter , Humans , Keratinocytes/drug effects , Keratinocytes/microbiology , Keratinocytes/pathology , Luciferases/genetics , Luciferases/immunology , Mice , Ovalbumin/pharmacology , Patulin/pharmacology , Permeability , Polymorphism, Genetic , Primary Cell Culture , Promoter Regions, Genetic , Risk Factors , Skin/drug effects , Skin/microbiology , Skin/pathology , Tight Junctions/drug effects , Tight Junctions/immunology , Tight Junctions/microbiology , Tight Junctions/pathologyABSTRACT
BACKGROUND: Exposure to perinatal anxiety affects disease susceptibility in offspring but studies on the association between perinatal anxiety and gene polymorphisms are lacking. This study aimed to elucidate the interaction between perinatal anxiety and polymorphisms in antioxidant defense and innate immunity genes on the development of respiratory tract infections (RTIs) during early infancy. METHODS: Trait anxiety levels in 440 women were assessed by the State-Trait Anxiety Inventory during late gestation. The occurrence of RTIs, including bronchiolitis, during the first year of life was assessed by parent-reported doctor diagnosis. Polymorphisms in glutathione S-transferase P-1 (GSTP1, rs1695) and CD14 (rs2569190) were genotyped using the TaqMan assay. Copy number variations of GSTT1 were measured by real-time polymerase chain reaction. RESULTS: Exposure to high levels of perinatal anxiety increased the risk of bronchiolitis in the first year of life (adjusted odds ratio [aOR], 1.30; 95% confidence interval [CI]: 1.00-1.80), in particular among children with the AG + GG genotype of GSTP1 or the GSTT1 null genotype (aOR 3.36 and 2.79). In infants with the TC + CC genotype of CD14, high levels of perinatal anxiety were associated with an increased risk of upper RTI, lower RTI, and bronchiolitis (aOR 2.51, 4.60, and 4.31, respectively). CONCLUSIONS: Perinatal maternal anxiety levels affect the occurrence of bronchiolitis in offspring. The effect of perinatal anxiety on the occurrence of bronchiolitis during infancy was influenced by genetic polymorphisms in antioxidant defense and innate immunity genes.
Subject(s)
Anxiety/psychology , Bronchiolitis/epidemiology , Glutathione S-Transferase pi/genetics , Glutathione Transferase/genetics , Immunity, Innate/genetics , Lipopolysaccharide Receptors/genetics , Respiratory Tract Infections/epidemiology , Adult , Anxiety/immunology , Bronchiolitis/etiology , Female , Genetic Predisposition to Disease , Genotype , Humans , Infant , Infant, Newborn , Male , Oxidative Stress/immunology , Peripartum Period/psychology , Polymorphism, Genetic , Pregnancy , Respiratory Tract Infections/etiologyABSTRACT
BACKGROUND: Antibiotic use in infancy induces alteration in intestinal microbiota and is associated with the development of allergic diseases. Mold exposure is also associated with allergic diseases. Genetic susceptibility may interact with specific environmental factors in allergic disease development. OBJECTIVE: To investigate independent and combined effects of antibiotic use and mold exposure in infancy on the risk of allergic rhinitis (AR) in adolescents. METHODS: Data on AR and environmental factors were collected using the International Study of Asthma and Allergies in Childhood questionnaire from 7,389 adolescents from Seoul, Korea. TaqMan genotyping was performed for interleukin 13 (IL-13) (rs20541) and Toll-like receptor 4 (rs1927911) polymorphisms in 1,395 adolescents. RESULTS: Age, parental history of AR, antibiotic use in infancy, and pet ownership during pregnancy or infancy were associated with an increased risk of current AR (diagnosis of AR and symptoms of AR within the preceding 12 months). Having older siblings was a protective effect. The adjusted odds ratio (aOR) for current AR for combined antibiotic use and mold exposure in infancy was 1.45 (95% confidence interval [CI], 1.01-2.09). For each factor separately, aORs were 1.25 (95% CI, 1.04-1.50) and 0.99 (95% CI, 0.75-1.31), respectively. Antibiotic and mold exposure in infancy, GA or AA genotypes of IL-13 (rs20541) (aOR 4.53; 95% CI, 1.66-12.38; P for interaction = .05), and CT+TT genotype of Toll-like receptor 4 (rs1927911) (aOR, 3.20; 95% CI, 1.24-8.26; P for interaction = .18) increased the risk of current AR. CONCLUSION: Antibiotic use and mold exposure in infancy have additive effects on the risk of current AR in genetically susceptible adolescents. Gene-environment interactions between IL-13 (rs20541) and antibiotics or mold may play a role in AR.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Environmental Exposure/adverse effects , Fungi , Gene-Environment Interaction , Rhinitis, Allergic, Perennial/epidemiology , Adolescent , Female , Genetic Predisposition to Disease , Humans , Interleukin-13/genetics , Intestines/microbiology , Male , Microbiota/drug effects , Polymorphism, Single Nucleotide , Republic of Korea , Rhinitis, Allergic , Rhinitis, Allergic, Perennial/etiology , Rhinitis, Allergic, Perennial/genetics , Risk Factors , Surveys and Questionnaires , Toll-Like Receptor 4/geneticsABSTRACT
PURPOSE: Bacillus Calmette-Guérin (BCG) is known to suppress the asthmatic responses in a murine model of asthma and to induce dendritic cells (DCs) maturation. Mature DCs play a crucial role in the differentiation of regulatory T cells (Tregs), which are known to regulate allergic inflammatory responses. To investigate whether BCG regulates Tregs in a DCs-mediated manner, we analyzed in a murine model of asthma. METHODS: BALB/c mice were injected intraperitoneally with BCG or intravenously with BCG-stimulated DCs and then sensitized and challenged with ovalbumin (OVA). Mice were analysed for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and histopathological changes in the lung. To identify the mechanisms, IgE, IgG1 and IgG2a in the serum were analysed and the CD25+ Tregs in the mice were depleted with anti-CD25 monoclonal antibody (mAb). RESULTS: BCG and the transfer of BCG-stimulated DCs both suppressed all aspects of the asthmatic responses, namely, BHR, the production of total IgE and OVA-specific IgE and IgGs, and pulmonary eosinophilic inflammation. Anti-CD25mAb treatment reversed these effects. CONCLUSIONS: BCG can attenuate the allergic inflammation in a mouse model of asthma by a Tregs-related mechanism that is mediated by DCs.
ABSTRACT
The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4.
Subject(s)
Acetaminophen/adverse effects , Asthma/genetics , Bronchial Hyperreactivity/genetics , Toll-Like Receptor 4/genetics , Acetaminophen/therapeutic use , Adolescent , Asthma/chemically induced , Asthma/epidemiology , Bronchial Hyperreactivity/chemically induced , Bronchial Hyperreactivity/epidemiology , Child , Cross-Sectional Studies , Eosinophils/immunology , Female , Genetic Predisposition to Disease , Genotype , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Inflammation/immunology , Male , Oxidative Stress/drug effects , Polymorphism, Single Nucleotide , Reactive Oxygen Species/immunology , Risk , Risk Factors , Surveys and QuestionnairesABSTRACT
PURPOSE: Recognition of microbes is important to trigger the innate immune system. Mycolic acid (MA) is a component of the cell walls of mycobacteria such as Mycobacterium bovis Bacillus Calmette-Guerin. MA has immunogenic properties, which may modulate the innate and adaptive immune response. This study aimed to investigate whether a novel synthetic MA (sMA) inhibits allergic inflammatory responses in a mouse model of asthma. METHODS: BALB/c mice were injected intraperitoneally with sMA followed by sensitization and challenge with ovalbumin (OVA). Mice were examined for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells into the lung tissues, histopathological changes in the lungs and CD4(+)CD25(+)Foxp3(+) T cells in the spleen, and examined the response after the depleting regulatory T cells (Tregs) with an anti-CD25mAb. RESULTS: Treatment of mice with sMA suppressed the asthmatic response, including BHR, bronchoalveolar inflammation, and pulmonary eosinophilic inflammation. Anti-CD25mAb treatment abrogated the suppressive effects of sMA in this mouse model of asthma and totally depleted CD4(+)CD25(+)Foxp3(+) T cells in the spleen. CONCLUSIONS: sMA attenuated allergic inflammation in a mouse model of asthma, which might be related with CD4(+)CD25(+)Foxp3(+) T cell.
ABSTRACT
PURPOSE: Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis and the formation of the skin barrier. Recent studies showed that atopic dermatitis (AD) associates closely with loss-of-function mutations in the FLG gene. Asian and European populations differ in the frequencies of FLG mutations. Several FLG mutations, including 3321delA, E2422X, K4671X, S2554X, and R501X, occur frequently in Chinese and Japanese populations. The association between three FLG null mutations and AD in Korean children was investigated. METHODS: The FLG mutations in 1,430 children (aged 0-18 years) with AD and 862 control subjects were genotyped by using the TaqMan assay. RESULTS: The FLG null mutation E2422X was not detected in any patients with AD or control subjects. The R501X null mutation was detected in only one child with AD (0.1%). Children with AD had the 3321delA deletion significantly more frequently (2.4%) than the control subjects (0.0%, P<0.001). Children with AD also had a significantly higher combined allele frequency of the three FLG null mutations (2.6%) than the controls (0.0%, P<0.001). The 3321delA null mutation did not associate significantly with AD severity (P=0.842). When the patients with AD were divided into allergic AD and non-allergic AD patient groups, these two groups did not differ in terms of the frequency of 3321delA. CONCLUSIONS: The Korean children had a lower frequency of FLG mutations than European populations. FLG null mutations may be associated with the development of AD in Korean children.
ABSTRACT
BACKGROUND: Recent studies have identified an increase in the prevalence of asthma associated with paracetamol use. OBJECTIVE: To identify the relationship among asthma, biomarkers, genes, and paracetamol use in preschool children. METHODS: We undertook a population-based, cross-sectional survey of 933 preschool children. Asthma status was classified according to medical history and asthmatic symptoms. History of paracetamol use in infancy was recorded. Impulse oscillometry, blood tests for eosinophils and total IgE, and genotyping of NAT2, Nrf2, and GSTP1 polymorphisms by TaqMan assay were conducted. RESULT: Paracetamol use in infancy was associated with an increased risk of treatment for asthma within the previous 12 months. Paracetamol use together with a family history of asthma increased the risk of asthma diagnosis ever, current asthma, and treatment for asthma within the previous 12 months. Gene polymorphisms in NAT2 (rs4271002), Nrf2 (rd6726395), and GSTP1 (rd1695) increased the risk of treatment for asthma within the last 12 months. Eosinophils were significantly elevated in the group with paracetamol use and a family history of asthma; however, the serum total IgE level and IOS did not show any significant difference. CONCLUSION: Paracetamol use in infancy was significantly associated with increased risk of asthma. The association is more significant in genetically susceptible children, related to antioxidant genes, and the effect may be mediated by eosinophilic inflammation.
Subject(s)
Acetaminophen/adverse effects , Analgesics, Non-Narcotic/adverse effects , Arylamine N-Acetyltransferase/genetics , Asthma/genetics , Glutathione S-Transferase pi/genetics , NF-E2-Related Factor 2/genetics , Asthma/immunology , Asthma/physiopathology , Child , Child, Preschool , Cross-Sectional Studies , Eosinophils/immunology , Female , Genetic Predisposition to Disease , Humans , Immunoglobulin E/blood , Leukocyte Count , Male , Oscillometry , Polymorphism, Genetic , Reactive Oxygen Species , RiskABSTRACT
In 2007, a genome-wide association study identified associations between variants involved in the regulation of ORMDL3 expression and asthma. These observations were subsequently replicated in case-control studies in several ethnic groups. We investigated the possible contribution of GSDMB/ORMDL3 variants to asthma susceptibility and intermediate asthma phenotypes in Korean children. The polymorphisms rs7216389, rs4794820, rs4065275, and rs11650680 were genotyped using the TaqMan assay in 931 asthmatics and 480 normal controls in a case-control study, and in 1907 elementary school children in a general population study. Each subject also underwent peripheral blood analysis of immunoglobulin E levels, eosinophil cationic protein (ECP) levels, and eosinophil percentage. Pulmonary function testing (FEV(1) and MMEF) and a methacholine provocation test (PC(20)) were also performed. The case-control study revealed a significant association between a linkage disequilibrium block, including rs7216389, rs4794820, and rs4065275, and susceptibility to asthma and atopic asthma. The CT and TT genotypes of rs11650680 were associated with lower logECP levels than the CC genotype in asthmatics, while the GA and AA genotypes of rs4794820 were associated with higher logPC(20) values than the GG genotype in atopic asthmatics. The haplotype (CAA) of rs7216389, rs4794820 and rs4065275 was associated with a lower risk of asthma susceptibility and a higher logPC(20). In the general population study, rs11650680 was significantly associated with a diagnosis of asthma. Moreover, the GA and AA genotypes of rs4794820 were associated with higher logPC(20) values and lower eosinophil percentages than the GG genotype in subjects who had been diagnosed with asthma, or showed bronchial hyperresponsiveness (PC(20)≤16). The GSDMB/ORMDL3 gene block, which includes rs7216389, rs4065275, rs4794820, and rs11650680, may be associated with asthma susceptibility in Korean children because it promotes eosinophilic inflammation, which induces bronchial hyperresponsiveness.
Subject(s)
Asthma/genetics , Asthma/immunology , Eosinophils/immunology , Membrane Proteins/genetics , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Asian People/genetics , Bronchial Hyperreactivity/genetics , Bronchial Hyperreactivity/immunology , Case-Control Studies , Child , Child, Preschool , Eosinophil Cationic Protein/blood , Eosinophil Cationic Protein/immunology , Female , Genetic Predisposition to Disease , Genotype , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Male , Phenotype , Republic of Korea , Respiratory Function TestsABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) has been described in patients with advanced stages of human immunodeficiency virus (HIV) infection, but rarely occurs during the seroconversion stage of acute HIV infection. We report a case of acute HIV syndrome that presented with virus-associated HLH. The patient recovered spontaneously without any immunomodulating therapy. This case suggests that acute HIV infection should be included in the differential diagnosis of HLH and indicates that HLH associated with acute HIV infection can have a favorable outcome.
Subject(s)
Acquired Immunodeficiency Syndrome/diagnosis , HIV Infections/diagnosis , Lymphohistiocytosis, Hemophagocytic/pathology , Acquired Immunodeficiency Syndrome/complications , Adult , Diagnosis, Differential , HIV Infections/complications , Humans , Korea , Lymphohistiocytosis, Hemophagocytic/etiology , MaleABSTRACT
Since a nationwide childhood vaccination with tetanus toxoid, tetanus has become a rare disease in Korea. However, we recently experienced 17 cases of adult tetanus in a university hospital during a 21-month period. Seventy percent of the patients were female, and the mean age was 63 yr (range, 29-87). The majority (88.2%) of the patients did not get primary vaccinations for tetanus and decennial tetanus-diphtheria toxoid booster. Most patients (88.2%), who sustained acute injury, did not seek medical care for their wounds or did not receive the prophylaxis for tetanus. Tetanus was found most frequently among farmers. Tetanus was diagnosed initially only in 53% of patients. The case-fatality ratio was 23.5%. These cases show that recently occurring tetanus in Korea is a disease, affecting the elderly and the female who may have a lower immunity against tetanus, and the farmers who are likely to be exposed to Clostridium tetani. In addition, diagnosis of tetanus is often delayed in area where cases are seen infrequently. Therefore, improved education among patients and physicians, emphasis of anti-tetanus immunization and awareness of tetanus respectively, may be essential for the prevention of disease and the reduction of its mortality.