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The hypothesis of autoimmune involvement in asthma has received much recent interest. Autoantibodies, such as anti-cytokeratin (CK) 18, anti-CK19, and anti-α-enolase antibodies, react with self-antigens and are found at high levels in the sera of patients with severe asthma (SA). However, the mechanisms underlying autoantibody production in SA have not been fully determined. The present study was conducted to demonstrate that neutrophil extracellular DNA traps (NETs), cytotoxic molecules released from neutrophils, are a key player in the stimulation of airway epithelial cells (AECs) to produce autoantigens. This study showed that NETs significantly increased the intracellular expression of tissue transglutaminase (tTG) but did not affect that of CK18 in AECs. NETs induced the extracellular release of both tTG and CK18 in a concentration-dependent manner. Moreover, NETs directly degraded intracellular α-enolase into small fragments. However, antibodies against neutrophil elastase (NE) or myeloperoxidase (MPO) attenuated the effects of NETs on AECs. Furthermore, each NET isolated from healthy controls (HC), nonsevere asthma (NSA), and SA had different characteristics. Taken together, these findings suggest that AECs exposed to NETs may exhibit higher autoantigen production, especially in SA. Therefore, targeting of NETs may represent a new therapy for neutrophilic asthma with a high level of autoantigens.
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Autoantígenos/metabolismo , Células Epiteliales/metabolismo , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Adulto , Células Cultivadas , Femenino , Proteínas de Unión al GTP/metabolismo , Humanos , Elastasa de Leucocito/metabolismo , Masculino , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas/metabolismo , Adulto JovenRESUMEN
Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty-eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA-sensitized and -challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus-containing goblet cells were reduced in clopidogrel-administered mice compared to vehicle-treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL-1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.
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Asma/patología , Hiperreactividad Bronquial/patología , Eosinófilos/patología , Inflamación/patología , Receptores Purinérgicos P2Y12/metabolismo , Animales , Asma/metabolismo , Hiperreactividad Bronquial/metabolismo , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Femenino , Inflamación/metabolismo , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/farmacologíaRESUMEN
BACKGROUND: Tissue transglutaminase (tTG) is a post-translational modifying enzyme located in airway epithelial cells. A potential contribution of serum specific IgG (sIgG) to tTG in airway inflammation of toluene diisocyanate (TDI)-induced occupational asthma (OA) has been suggested. OBJECTIVE: To prepare a TDI-tTG conjugate and detect serum specific antibodies in sera of patients with TDI-OA to understand this mechanism. METHODS: Ninety-nine patients with TDI-OA, 76 asymptomatic exposed controls, 208 patients with non-OA, and 74 unexposed controls were enrolled for this study. The TDI-tTG conjugate was prepared and confirmed by a native gel. Serum sIgG and/or sIgE antibodies to tTG, TDI-tTG, TDI conjugated to human serum albumin, cytokeratin 19, and serum cytokine levels, such as interleukin-8, transforming growth factor-ß1, and tissue inhibitor of metalloproteinase-1, were measured by enzyme-linked immunosorbent assay. The level of interleukin-8 produced from airway epithelial cells (A549) treated with tTG was evaluated to investigate the inflammatory effect of tTG and TDI-tTG. RESULTS: In the TDI-OA group, the prevalence of serum sIgG to TDI-tTG (17.2%) was higher than that of sIgG to tTG (11.1%), which were significantly higher than those of the 3 control groups (P < .05 for all groups). TDI-exposed subjects with high levels of serum sIgG to TDI-tTG had a high prevalence of sIgG to cytokeratin 19 and higher serum levels of transforming growth factor-ß1 and tissue inhibitor of metalloproteinase-1. The tTG and TDI-tTG dose-dependently increased interleukin-8 production from A549 cells. CONCLUSION: These findings suggest that TDI exposure in the workplace binds to tTG to form a conjugate that can induce serum sIgG antibody production, airway inflammation, and airway remodeling in patients with TDI-OA.
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Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma Ocupacional/sangre , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , 2,4-Diisocianato de Tolueno/efectos adversos , Transglutaminasas/efectos adversos , Adulto , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma Ocupacional/inducido químicamente , Asma Ocupacional/enzimología , Asma Ocupacional/inmunología , Estudios de Casos y Controles , Línea Celular Tumoral , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Interleucina-8/sangre , Interleucina-8/inmunología , Queratina-19/química , Masculino , Persona de Mediana Edad , Albúmina Sérica/química , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidor Tisular de Metaloproteinasa-1/inmunología , 2,4-Diisocianato de Tolueno/química , 2,4-Diisocianato de Tolueno/inmunología , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/inmunología , Transglutaminasas/química , Transglutaminasas/inmunologíaRESUMEN
INTRODUCTION: Moisturizers play an essential role in maintaining the integrity of the skin barrier by increasing stratum corneum hydration (SCH) and reducing transepidermal water loss (TEWL). According to dermatology and allergy guidelines, moisturizers should be applied on the skin within 3 min after bathing or showering. However, there is very little evidence supporting this recommendation. This study aimed to investigate the effectiveness of immediate and delayed moisturizing after bathing/washing on the improvement of SCH and TEWL. METHODS: This was a crossover study of 60 healthy Vietnamese volunteers aged 18-25 years. In each subject, SCH and TEWL levels were measured at three areas: non-moisturized, immediate moisturizing after washing, and delayed moisturizing at 30 min after washing. RESULTS: In non-moisturized skin, SCH and TEWL levels were significantly different from the baseline at 60 min after washing, while significantly decreased TEWL levels were observed immediately after moisturizing. In addition, moisturized skin had significantly higher SCH and lower TEWL levels compared with non-moisturized areas at every time point (p < 0.05). Interestingly, the percentage changes of SCH and TEWL levels from baseline did not differ between immediately and delayed moisturized areas. CONCLUSIONS: Tested moisturizer helped increase SCH and decrease TEWL; however, there was no difference in moisturizing effectiveness between immediate and delayed moisturizing in healthy skin. The recommendation of immediate application of moisturizers after bathing/washing should be reconsidered, and more studies are needed to establish a stronger recommendation.
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Epidermis , Piel , Humanos , Adolescente , Adulto Joven , Adulto , Estudios Cruzados , Piel/metabolismo , Agua/metabolismo , Pérdida Insensible de AguaRESUMEN
BACKGROUND: Vitiligo is a chronic condition characterized by skin depigmentation. Although not life-threatening, it significantly impacts quality of life. The pathophysiology of vitiligo remains poorly understood, and treatment options are limited. Mounting evidence supports the importance of autoreactive T cells and, particularly interleukin-17A- (IL-17A-) secreting Th17 cells, in vitiligo. IL-17A targeting has been proven successful in various inflammatory dermatological conditions, including psoriasis and lupus erythematosus. OBJECTIVE: We evaluated the relationship between serum levels of IL-17A and the clinicopathological characteristics of Vietnamese vitiligo patients. METHODS: In this cross-sectional study, we analyzed data from 52 nonsegmental vitiligo patients and 50 age- and sex-matched healthy individuals. Serum levels of IL-17A were measured using an enzyme-linked immunosorbent assay. We evaluated the correlation between IL-17A levels and clinical characteristics including leukotrichia, disease duration, vitiligo activity, and body surface area involvement. RESULTS: Patients with progressive vitiligo had significantly higher IL-17A levels than patients with stable vitiligo (P = 0.014) or healthy individuals (P = 0.002). In addition, serum IL-17A levels were higher in vitiligo patients with leukotrichia than in patients without it (P = 0.04). Furthermore, serum IL-17A levels were negatively correlated with age (r = -0.39, P = 0.004) and age of onset (r = -0.33, P = 0.016) in vitiligo patients. CONCLUSIONS: Higher serum levels of IL-17A in patients with progressive vitiligo and leukotrichia suggest a potential role of IL-17A in melanocyte destruction in the epidermis and the follicular matrix.
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Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively prescribed in daily clinical practice. NSAIDs are the main cause of drug hypersensitivity reactions all over the world. The inhibition of cyclooxygenase enzymes by NSAIDs can perpetuate arachidonic acid metabolism, shunting to the 5-lipoxygenase pathway and its downstream inflammatory process. Clinical phenotypes of NSAID hypersensitivity are diverse and can be classified into cross-reactive or selective responses. Efforts have been made to understand pathogenic mechanisms, in which, genetic and epigenetic backgrounds are implicated in various processes of NSAID-induced hypersensitivity reactions. Although there were some similarities among patients, several genetic polymorphisms are distinct in those exhibiting respiratory or cutaneous symptoms. Moreover, the expression levels, as well as the methylation status of genes related to immune responses were demonstrated to be involved in NSAID-induced hypersensitivity reactions. There is still a lack of data on delayed type reactions. Further studies with a larger sample size, which integrate different genetic pathways, can help overcome current limitations of gen etic/epigenetic studies, and provide valuable information on NSAID hypersensitivity reactions.
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Alérgenos/farmacología , Células Epiteliales/efectos de los fármacos , Extractos Vegetales/farmacología , Polen/inmunología , Mucosa Respiratoria/efectos de los fármacos , Alérgenos/inmunología , Dióxido de Carbono/química , Línea Celular , Citocinas/agonistas , Citocinas/genética , Citocinas/inmunología , Células Epiteliales/citología , Células Epiteliales/inmunología , Regulación de la Expresión Génica , Humanos , Humulus/química , Humulus/inmunología , Ocludina/genética , Ocludina/inmunología , Permeabilidad , Extractos Vegetales/inmunología , Polen/química , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/inmunología , Receptor PAR-2/agonistas , Receptor PAR-2/genética , Receptor PAR-2/inmunología , Mucosa Respiratoria/citología , Mucosa Respiratoria/inmunología , Transducción de Señal , Temperatura , Linfopoyetina del Estroma TímicoRESUMEN
Protein tyrosine phosphatase-22 (PTPN22) gene encodes lymphoid-specific tyrosine phosphatase (Lyp), an inhibitor of T cell activation. A polymorphism of the PTPN22 gene has been found to be associated with chronic urticaria (CU). We investigated the associations between PTPN22 gene polymorphisms and CU characteristics, including serum specific IgE antibodies response to toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin A (SEA). CU patients (n=409) and normal healthy controls (n=388) were enrolled in the present study. Serum specific IgE to TSST-1 and SEA were measured by ImmunoCAP®. Five PTPN22 single nucleotide polymorphisms, -1123G>C, 1858C>T, 13145A>G, 14943C>T, and 20628A>G, were genotyped. There were no significant differences in genotype or haplotype frequencies of these polymorphisms between the 2 groups. CU patients carrying the GG genotype at 20628A>G (P=0.035) or haplotype 3 [GGG] (P=0.047) had a significantly higher prevalence of serum specific IgE to TSST-1 compared to non-carriers. Similarly, CT/TT genotype at 14943C>T had a significantly higher prevalence of serum specific IgE to SEA (P=0.045). The findings suggest that the PTPN22 gene polymorphisms at 20628A>G and 14943C>T may enhance serum specific IgE responses to TSST-1 and SEA, which may contribute to CU pathogenesis.
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PURPOSE OF REVIEW: A variety of novel asthma treatments have been developed based on phenotypes, and the clinical trial results show promising responses. This review summarizes the current knowledge of biomarkers for the determination of asthma phenotypes. RECENT FINDINGS: Eosinophilic inflammation is the most focused phenotype because most novel asthma treatments have targeted T-helper type 2 (Th2) pathway. Fractional-exhaled nitric oxide (FeNO) is a new method that represents an eosinophilic airway inflammation with a significant correlation with sputum eosinophilia and asthma severity instead of sputum eosinophil count that easily influenced by corticosteroid therapy. However, some reports indicated the discordance between treatment response or adjustment and FeNO levels. Serum periostin is a strong serum biomarker for eosinophilic airway inflammation and an indicator of Th2-targeted therapy (such as lebrikizumab or omalizumab) and airflow limitation. YKL-40 is associated with asthma severity and airway remodeling. In addition, genetic and metabolomic approaches have been made to determine asthma phenotypes and severity. SUMMARY: Biomarkers such as FeNO and serum periostin represent eosinophilic airway inflammation, together with eosinophil-derived neurotoxin and osteopontin (OPN) needed more replication studies. Periostin, YKL-40, OPN and some metabolites (choline, arginine, acetone and protectin D1) are related to asthma severity and airflow limitation.
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Adipoquinas/metabolismo , Asma/diagnóstico , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Eosinófilos/metabolismo , Inflamación/diagnóstico , Lectinas/metabolismo , Óxido Nítrico/metabolismo , Adulto , Asma/clasificación , Proteína 1 Similar a Quitinasa-3 , Progresión de la Enfermedad , Humanos , Terapia Molecular Dirigida , Osteopontina/metabolismoRESUMEN
PURPOSE OF REVIEW: Diisocyanates are the most common cause of occupational asthma in many industrialized countries, and various pathogenic mechanisms have been suggested to be involved. Occupational asthma causes airway remodeling unless diagnosed and treated within a proper time frame. However, treatment modalities are limited because of an insufficient understanding regarding underlying pathogenic mechanisms. RECENT FINDINGS: Several immunological and nonimmunological mechanisms have been suggested, indicating that the pathogenesis of occupational asthma may be more complex than other types of asthma. Airway epithelial cells are the first to encounter diisocyanates and orchestrate various responses, such as cytokine release, oxidative stress generation, and autoantibody formation. Some evidence supports the involvement of adaptive immune responses. Additional evidence suggests that other mechanisms are involved in diisocyanate-induced occupational asthma. One such candidate mechanism is oxidative stress. Oxidative stress has been shown to trigger and aid in the development of diisocyanate-induced occupational asthma in human samples and genetic studies, and some therapeutic trials were performed based on this finding. SUMMARY: Diisocyanate-induced occupational asthma may be caused by a complex interaction of innate and adaptive immune responses. The knowledge presented in this review may help lead to the development of new treatment modalities through an increased understanding of occupational asthma pathogenesis.