RESUMO
Inhaled aeroallergens can directly activate airway epithelial cells (AECs). Exposure to cockroach allergens is a strong risk factor for asthma. Cockroach allergens mediate some of their effects through their serine protease activity; protease activity is also a major contributor to allergenicity. The Th2 cytokine interleukin-13 (IL-13) induces upregulation of the eosinophil chemotactic factor CCL26. CCL26 induces eosinophil migration in allergic inflammation. In this work, we studied the effect of cockroach proteases on IL-13-induced effects. Immersed cultures of the human bronchial epithelial cell line BEAS-2B and air-liquid interface (ALI) cultures of primary normal human bronchial epithelial (NHBE) cells were stimulated with IL-13, Blattella Germanica cockroach extract (CE), or both. IL-13-induced genes were analyzed with qRT-PCR. IL-13 induced upregulation of CCL26, periostin, and IL-13Rα2 in bronchial epithelial cells which were decreased by CE. CE was heat-inactivated (HICE) or pre-incubated with protease inhibitors. HICE and CE preincubated with serine protease inhibitors did not prevent IL-13-induced CCL26 upregulation. CE-degraded IL-13 and specific cleavage sites were identified. CE also decreased IL-4-induced CCL26 upregulation and degraded IL-4. Other serine proteases such as bovine trypsin and house dust mite (HDM) serine proteases did not have the same effects on IL-13-induced CCL26. We conclude that CE serine proteases antagonize IL-13-induced effects in AECs, and this CE effect is mediated primarily through proteolytic cleavage of IL-13. IL-13 cleavage by cockroach serine proteases may modulate CCL26-mediated effects in allergic airway inflammation by interfering directly with the pro-inflammatory effects of IL-13 in vivo.
Assuntos
Blattellidae , Humanos , Animais , Bovinos , Interleucina-13 , Interleucina-4 , Serina Proteases , Serina Endopeptidases , Inflamação , Quimiocina CCL26RESUMO
BACKGROUND: Myeloid cells, especially dendritic cells and macrophages, play important roles in asthma pathophysiology. Monocytes (Mo) and macrophages express protease-activated receptor-2 (PAR-2), a proinflammatory serine protease receptor implicated in the pathophysiology of allergic airway inflammation. We have revealed that patients with severe asthma and those with a history of frequent asthma exacerbations exhibit increased PAR-2 expression on peripheral blood monocytes. OBJECTIVE: To determine PAR-2 expression on peripheral blood intermediate monocytes (IMMo) in subjects with increased airway inflammation, either as a result of an asthma exacerbation or after an inhalation allergen challenge. METHODS: A total of 16 adults who presented to the emergency department with asthma exacerbations were recruited after giving an informed consent. After 2 weeks, 10 patients returned for follow-up. A total of 11 patients with mild asthma treated only with as-needed bronchodilators were recruited and underwent inhalation allergen challenge after providing an informed consent. Immune cell profiling was performed by whole blood flow cytometry in both groups of patients. RESULTS: PAR-2 expression in peripheral blood IMMo increased in patients with an asthma exacerbation compared with those with stable disease, but this expression decreased after treatment of the asthma exacerbation. Subjects with mild asthma had an increase in percentages of IMMo expressing PAR-2 after an allergen challenge. Patients who presented to the emergency department had lower dendritic cell and dendritic cell subset numbers in peripheral blood during exacerbation compared with after treatment. CONCLUSION: Increased PAR-2 expression on Mo during periods of increased airway inflammation may initiate a positive feedback loop leading to systemic inflammatory changes.
Assuntos
Asma/sangue , Testes de Provocação Brônquica , Células Dendríticas/imunologia , Leucócitos Mononucleares/metabolismo , Receptor PAR-2/sangue , Adolescente , Adulto , Asma/patologia , Contagem de Células , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor PAR-2/biossíntese , Adulto JovemRESUMO
BACKGROUND: Platelets are actively involved in immune inflammatory processes that release inflammatory mediators. Platelet activation has been reported in various inflammatory diseases; however, few studies have described platelet involvement in chronic urticaria (CU). OBJECTIVE: To investigate platelet-activation markers, namely P2Y12 receptor and P-selectin expression, and soluble P-selectin level in patients with aspirin-intolerant CU (AICU) and aspirin-tolerant CU (ATCU). METHODS: Forty-eight patients with CU and 25 normal controls were enrolled in this study. Aspirin intolerance in patients with CU was confirmed by an oral provocation test. P2Y12 and P-selectin expressions on platelets were measured using flow cytometry; soluble P-selectin level in plasma was measured by enzyme-linked immunosorbent assay. To study the functional effects of aspirin, platelets were treated with aspirin (2 mmol/L) and the expressions of P2Y12 and P-selectin were compared between the AICU and ATCU groups. RESULTS: The expression of P2Y12 was significantly higher in patients with CU compared with controls, whereas no significant difference was noted in the expression of P-selectin level. The levels were not significantly different according to urticaria symptom score, symptom control status, and aspirin intolerance. Soluble P-selectin level was significantly higher in the AICU group than in the ATCU group compared with controls. Aspirin did not significantly suppress P2Y12 and P-selectin expressions on platelets in the AICU group, whereas significant suppression was noted in the ATCU group. CONCLUSION: These findings suggest that increased platelet activation contributes to skin inflammation in patients with AICU and those with ATCU. The functional difference of platelets in response to aspirin may contribute to persistent skin inflammation in patients with AICU.
Assuntos
Ativação Plaquetária/imunologia , Urticária/imunologia , Adulto , Aspirina/imunologia , Biomarcadores/metabolismo , Plaquetas/imunologia , Plaquetas/metabolismo , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Selectina-P/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Receptores Purinérgicos P2Y12/metabolismo , Urticária/sangue , Urticária/metabolismo , Adulto JovemRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects up to 10% of Canadians. Patients with COPD may present with secondary humoral immunodeficiency as a result of chronic disease, poor nutrition or frequent courses of oral corticosteroids; decreased humoral immunity may predispose these patients to mucosal infections. We hypothesized that decreased serum immunoglobulin (Ig) levels was associated with the severity of an acute COPD exacerbations (AECOPD). METHODS: A prospective study to examine cardiovascular risks in patients hospitalized for AECOPD, recruited patients on the day of hospital admission and collected data on length of hospital stay at index admission, subsequent emergency department visits and hospital readmissions. Immunoglobulin levels were measured in serum collected prospectively at recruitment. RESULTS: Among the 51 patients recruited during an admission for AECOPD, 14 (27.5%) had low IgG, 1 (2.0%) low IgA and 16 (31.4%) low IgM; in total, 24 (47.1%) had at least one immunoglobulin below the normal range. Patients with low IgM had longer hospital stay during the index admission compared to patients with normal IgM levels (6.0 vs. 3.0 days, p = 0.003), but no difference in other clinical outcomes. In the whole cohort, there was a negative correlation between serum IgM levels and length of hospital stay (R = - 0.317, p = 0.024). There was no difference in clinical outcomes between subjects with normal and low IgG levels. CONCLUSION: In patients presenting with AECOPD, low IgM is associated with longer hospital stay and may indicate a patient phenotype that would benefit from efforts to prevent respiratory infections. Trial registration statement: Retrospectively registered.
RESUMO
Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria- and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at -1254 G>A showed significantly higher frequency compared with NC (P=0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P=0.031). In vitro functional study demonstrated that the -1254 G allele had lower luciferase activity (P<0.001) in HMC-1 cells. EMSA finding showed that PTGER4 -1254 G produced a specific band. Significantly decreased PTGER4 expression (P=0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P=0.001). The PTGER4 -1254 G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.
Assuntos
Aspirina , Hipersensibilidade a Drogas/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Urticária/genética , Adulto , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Hipersensibilidade a Drogas/metabolismo , Feminino , Frequência do Gene , Humanos , Imunoglobulina E/sangue , Coreia (Geográfico) , Masculino , Mastócitos/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Urticária/sangue , Urticária/tratamento farmacológico , Urticária/imunologiaAssuntos
Asma Induzida por Aspirina/genética , Receptores Purinérgicos P2Y12/genética , Adulto , Asma Induzida por Aspirina/imunologia , Estudos de Casos e Controles , Eosinófilos/imunologia , Feminino , Genótipo , Humanos , Masculino , Ativação Plaquetária/genética , Ativação Plaquetária/imunologia , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
PURPOSE: Psychological stress shifts the immune system toward the production of T-helper (Th)-2-mediated cytokines and eosinophilia, increases the risks for both asthma and depression, and can precipitate asthma exacerbations. Th2-mediated inflammation is a characteristic of allergic asthma. We have shown that the levels of CD4+ Th2 cells in the peripheral blood of patients with asthma are associated with severity and/or control of the disease. To improve our understanding of the interactions between stress and asthma symptoms, we evaluated the effects of psychological comorbidity on Th2-mediated inflammation in patients with asthma. METHODS: Sixty-six asthmatic patients were recruited from the University of Alberta Asthma Clinic after they gave informed consent. Stress-related effects on asthma and psychological morbidity were assessed using the Asthma Control Questionnaire, completed by the patients at recruitment. Venous blood was collected at recruitment and Th2-mediated immunity evaluated by flow cytometry, quantitative real-time reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. FINDINGS: Patients with stress-triggered asthma (n = 12) had higher percentage of CD4+ T cells (P = 0.006) and Th2 cells (CD4+CRTh2+ T cells; P = 0.002) in peripheral blood compared to patients with asthma who did not experience stress-related worsening of disease (n = 54). The same was true when we analyzed patients with any form of psychological comorbidity (n = 19) compared to those without psychological comorbidities (n = 47). These differences were evident among women, but not among men. Women with psychological comorbidity also required higher doses of inhaled and oral corticosteroids compared to those without psychological comorbidity. IMPLICATIONS: Asthma involving psychological morbidity associates with an elevated level of circulating Th2 cells and increased corticosteroid usage, and may be more prevalent in women. Larger-scale prospective studies are required for assessing whether these women constitute a new endotype of Th2-high asthma responsive to treatments aimed to improve psychological comorbidities.
Assuntos
Asma/imunologia , Estresse Psicológico/imunologia , Células Th2/imunologia , Corticosteroides/uso terapêutico , Adulto , Asma/tratamento farmacológico , Asma/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Prevalência , Estresse Psicológico/epidemiologiaRESUMO
BACKGROUND: Glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine expression and induce apoptosis. Asthma severity is associated with type 2 inflammation, circulating Th2 cells and higher GC requirements. OBJECTIVE: The aim of this study was to assess whether ex vivo production of interleukin 2 (IL-2), a T-cell survival factor, associated with clinical features of asthma severity, the proportion of blood Th2 cells and Th2 cell responses to GC. METHODS: Peripheral blood from asthma patients (n = 18) was obtained and the proportion of Th2 cells determined by flow cytometry. Peripheral blood cells were activated with mitogen (24 hours) and supernatant levels of IL-2 and IL-13 measured by enzyme-linked immunosorbent assay. In vitro differentiated Th2 cells were treated with dexamethasone (DEX) and IL-2 and assessed for apoptosis by flow cytometry (annexin V). Level of messenger RNA (mRNA) for antiapoptotic (BCL-2) and proapoptotic (BIM) genes, IL-13, GC receptor (GR) and FKBP5 were determined by quantitative real-time polymerase chain reaction. GR binding was assessed by chromatin immunoprecipitation. RESULTS: IL-2 produced by activated peripheral blood cells correlated negatively with lung function and positively with a daily dose of inhaled GC. When patients were stratified based on IL-2 level, high IL-2 producers made more IL-13 and had a higher proportion of circulating Th2 cells. In vitro, increasing the level of IL-2 in the culture media was associated with resistance to DEX-induced apoptosis, with more BCL-2/less BIM mRNA. Th2 cells cultured in high IL-2 had more IL-13, less GR mRNA, showed reduced binding of the GR to FKBP5, a known GC-induced gene, and required higher concentrations of DEX for cytokine suppression. CONCLUSIONS AND CLINICAL RELEVANCE: IL-2 downregulates Th2 cell responses to GC, supporting both their survival and pro-inflammatory capacity. These results suggest that a patient's potential to produce IL-2 may be a determinant in asthma severity.
Assuntos
Asma/tratamento farmacológico , Citocinas/imunologia , Glucocorticoides/farmacologia , Inflamação/imunologia , Interleucina-2/imunologia , Células Th2/imunologia , Adulto , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Asma/genética , Asma/metabolismo , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/imunologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Dexametasona/farmacologia , Feminino , Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-2/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA/genética , RNA/imunologia , RNA/metabolismo , Células Th2/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: The high-affinity IgE receptor comprises a tetramer of the ligand-binding alpha chain, a signal-augmenting beta chain, and a signal-transducing gamma chain dimer on mast cells. We hypothesized that the three subsets of the FCER1 gene may play a role in the development of the aspirin-intolerant asthma (AIA) phenotype and analyzed these genetic polymorphisms in association with clinical parameters in AIA patients. SUBJECTS AND METHODS: Six polymorphisms of FCER1 (FCERIA-344C>T, FCER1A-95T>C, MS4A2-109T>C, MS4A2 E237G, FCER1G-237A>G, FCER1G-54G>T) were genotyped in 126 AIA patients compared to 177 patients with aspirin-tolerant asthma (ATA) and 222 normal health controls (NC). RESULTS: A significant difference in the genotype frequencies of FCER1G-237A>G was detected between AIA and ATA patients (p<0.05) both in co-dominant and recessive analysis models, whereas no significant relationships were identified between the frequencies of the other five single-nucleotide polymorphisms and AIA, ATA, and NC subjects. In addition, AIA patients carrying the homozygous AA genotype of FCER1G-237A>G exhibited significantly higher total serum IgE levels than did those with the GG/AG genotype (p=0.012). AIA patients expressing the CT/TT genotype at FCERIA-344C>T showed a higher prevalence of serum IgE specific to Staphylococcal enterotoxin A than did those with the CC genotype (p=0.008). CONCLUSION: The FCER1G-237A>G and FCERIA-344C>T polymorphisms may contribute to the development of AIA in a Korean population.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgE/genética , Adulto , Anticorpos Antibacterianos/sangue , Asma/induzido quimicamente , Asma/imunologia , Asma/fisiopatologia , Testes de Provocação Brônquica/métodos , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Superantígenos/imunologiaRESUMO
CRTh2 (encoded by PTGDR2) is a G-protein coupled receptor expressed by Th2 cells as well as eosinophils, basophils and innate lymphoid cells (ILC)2s. Activation of CRTh2, by its ligand prostaglandin (PG)D2, mediates production of type 2 cytokines (IL-4, IL-5 and IL-13), chemotaxis and inhibition of apoptosis. As such, the PGD2-CRTh2 pathway is considered important to the development and maintenance of allergic inflammation. Expression of CRTh2 is mediated by the transcription factor GATA3 during Th2 cell differentiation and within ILC2s. Other than this, relatively little is known regarding the cellular and molecular mechanisms regulating expression of CRTh2. Here, we show using primary human Th2 cells that activation (24hrs) through TCR crosslinking (αCD3/αCD28) reduced expression of both mRNA and surface levels of CRTh2 assessed by flow cytometry and qRT-PCR. This effect took more than 4 hours and expression was recovered following removal of activation. EMSA analysis revealed that GATA3 and NFAT1 can bind independently to overlapping sites within a CRTh2 promoter probe. NFAT1 over-expression resulted in loss of GATA3-mediated CRTh2 promoter activity, while inhibition of NFAT using a peptide inhibitor (VIVIT) coincided with recovery of CRTh2 expression. Collectively these data indicate that expression of CRTh2 is regulated through the competitive action of GATA3 and NFAT1. Though prolonged activation led to NFAT1-mediated downregulation, CRTh2 was re-expressed when stimulus was removed suggesting this is a dynamic mechanism and may play a role in PGD2-CRTh2 mediated allergic inflammation.
Assuntos
Fator de Transcrição GATA3/genética , Regulação da Expressão Gênica/imunologia , Fatores de Transcrição NFATC/genética , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Células Th2/imunologia , Anticorpos Monoclonais/farmacologia , Sequência de Bases , Sítios de Ligação , Ligação Competitiva , Antígenos CD28/antagonistas & inibidores , Antígenos CD28/genética , Antígenos CD28/imunologia , Complexo CD3/antagonistas & inibidores , Complexo CD3/genética , Complexo CD3/imunologia , Fator de Transcrição GATA3/imunologia , Humanos , Células Jurkat , Ativação Linfocitária/efeitos dos fármacos , Fatores de Transcrição NFATC/imunologia , Cultura Primária de Células , Regiões Promotoras Genéticas , Prostaglandina D2/metabolismo , Prostaglandina D2/farmacologia , Ligação Proteica , Receptores Imunológicos/agonistas , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/imunologia , Transdução de Sinais , Células Th2/citologia , Células Th2/efeitos dos fármacosAssuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Interleucina-10/genética , Urticária/induzido quimicamente , Urticária/genética , Aspirina/imunologia , DNA/química , DNA/genética , Predisposição Genética para Doença , Genótipo , Humanos , Imunoglobulina E/sangue , Interleucina-10/imunologia , Modelos Logísticos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , República da Coreia , Urticária/imunologiaRESUMO
THREE DIISOCYANATES CAN CAUSE OCCUPATIONAL ASTHMA (OA): toluene diisocyanate (TDI), 4,4 diphenylmethane diisocyanate (MDI), and 1,6-hexamethylene diisocyanate (HDI). We analyzed potential biomarkers of isocyanate-induced OA, based on investigated immunologic, genetic, neurogenic, and protein markers, because there is no serological testing method. The prevalence of serum IgG to cytokeratin (CK)18 and CK19 in TDI-OA was significantly higher than in controls, although the prevalence of these antibodies was too low for them to be used as biomarkers. Another candidate biomarker was serum IgG to tissue transglutaminase (tTG), because the prevalence of serum specific IgG to tTG was significantly higher in patients with TDI-OA than in controls. The human leukocyte antigen (HLA) DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be used as a genetic marker for TDI-OA in Koreans via enhanced specific IgE sensitization in exposed subjects. The genetic polymorphisms of catenin alpha 3, alpha-T catenin (CTNNA3) were significantly associated with TDI-OA. Additionally, examining the neurokinin 2 receptor (NK2R) 7853G>A and 11424 G>A polymorphisms, the NK2R 7853GG genotype had higher serum vascular endothelial growth factor (VEGF) levels than the GA or AA genotypes among Korean workers exposed to TDI. To identify new serologic markers using a proteomic approach, differentially expressed proteins between subjects with MDI-OA and asymptomatic exposed controls in a Korean population showed that the optimal serum cutoff levels were 69.8 ng/mL for ferritin and 2.5 µg/mL for transferrin. When these two parameters were combined, the sensitivity was 71.4% and the specificity was 85.7%. The serum cytokine matrix metalloproteinase-9 (MMP-9) level is a useful biomarker for identifying cases of TDI-OA among exposed workers. Despite these possible biomarkers, more effort should be focused on developing early diagnostic biomarkers using a comprehensive approach based on the pathogenic mechanisms of isocyanate-induced OA.
RESUMO
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.
RESUMO
Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9(*)3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.
RESUMO
PURPOSE OF REVIEW: The purpose of this article is to review the recent findings of studies reporting on the genetic and ethnic factors associated with hypersensitivity reactions to common drugs such as acetyl salicylic acid/NSAIDs, antibiotics, antituberculus medications, and other drugs including carbamazepine (CBZ), abacarvir, and allopurinol that can cause severe hypersensitivity reactions. RECENT FINDINGS: Aspirin hypersensitivity has recently been associated with a variety of genetic polymorphisms associated with leukotriene overproduction, eosinophil infiltration, and histamine-related genes. Recently, beta-lactam antibiotic hypersensitivity has been reported to be associated with interleukin (IL)-4 and IL-13 receptors in Italian, Chinese, and French populations. Moreover, a significant association of CYP2E1 in the Chinese, NAT2 in Koreans and glutathione S-transferase genotypes in Caucasians has been reported with antituberculus drug-induced hepatitis. The association of the HLA-B*1502 allele with CBZ-induced Stevens-Johnson syndrome in Asian population has also recently been observed. SUMMARY: Aspirin hypersensitivity has been associated with various genetic polymorphisms. Human leukocyte antigen (HLA)-related markers and a variety of genetic polymorphisms of leukotriene-related genes, eosinophil-related genes, and genes associated with immune function have been described according to ethnicity. The genetic mechanisms of antibiotic hypersensitivity have been reported in Italian, French, and Chinese populations in addition to antibiotics-induced cutaneous reactions in the Korean population. Most prior genetic studies on antituberculus drug-induced hepatitis have focused on a few drug-metabolizing enzymes such as cytochrome P450 and N-acetyltransferase 2. HLA-related markers associated with CBZ, lamotrigine, and abacavir-induced severe hypersensitivity reactions have been described.
Assuntos
Hipersensibilidade a Drogas/etnologia , Hipersensibilidade a Drogas/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Povo Asiático/genética , Hipersensibilidade a Drogas/etiologia , Humanos , Fatores de Risco , População Branca/genéticaRESUMO
PURPOSE: Aspirin-intolerant asthma (AIA) is characterized by moderate to severe asthma that is aggravated by aspirin or other non-steroidal anti-inflammatory drugs. Affected patients frequently have chronic rhinosinusitis and nasal polyposis due to persistent upper and lower airway inflammation with marked eosinophilia. IL-13 plays a crucial role in the development of allergic asthma by inducing airway eosinophilia and hyper-reactivity and it has been correlated with an increased eosinophil count. METHODS: Two promoter polymorphisms of the IL-13 gene (-1510 A>C and -1055C>T) and one coding nonsynonymus Arg110Gln (110G>A) polymorphism were genotyped using primer extension methods in 162 patients with AIA, 301 patients with aspirin-tolerant asthma (ATA), and 430 normal healthy controls (NC). RESULTS: There was no significant difference in the genotype, allele, and haplotype frequencies of the three polymorphisms among the three groups. AIA patients with the AA genotype -1510A>C (P=0.012) and CC genotype -1055C>T (P<0.001) had a significantly higher frequency of rhinosinusitis, as compared to those with the minor alleles of these two single nucleotide polymorphisms. AIA patients with the GG genotype had a higher peripheral eosinophil count (P=0.025) and a higher serum eotaxin-1 level (P=0.044), as compared to patients with the AA genotype IL-13 Arg110Gln (110G>A). CONCLUSIONS: These findings suggest that the IL-13 polymorphisms at -1510A>C and 1055C>T are associated with the development of rhinosinusitis in AIA patients. IL-13 Arg110Gln may be associated with an increased eosinophil count and eotaxin-1 level and could increase eosinophilic inflammation in the upper and lower airways of patients with AIA.
RESUMO
Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.
Assuntos
Asma Induzida por Aspirina/genética , Asma Induzida por Aspirina/imunologia , Animais , Asma Induzida por Aspirina/tratamento farmacológico , Eosinófilos/metabolismo , Predisposição Genética para Doença/genética , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Leucotrienos/metabolismo , Modelos Biológicos , Polimorfismo Genético/genética , Polimorfismo Genético/fisiologiaRESUMO
INTRODUCTION: Chronic urticaria (CU), defined as the recurring incidence of wheals with or without angioedema for more than 6 weeks, is a common disorder associated with mast cell activation, degranulation, and histamine release. Considering the association between the CRTH2 gene and mast cells, we investigated the association of this gene polymorphism with the CU phenotype and antihistamine drug requirement in patients with CU. MATERIALS & METHODS: Two groups consisting of 384 patients with CU and 231 patients as normal controls (NCs) were enrolled from the Department of Allergy and Rheumatology, Ajou University Hospital, Suwon, Korea. Two polymorphisms of the CRTH2 gene, -466T>C and -129C>A were genotyped using primer extension methods. RESULTS: No significant differences were detected in the genotype and allele frequencies of the two CRTH2 polymorphisms between the CU and NC groups, and no significant associations were observed with clinical parameters, such as atopy status, serum total IgE, prevalence of autoantibodies and duration of CU. However, CU patients with homozygous TT genotypes had significantly higher dose requirements of antihistamines to control the CU symptoms (164.56 +/- 115.62 vs 137.38 +/- 90.15 loratadine equivalents, mg/week) than those with the CT and CC genotypes (p = 0.025). The luciferase activity was significantly enhanced in the construct containing CRTH2 466C compared with the -466T-containing construct (p < 0.001). Co-transfection experiments with GATA-3 (300 ng) and the -466T and -466C CRTH2 alleles revealed that the CRTH2 -466T allele produced a greater increase in induction of luciferase activity than the -466C allele (p < 0.001). CONCLUSION: The CRTH2 -466T>C gene polymorphism may not affect on the phenotype of CU, but contributes to the required dose of antihistamines in patients with CU.
Assuntos
Antagonistas dos Receptores Histamínicos/uso terapêutico , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Urticária/genética , Linhagem Celular , Doença Crônica , Primers do DNA , Fator de Transcrição GATA3/genética , Frequência do Gene , Genótipo , Liberação de Histamina , Humanos , Imunoglobulina E/sangue , Mastócitos/fisiologia , Fenótipo , Plasmídeos , Regiões Promotoras Genéticas , Valores de Referência , Transfecção , Urticária/tratamento farmacológico , Urticária/imunologia , Urticária/fisiopatologiaRESUMO
Aspirin-intolerant chronic urticaria (AICU) is a common condition among the chronic urticaria population, but the genetic mechanism is not yet understood. In this study, the genotypes and haplotypes of three interleukin (IL)-13 polymorphisms, -1510 A>C, -1055C>T, and Arg110Gln (110G>A), as well as their respective clinical phenotypes were examined to determine whether genetic variants of IL-13 play a role in AICU. Single-nucleotide polymorphism (SNP) genotyping was used to compare IL-13 genotype and allele frequencies among 135 patients with AICU, 146 with aspirin-tolerant chronic urticaria (ATCU), and 430 normal controls (NC). Relationships among the AICU phenotype, atopy, and total IgE level were also investigated. The results failed to show a significant difference in the allele or genotype frequencies between the AICU group and either the ATCU or NC group (P>0.05, respectively). Haplotype analysis confirmed that there was no significant difference among the three study groups (P>0.05), nor was there a significant difference in atopy or total IgE level according to the three genetic polymorphisms (P>0.05, respectively). Our data lead to the conclusion that there is no evidence supporting genetic polymorphisms in IL-13 as a genetic risk factor for the development of AICU.