Epithelial Barrier Theory: The Role of Exposome, Microbiome, and Barrier Function in Allergic Diseases

Losol Purevsuren,Sokolowska Milena,Hwang Yu-Kyoung,Ogulur Ismail,Mitamura Yasutaka,Yazici Duygu,Pat Yagiz,Radzikowska Urszula,Ardicli Sena,Yoon Jeong-Eun,Choi Jun-Pyo,Kim Sae-Hoon,van de Veen Willem,A 대한천식알레르기학회 2023 Allergy, Asthma & Immunology Research Vol.15 No.6

Allergic diseases are a major public health problem with increasing prevalence. These immune-mediated diseases are characterized by defective epithelial barriers, which are explained by the epithelial barrier theory and continuously emerging evidence. Environmental exposures (exposome) including global warming, changes and loss of biodiversity, pollution, pathogens, allergens and mites, laundry and dishwasher detergents, surfactants, shampoos, body cleaners and household cleaners, microplastics, nanoparticles, toothpaste, enzymes and emulsifiers in processed foods, and dietary habits are responsible for the mucosal and skin barrier disruption. Exposure to barrier-damaging agents causes epithelial cell injury and barrier damage, colonization of opportunistic pathogens, loss of commensal bacteria, decreased microbiota diversity, bacterial translocation, allergic sensitization, and inflammation in the periepithelial area. Here, we review scientific evidence on the environmental components that impact epithelial barriers and microbiome composition and their influence on asthma and allergic diseases. We also discuss the historical overview of allergic diseases and the evolution of the hygiene hypothesis with theoretical evidence.

Molecular Genetic Mechanisms of Chronic Urticaria

Losol, Purevsuren,Yoo, Hye-Soo,Park, Hae-Sim The Korean Academy of Asthma, Allergy and Clinical 2014 Allergy, Asthma & Immunology Research Vol.6 No.1

<P>Chronic urticaria (CU) is a common allergic skin disease that requires long-term pharmacological treatment. Some patients with severe CU suffer a poor quality of life. Although the pathogenic mechanisms of CU are not clearly understood, several groups have suggested that genetic mechanisms are involved in various CU cohorts. To further understand the molecular genetic mechanisms of CU, we summarize recent genetic data in this review. Although a few HLA alleles were suggested to be candidate markers in different ethnic groups, further replication studies that apply the recent classification are needed. Genetic polymorphisms in histamine-related genes, including <I>FcεRI</I> and <I>HNMT</I>, were suggested to be involved in mast cell activation and histamine metabolism. Several genetic polymorphisms of leukotriene-related genes, such as <I>ALOX5</I>, <I>LTC4S</I>, and the PGE2 receptor gene <I>PTGER4</I>, were suggested to be involved in leukotriene overproduction, a pathogenic mechanism. Further investigations using candidate gene approaches and genome-wide association studies (GWAS) will provide new insights into the molecular genetic mechanisms of CU, which will provide new marker genes for differentiation of CU phenotypes and identification of potential therapeutic targets.</P>

A genetic effect of IL-5 receptor a polymorphism in patients with aspirin-exacerbated respiratory disease

Purevsuren Losol,김승현,Yoo Seob Shin,예영민,박해심 생화학분자생물학회 2013 Experimental and molecular medicine Vol.45 No.3

Persistent eosinophil activation in both the upper and lower airway mucosa is a central feature of aspirin-exacerbated respiratory disease (AERD). Eosinophil activation and survival are profoundly influenced by interleukin 5 (IL-5) and its receptor, IL-5R. In patients susceptible to allergic disorders, IL-5 receptor a (IL5RA) polymorphisms have been reported;however, an association with AERD remains unclear. We hypothesize that IL5RA polymorphisms may contribute to eosinophil activation in AERD patients. We recruited 139 AERD patients, 171 aspirin-tolerant asthma patients and 160 normal controls. IL5RA polymorphisms (5993G4A, 5567C4G and 5091G4A) were genotyped and functional activity of polymorphism was assessed by luciferase reporter assay and electrophoretic mobility shift assay (EMSA). There was no significant difference in the genotype frequency of the three polymorphisms among the three groups. AERD patients carrying the AA genotype at 5993G4A had a significantly higher presence of serum-specific immunoglobulin E (IgE) to staphylococcal enterotoxin A (P¼0.008) than those with the GG/GA genotype. In vitro, the 5993A allele had a higher promoter activity compared with the 5993G allele in human mast cell (HMC-1; P¼0.030) and human promyelocytic leukemia (HL-60; P¼0.013) cells. In EMSA, a 5993A probe produced a specific shifted band than the 5993G had. These findings suggest that a functional polymorphism in IL5RA may contribute to eosinophil and mast cell activation along with specific IgE responses to staphylococcal enterotoxin A in AERD patients.

IL-5 Promoter Polymorphism Enhances IgE Responses to Staphylococcal Superantigens in Adult Asthmatics

Purevsuren Losol,김승현,황의경,신유섭,박해심 대한천식알레르기학회 2013 Allergy, Asthma & Immunology Research Vol.5 No.2

Interleukin 5 (IL-5) is a key cytokine involved in the induction of T-helper type 2 (Th2) responses in the asthmatic airway. We investigated IL-5 geneticpolymorphisms associated with asthma phenotypes, including IgE responses to staphylococcal enterotoxins A and B (SEA and SEB, respectively), inasthmatics. Adult asthmatics (n=310) and normal controls (n=160) were enrolled in the present study. Serum total and specific IgE to SEA and SEBwere measured. Two IL-5 polymorphisms, -746A>G and +4499T>G, were genotyped using the primer-extension method. There were no significantdifferences in genotype or haplotype frequencies of these polymorphisms between the two groups. Asthmatics carrying the AG/GG genotype at-746A>G had a significantly higher prevalence of serum specific IgE to SEA (P=0.008), higher total IgE levels (P=0.014), and lower PC20 methacholinelevels (P=0.002) compared to those with the AA genotype. These findings suggest that the IL-5 promoter polymorphism at -746A>G enhancesserum total and specific IgE responses to SEA, which may augment airway hyperresponsiveness in adult asthmatics.

Cytokine Inductions and Intracellular Signal Profiles by Stimulation of dsRNA and SEB in the Macrophages and Epithelial Cells

최준표,Losol Purevsuren,Ayoub Ghazal,지미홍,김세훈,조상헌,장윤석 대한면역학회 2022 Immune Network Vol.22 No.2

Foreign molecules, including viruses and bacteria-derived toxins, can also induce airway inflammation. However, to the best of our knowledge, the roles of these molecules in the development of airway inflammation have not been fully elucidated. Herein, we investigated the precise role and synergistic effect of virus-mimicking double-stranded RNA (dsRNA) and staphylococcal enterotoxin B (SEB) in macrophages and epithelial cells. To identify cytokine expression profiles, both the THP-1-derived macrophages and BEAS-2B epithelial cells were stimulated with dsRNA or SEB. A total of 21 cytokines were evaluated in the culture supernatants. We observed that stimulation with dsRNA induced cytokine production in both cell types. However, cytokine production was not induced in SEB-stimulated epithelial cells, compared to the macrophages. The synergistic effect of dsRNA and SEB was evaluated observing cytokine level and intracellular phospho-signaling. Fifteen different types were detected in high-dose dsRNA-stimulated epithelial cells, and 12 distinct types were detected in macrophages; those found in macrophages lacked interferon production compared to the epithelial cells. Notably, a synergistic effect of cytokine induction by co-stimulation of dsRNA and SEB was observed mainly in epithelial cells, via activation of most intracellular phosphor-signaling. However, macrophages only showed an accumulative effect. This study showed that the type and severity of cytokine productions from the epithelium or macrophages could be affected by different intensities and a combination of dsRNA and SEB. Further studies with this approach may improve our understanding of the development and exacerbation of airway inflammation and asthma.

COMMUNICATION TECHNOLOGY INFLUENCE IN STUDENTS LEARNING

Urtnasan. G,Losol. A 대한전자공학회 2006 ICEIC:International Conference on Electronics, Inf Vol.2006 No.6

Slide Session : OS-ALG-04 ; Allergy : Association of Autophagy Related Gene Polymorphisms with Neutrophilic Asthma Phenotype in Korean Adult Asthmatics

( Le Duy Pham ),( Seung Hyun Kim ),( Purevsuren Losol ),( Eun Mi Yang ),( Yoo Seob Shin ),( Young Min Ye ),( Hae Sim Park ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: Role of autophagy in neutrophil function and the association of autophagy and autophagy related gene (ATG) polymorphisms with asthma susceptibility were suggested. In this study, we investigated the association of ATG5 and ATG7 polymorphisms with asthma risk, severity and neutrophilic phenotype of asthma. Methods: We recruited 408 asthma patients and 201 healthy controls (NC). Sputum neutrophil counts were determined by H&E staining. Serum IL-8 levels were measured by ELISA. ATG5 gene polymorphisms (-769T>C, -335G>A and 8830C>T) and ATG7 gene polymorphisms (-100A>G and 25108G>C) were genotyped. The functional activities of ATG5 -769T>C and -335G>A variants were investigated by luciferase reporter assays. Results: No associations of ATG5 and ATG7 gene polymorphisms with asthma susceptibility and severity were found. ATG5 -769T>C and -335G>A were in complete linkage disequilibrium. In the asthma group, GA/AA genotypes at ATG5 -335G>A were associated with higher neutrophil counts in sputum (P<0.05); CC/TT genotype at ATG5 8830C>T associated with lower % FEV1 predicted value (P<0.05). DNA fragments containing ATG5 -769T and -335G alleles had higher promoter activities compared to those with -769C and -335A in both human airway epithelial cells (A549, P<0.01) and human mast cell (HMC-1, P<0.001). GG and CC genotype at ATG7 -100A>G and 25108G>C were significantly associated with high serum levels of IL-8 (P<0.05 for both variants). Conclusions: Polymorphisms of ATG5 and ATG7 genes could contribute to neutrophilic phenotype in the pathogenesis of adult asthma.

Role of Toll-like Receptor 3 Variants in Aspirin-Exacerbated Respiratory Disease

Nami Shrestha Palikhe,김승현,김주희,Purevsuren Losol,예영민,박해심 대한천식알레르기학회 2011 Allergy, Asthma & Immunology Research Vol.3 No.2

Purpose: Although the mechanism of virus-induced, aspirin-exacerbated respiratory disease (AERD) is not known fully, direct activation of viral components through Toll-like receptor 3 (TLR3) has been suggested. TLR3 recognizes double-stranded RNA (dsRNA), and activates nuclear factor-κB and increases interferon-γ, which signals other cells to induce airway inflammation in asthma. Considering the association of TLR3 in viral infections and AERD, we investigated whether promoter and non-synonymous variants of TLR3 were associated with AERD. Methods: The three study groups, 203 with AERD, 254 with aspirin-tolerant asthma (ATA), and 274 normal healthy controls (NC) were recruited from Ajou University Hospital, Korea. Two polymorphisms, -299698G>T and 293391G>A [Leu412Phe], were genotyped using primer extension methods. Results: Genetic associations were examined between two genetic polymorphisms of TLR3 (-299698G>T and 293391G>A [Leu412Phe]) in the three study groups. AERD patients that carried the GG genotype of 293391G>A showed a significantly lower frequency compared with ATA in both co-dominant (P=0.025) and dominant models (P=0.036). Similarly, in the minor allele frequency, the A allele was significantly higher (P=0.023) in AERD compared with ATA for this polymorphism. AERD patients who carried HT2 [GA] showed a significantly higher frequency than other haplotypes in co-dominant (P=0.02) and recessive (P=0.026) models. Conclusions: Our findings suggest that the -299698G>T and 293391G>A [Leu412Phe] polymorphisms of the TLR3 gene are associated with the AERD phenotype.

Association of autophagy related gene polymorphisms with neutrophilic airway inflammation in adult asthma

( Duy Le Pham ),( Seung Hyun Kim ),( Purevsuren Losol ),( Eun Mi Yang ),( Yoo Seob Shin ),( Young Min Ye ),( Hae Sim Park ) 대한내과학회 2016 The Korean Journal of Internal Medicine Vol.31 No.2

Background/Aims: Role of autophagy in neutrophil function and the association of autophagy and autophagy related (ATG) gene polymorphisms with asthma susceptibility were suggested. In this study, we investigated the genetic association of ATG5 and ATG7 polymorphisms with asthma risk, severity and neutrophilic airway inflammation. Methods: We recruited 408 asthma patients and 201 healthy controls. Sputum neutrophil counts were determined by H&E staining. Serum interleukin 8 (IL-8) levels were measured by enzyme-linked immunosorbent assay (ELISA). Genetic polymorphisms of ATG5 (-769T>C, -335G>A, and 8830C>T) and ATG7 (-100A>G and 25108G>C) were genotyped. The functional activities of ATG5 -769T>C and -335G>A variants were investigated by luciferase reporter assays. Results: No associations of ATG5 and ATG7 polymorphisms with asthma susceptibility and severity were found. ATG5 -769T>C and -335G>A were in complete linkage disequilibrium. In the asthma group, GA/AA genotypes at ATG5 -335G>A were associated with higher neutrophil counts in sputum (p < 0.05); CC/TT genotype at ATG5 8830C>T associated with lower FEV1% predicted value (p < 0.05). DNA fragments containing ATG5 -769T and -335G alleles had higher promoter activities compared to those with -769C and -335A in both human airway epithelial cells (A549, p < 0.01) and human mast cell (HMC-1, p < 0.001). GG and CC genotype at ATG7 -100A>G and 25108G>C were significantly associated with high serum levels of IL-8 (p < 0.05 for both variants). Conclusions: Genetic polymorphisms of ATG5 and ATG7 could contribute to neutrophilic airway inflammation in the pathogenesis of adult asthma.