Search

Background: Urticaria is the commonest cutaneous reaction caused by aspirin or other nonsteroidal anti-inflammatory drugs. The pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, but appears to involve mast cell activation and neutrophil infiltration., Objectives: To investigate the genetic contribution of interleukin (IL)-18, which can amplify acute inflammation by promoting mast cell activation, neutrophil migration and cytokine production, to the pathogenesis of AIU., Methods: A case-control association study was performed using 275 patients with AIU and 196 normal healthy controls in a Korean population. Two promoter polymorphisms of the IL18 gene (-607A/C and -137G/C) were genotyped using the primer extension method. The functional effect of the IL18 gene promoter polymorphism was investigated through in vitro studies including a luciferase reporter assay and electrophoretic mobility shift assays (EMSAs) and ex vivo studies involving neutrophil chemotaxis assays., Results: A significant association was detected between both AIU in general and the aspirin-intolerant acute urticaria (AIAU) phenotype and the IL18 promoter polymorphism -607A/C. Patients with AIAU showed higher frequencies of the C(-607) G(-137) haplotype, ht1 [CG], compared with controls (P=0·02). Moreover, ht1 [CG] showed a high transcript haplotype by the luciferase activity assay, and EMSAs identified a -607C allele-specific DNA-binding protein as CREB2. Neutrophil chemotactic activity was highest in subjects with AIU exhibiting the high transcript haplotype, ht1 [CG] (P=0·019)., Conclusions: The high transcript haplotype ht1 [CG] of the IL18 gene may contribute to the development of acute cutaneous inflammation sensitive to aspirin, leading to the clinical presentation of AIAU., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Background: The thromboxane A2 receptor (TBXA2R) is a potent broncho- and vaso-constrictor and is associated with leukotriene synthesis. Polymorphisms in the TBXA2R gene have been linked to atopy, asthma, and atopic dermatitis. This study evaluated the association between genetic TBXA2R variants and the development of acetyl salicylic acid (ASA)-intolerant acute urticaria (AIAU)., Methods: AIAU patients (n=167), ASA-intolerant chronic urticaria (AICU) patients (n=149), and healthy controls (NC) (n=265) were included. All patients were enrolled at Ajou University Hospital in Suwon, Korea. Two TBXA2R polymorphisms (-4684T>C and 795T>C) were genotyped by primer extension using a SNAPshot ddNTP primer extension kit. Luciferase activity was measured using a dual-luciferase reporter assay kit. An electrophoretic mobility shift assay (EMSA) was performed using a nuclear extract from a human mast cell line (HMC-1)., Results: Genetic association data demonstrated that compared with NC subjects, AIAU patients had a significantly higher frequency of the homozygous TT genotype of TBXA2R-4684T>C (P=0.005, P(corr) =0.03). No differences were identified between the AICU and the NC groups. Luciferase activity, reflecting promoter activity, was significantly lower with the TBXA2R-4684T-containing construct than with the -4684C-containing construct (P<0.001); the activity decreased further upon co-transfection with ETS-like gene transcription factor-1 (ELK-1) (P=0.012). EMSA revealed that the -4684T allele produced a specific shifted band, with a greater affinity than that produced by the -4684C allele., Conclusion and Clinical Relevance: These results suggest that the TBXA2R-4684T allele may be associated with lower TBXA2R expression, which may contribute to the development of the AIAU phenotype., (© 2010 Blackwell Publishing Ltd.)

Background: To improve understanding of aspirin hypersensitivity, this study focused on adenosine as a noncyclooxygenase target molecule of aspirin. Adenosine may affect the release of histamine from cutaneous mast cells through a mechanism mediated by the adenosine A3 receptor., Objectives: To investigate the genetic contribution of adenosine A3 receptor gene (ADORA3) polymorphisms in the pathogenesis of aspirin-induced urticaria (AIU) in a case-control association study in a Korean population., Methods: A case-control association study was performed in 385 patients with AIU and 213 normal controls from a Korean population. The functional variability of genetic polymorphisms in the ADORA3 gene was analysed in in vitro studies that included a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA), and ex vivo studies that included real-time polymerase chain reaction for mRNA expression in peripheral blood mononuclear cells and a histamine release assay., Results: A significant association of ADORA3 promoter polymorphism at -1050G/T was found with the phenotype of AIU. Patients with AIU showed higher frequency of the haplotype, ht1 (T(-1050) C(-564) ), compared with normal healthy controls. Moreover, ht1 (TC) was found to be a high-transcript haplotype by the luciferase activity assay, and a -564C allele-specific DNA binding protein was found by EMSA. Increased basophil histamine release was noted in subjects who had the high-transcript haplotype, ht1 (TC)., Conclusion: These results suggest that the high-transcript haplotype, ht1 (TC), of the ADORA3 gene may contribute to the development of cutaneous hyper-reactivity to aspirin, leading to the clinical presentation of AIU., (© 2010 The Authors. BJD © 2010 British Association of Dermatologists.)

Background: It has been known that interleukin (IL)-10 promoter polymorphisms at -1082A/G, -819T/C and -592A/C, may influence IL-10 expression and associate with asthma. Interleukin-10 facilitates the regulatory function of transforming growth factor (TGF)-beta. The goal of this study was to investigate a gene-gene interaction between IL-10 and TGF-beta1 polymorphisms in Korean asthmatics with aspirin hypersensitivity., Methods: Single-nucleotide polymorphism genotyping of IL-10 and TGF-beta1 genes was performed and the functional effect of the IL-10 polymorphisms was analysed applying a luciferase reporter assay and an electrophoretic mobility shift assay., Results: Among the patients with asthma, polymorphism at -1082A/G was significantly associated with the phenotype of aspirin-intolerant asthma, AIA (P = 0.007, P(c) = 0.021). Moreover, a synergistic effect between the TGF-beta1-509C/T and IL-10-1082A/G polymorphisms on the phenotype of AIA was noted; when stratified by the presence of rhinosinusitis, the frequency of rare alleles (the CT or TT genotype of TGF-beta1-509C/T and AG or GG genotype of IL-10-1082A/G) was significantly higher in the patients with AIA (15.2%) when compared with those with ATA (6.3%, P = 0.031; odds ratio 4.111; 95% confidence interval 1.504-11.235). In an in vitro functional assay, the -1082G reporter plasmid exhibited significantly greater promoter activity when compared with the -1082A construct in Jurkat T cells (P = 0.011). Moreover, we found that the transcription factor Myc-associated zinc-finger protein preferentially bound the -1082G allele., Conclusion: Our results suggest that IL-10 promoter polymorphisms contribute to the development of AIA and that rhinosinusitis may interact genetically with TGF-beta1.

Objective: Although the pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, mast cell activation has been noted in patients with AIU. Tumour necrosis factor (TNF)-alpha, a potent pro-inflammatory cytokine, is released by human skin mast cells and other inflammatory cells in patients with urticaria. To investigate the role of TNF-alpha promoter polymorphisms in the development of AIU, we performed an association study of TNF-alpha promoter polymorphisms with AIU phenotype., Methods: Two hundred thirty-nine patients with AIU consisting of 120 patients with aspirin intolerant chronic urticaria (AICU) and 119 with aspirin-intolerant acute urticaria (AIAU), and 524 normal controls were enrolled. AIU was confirmed by oral aspirin challenge test. Five SNPs in the TNF-alpha gene (-1031T>C, -863C>A, -857C>T, -308G>A, -238G>A) were genotyped by a single-base extension method. Haplotype analyses were done., Results: The genotype frequencies of TNF-1031T>C and TNF-863C>A were significantly higher in the AIU patients than in the normal controls in both co-dominant (P = 0.014, P = 0.007) and dominant (P = 0.007, P = 0.004) models. The frequency of TNF-ht2[CACGG] containing a genotype in the AIU group was significantly higher in the normal controls with both co-dominant (P = 0.004, Pc = 0.02) and dominant models (P = 0.002, Pc = 0.01)., Conclusions: These findings suggest that the two promoter polymorphisms of TNF-alpha at -1031T>C and -863C>A may contribute to the development of AIU.

Background: Histamine plays an important role in allergic inflammation. Histamine levels are regulated by histamine N-methyltransferase (HNMT)., Objective: To investigate the functional variability of HNMT gene in relation to genetic polymorphisms in patients with aspirin intolerant chronic urticaria (AICU)., Methods: Two single-nucleotide polymorphisms of the HNMT gene (314C>T, 939A>G) were genotyped in chronic urticaria patients. The functional variability of 3'-untranslated region polymorphism (3'-UTR) was assessed using the pEGFP-HNMT 3'-UTR reporter construct to examine mRNA stability and fluorescence-tagged protein expression. The HNMT enzymatic activities related to the 939A>G polymorphism were examined both in the human mast cells (HMC-1) transfected with the pHNMT CDS-3'-UTR construct and in the patients' red blood cells (RBCs). Histamine release from the basophils of AICU patients was examined., Results: The 939A>G polymorphism was significantly associated with the AICU phenotype, while no association was found with the 314C>T polymorphism. An in vitro functional study using HMC-1 cells demonstrated that the 939A allele gave lower levels of HNMT mRNA stability, HNMT protein expression, and HNMT enzymatic activity and higher histamine release than the 939G allele. The in vivo functional study demonstrated that the AICU patients with the 939A allele had lower HNMT activity in RBC lysates and higher histamine release from their basophils., Conclusion: The HNMT 939A>G polymorphism lowers HNMT enzymatic activity by decreasing HNMT mRNA stability, which leads to an increase in the histamine level and contributes to the development of AICU.

Background: Chronic urticaria/angioedema is a common phenotype in patients with aspirin sensitivity; however, its genetic mechanism is not understood. Transforming growth factor (TGF)beta1 is a key regulatory cytokine involved in allergic inflammation., Objective: We examined the association of a TGFbeta1 genetic polymorphism with aspirin-intolerant chronic urticaria (AICU) and aspirin-tolerant chronic urticaria (ATCU) in a Korean population., Methods: A promoter polymorphism in the TGFbeta1 gene, TGFbeta1 -509C>T, was analysed in 112 AICU patients, 153 ATCU patients and 457 normal controls (NC), and the frequency was compared among the groups. Serum TGFbeta1 levels were measured by ELISA., Results: The minor allele frequency of the -509C>T polymorphism was significantly higher in patients with AICU compared with the other two groups (P < 0.02 for AICU vs. NC; P < 0.05 for AICU vs. ATCU). Among the AICU patients, those with the T allele tended to have lower serum TGFbeta1 levels., Conclusion: These findings suggest that the -509C>T polymorphism in the TGFbeta1 promoter may contribute to the development of the AICU phenotype.

Background: Aspirin-intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Angiotensin I-converting enzyme (ACE), a membrane-bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma., Methods: We screened a Korean asthma cohort (581 asthmatics including 81 aspirin-intolerant asthmatics and 231 aspirin-tolerant asthmatics, and 181 normal controls) for four single nucleotide polymorphisms (SNPs; -262 A>T and -115 T>C in the 5'-flanking region and +5467 T>C [Pro450Pro] and+11860 A>G [Thr776Thr] in the coding region) and one ins/del (+21288 CT) in the ACE gene., Results: None of the SNPs or haplotypes showed any association with the development of asthma, but they were significantly associated with the risk of AIA. Logistic regression indicated that the frequency of the rare alleles of -262 A>T and -115 T>C was higher in subjects with AIA than in subjects with aspirin-tolerant asthma (ATA) (P=0.003-0.01, P( corr)=0.015-0.05). Subjects homozygous for the rare alleles of -262 A>T and -115 T>C showed a greater decline in forced expiratory volume in 1 s (FEV(1)) after aspirin provocation than those homozygous for the common alleles (P<0.05). A luciferase reporter assay indicated that ACE promoters containing the rare -262 A>T allele possessed lower activity than did those containing the common allele (P=0.009). In addition, ACE promoters bearing the rare -115 T>C allele had no luciferase activity. DNA-protein binding assays revealed a band containing the ACE promoter region (including -262 A) and a protein complex., Conclusion: The -262 A>T polymorphism in the promoter of the ACE gene is associated with AIA, and the rare allele of -262 A>T may confer aspirin hypersensitivity via the down-regulation of ACE expression.

Although acetylsalicylic acid is prescribed for a broad range of diseases, it can induce a wide array of clinically recognized hypersensitivity reactions, including aspirin-intolerant asthma (AIA) with rhinitis and aspirin-intolerant urticaria (AIU) with anaphylaxis. Altered eicosanoid metabolism is the generally accepted mechanism of aspirin intolerance; the overproduction of cysteinyl leucotrienes has been suggested to play a causative role in both AIA and AIU. Genetic markers suggested for AIA include HLA-DPBI*0301, leucotriene C4 synthase (LTC4S), ALOX5, CYSLT, PGE2, TBXA2R and TBX21. Similarly, HLA-DB1*0609, ALOX5, FCER1A and HNMT have been identified as possible genetic markers for AIU. An additional low-risk genetic marker for AIA is MS4A2, which encodes the beta-chain of FCER1. Other single and sets of two or more interacting genetic markers are currently being investigated. Analyses of the genetic backgrounds of patients with AIA and AIU will promote the development of early diagnostic and therapeutic interventions, which may reduce the incidence of AIA and AIU.

Background and Objective: The MS4A2 gene, the beta chain of the high-affinity receptor for immunoglobulin (Ig)E, has previously been linked to atopy and asthma. The beta-chain of FcepsilonR1 enhances receptor maturation and signal transduction capacity, leading to the release of proinflammatory mediators and cytokines that can exacerbate the symptom of asthma. This study was performed to evaluate whether two genetic polymorphisms of the FcepsilonR1beta gene (FcepsilonR1beta-109T > C and FcepsilonR1beta E237G) are associated with aspirin-intolerant asthma (AIA). The MS4A2 gene polymorphisms (FcepsilonR1beta-109T > C and FcepsilonR1beta E237G) were determined by SNP-IT assays in patients with AIA (N = 164), aspirin-tolerant asthma (ATA, N = 144) and normal controls (NC, N = 264) recruited from a Korean population., Results: The genotype frequencies of FcepsilonR1beta-109T > C and E237G polymorphisms were not significantly associated with the pathogenesis of AIA. However, FcepsilonR1beta-109T > C polymorphism was significantly associated with the presence of specific IgE to Staphylococcal enterotoxin B (SEB); the number of subjects carrying both homozygous TT genotype of FcepsilonR1beta-109T > C and specific IgE to SEB was significantly higher in the AIA group when compared with the other control groups (P = 0.01, odds ratio (OR) = 7.723, 95% confidence interval (CI) = 1.327-39.860 for AIA vs. ATA; P = 0.02, OR = 6.364, 95% CI = 1.149 approximately 35.229 for AIA vs. NC). In addition, luciferase reporter assays also showed that the FcepsilonR1beta-109T allele was associated with higher promoter activity of MS4A2 in both RBL-2H3 and A549 cell lines., Conclusion: FcepsilonR1beta-109T > C polymorphism may increase expression of MS4A2 by mast cells, leading to enhanced release of proinflammatory mediators in the asthmatic airway, contributing to increased susceptibility to AIA.

In aspirin-intolerant subjects, adverse bronchial and nasal reactions to cyclooxygenase (COX) inhibitors are associated with over-production of cysteinyl-leukotrienes (cys-LTs) generated by the 5-lipoxygenase (5-LO) pathway. In the bronchi of patients with aspirin-intolerant asthma, we previously linked cys-LT over-production and aspirin hyper-reactivity with elevated immunoexpression in eosinophils of the terminal enzyme for cys-LT production, LTC4 synthase. We investigated whether this anomaly also occurs in the nasal airways of these patients. Immunohistochemical expression of 5-LO and COX pathway proteins was quantified in nasal polyps from 12 patients with aspirin-intolerant asthma and 13 with aspirin-tolerant asthma. In the mucosa of polyps from aspirin-intolerant asthmatic patients, cells immunopositive for LTC4 synthase were four-fold more numerous than in aspirin-tolerant asthmatic patients (p=0.04). There were also three-fold more cells expressing 5-LO (p=0.037), with no differences in 5-LO activating protein (FLAP), COX-1 or COX-2. LTC4 synthase-positive cell counts correlated exclusively with mucosal eosinophils (r=0.94, p<0.001, n=25). Co-localisation confirmed that five-fold higher eosinophil counts (p=0.007) accounted for the increased LTC4 synthase expression in polyps from aspirin-intolerant asthmatic patients, with no alterations in mast cells or macrophages. Within the epithelium, increased counts of eosinophils (p=0.006), macrophages (p=0.097), and mast cells (p=0.034) in aspirin-intolerant asthmatic polyps were associated only with 2.5-fold increased 5-LO-positive cells (p<0.05), while the other enzymes were not different. Our results indicate that a marked over-representation of LTC4 synthase in mucosal eosinophils is closely linked to aspirin intolerance in the nasal airway, as in the bronchial airways., (Copyright (c) 2006 Pathological Society of Great Britain and Ireland.)

Background: Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA)., Methods: To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC)., Results: Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04)., Conclusion: These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.

Background: 5-Lipooxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) are known as key enzymes in cysteinyl-leukotriene (cys-LT) production, critical mediators in aspirin acetylsalicyclic acid (ASA)-intolerant asthma (AIA). To date, studies of the promoter region of ALOX5 gene has revealed the potential influence of a variable number of tandem repeats of a Sp1- and Egr1-binding motif, on the transcription rate., Methods: To understand the pathological process that arises from cys-LT overproduction in AIA, we genotyped ALOX5 Sp1 and ALOX5AP poly(A) repeat promoter polymorphism by fluorescent-based capillary electrophoresis in the Korean population., Results: No significant differences in allele and genotype frequencies of the ALOX5 and ALOX5AP promoter polymorphisms were observed between the three groups. However, there was a strong association of the ALOX5 Sp1 repeat polymorphism with airway hyperresponsiveness (AHR; PC20 methacholine); AIA patients carrying a mutant allele (n > 5 or n < 5 repeats) showed increased AHR compared to AIA patients with wild-type genotype (P=0.003)., Conclusion: Although the alleles of the ALOX5 and ALOX5AP promoter cannot be considered as a prominent risk factor in the development of AIA, the genetic variant of tandem repeat (GGGCGG; Sp1-binding motif) in ALOX5 promoter is associated with the severity of airway hyperresponsiveness in AIA patients.

Background and Objective: The thromboxane A2 receptor (TBXA2R) is a receptor for a potent bronchoconstrictor, TBXA2 which is known to be related to bronchial asthma and myocardial infarction. TBXA2R antagonist and TBX synthase inhibitors have been found to be effective in the management of asthmatic patients. This study was aimed to evaluate whether genetic variants of TBXA2R may be related with development of acetyl salicylic acid (ASA)-intolerant asthma (AIA)., Methods: TBXA2R gene polymorphisms (TBXA2R+795T>C, TBXA2R+924T>C) were determined using a single-base extension method in 93 AIA patients compared with 172 patients with ASA-tolerant asthma (ATA) and 118 normal controls (NCs) recruited from the Korean population. HLA DPB1*0301 genotype was performed using a direct sequencing method., Results: The rare C allele frequency of TBXA2R+795T>C was significantly higher in AIA than in ATA (P=0.03) and the TBXA2R+795T>C polymorphism was also associated with extent of percent fall in forced expiratory volume in 1 s (FEV1) after the inhalation of lysine-acetyl salicylic acid in AIA patients (P=0.009); AIA patients homozygous for the +795 C allele had a greater percent fall of FEV1 compared with individuals with TBXA2R+795 CT or TT genotypes. The frequency of patients carrying both the TBXA2R+795T>C rare allele and HLA DPB1(*)0301 was significantly higher in AIA patients (29.4%) than in ATA patients (7.3%) (P=0.008, odds ratio=5.3)., Conclusion: These results suggest that the polymorphism of TBXA2R+795T>C may increase bronchoconstrictive response to ASA, which could contribute to the development of the AIA phenotype.

Background: Urticaria/angioedema is a common aspirin-induced allergy; however, its pathogenic mechanism is not understood., Objective: In order to uncover the genetic mechanism, we studied the associations of the human leucocyte antigen (HLA) genotypes in patients with aspirin-induced urticaria compared with aspirin-intolerant asthma and normal control in a Korean population., Methods: Ninety-four aspirin-induced urticaria patients presenting urticaria/angioedema-induced by both ASA and NSAID (50 had underlying chronic urticaria) and showing positive responses on oral aspirin challenge test, 76 aspirin-intolerant asthmatics with positive responses on lysine-aspirin bronchoprovocation test, and 185 normal healthy controls were enrolled. HLA-DRB1, DQB1, and DPB1 genotypings were performed by direct DNA sequencing analysis., Results: The allele frequencies of HLA-DRB1(*)1302 (18.1%) and HLA-DQB1(*)0609 (10.1%) in aspirin-induced urticaria were significantly higher than in aspirin-intolerant asthma (5.3%, P=0.0004; 2.0%, P=0.0024) and in normal controls (8.1%, P=0.0005; 3.2%, P=0.0008), and they remained significant after correcting for multiple comparisons. The patients with these two HLA markers had a significantly younger age than patients without, while no associations were found in with respect to atopic status, a history of previous allergic diseases, total IgE level, or presence of underlying chronic urticaria (P>0.05, respectively). In haplotype analysis, the HLA-DRB1(*)1302-DQB1(*)0609-DPB1(*)0201 was significantly higher in the aspirin-induced urticaria (8.0%) than in the aspirin-intolerant asthma (0.7%, P=0.0014) and normal controls (2.0%, P=0.0006)., Conclusion: These findings suggest that the HLA-DRB1(*)1302-DQB1(*)0609-DPB1(*)0201 may be a strong genetic marker to determine the aspirin-induced urticaria phenotype.

Background: The immunopathologic mechanism of nasal polyp in aspirin-sensitive asthma remains to be further defined., Objective: To characterize the features of the inflammatory cellular infiltrate in the nasal polyp tissue from aspirin-sensitive asthmatic patients., Methods: We have taken nasal polyp tissue during nasal polyp resection from 13 aspirin-sensitive asthma, 6 allergic, and 12 non-allergic subjects. Immunohistochemistry was employed to stain and enumerate the individual inflammatory cell types using monoclonal antibodies against tryptase (AA1) to identify mast cells, against secreted forms of eosinophil cationic protein (EG2), to identify activated eosinophils, against neutrophil elastase (NE) for neutrophils and against T cell surface markers (CD3) to identify total T cells., Results: There were no significant differences in AA1 + cells among three groups (P>.05). EG2 + cells tended to be higher in ASA-sensitive asthmatic patients than in allergic and non-allergic subjects, but no statistical significance was observed. NE+ cells were found in most subjects of the three groups and their numbers were significantly higher in allergic subjects than in aspirin-sensitive asthma (P<.05). Some patients had CD3+ cells with no statistical significance among the three groups. Significant correlation was found in numbers between NE+ cell and AA1+ cell (r=.44, P=.01), and between NE+ cell and EG2+ cell (r=.40, P=.02)., Conclusion: These findings suggested that major effector cells such as mast cells and eosinophils might be placed in the center of the inflammatory response of nasal polyps, regardless of their association with aspirin sensitivity.

Background & Objectives: The pathogenic mechanism of aspirin-sensitive asthma (ASA-BA) remains to be further defined. To evaluate the role of circulating immune complex (CIC) in ASA-BA., Subjects & Methods: We measured IgG- and IgA-IC level by ELISA using anti-C3 antibody in 33 ASA-BA patients whose sensitivity was confirmed by lysine-aspirin bronchoprovocation test, and compared with those of 14 allergic, 14 intrinsic asthma patients and 7 healthy controls., Results: There was no significant difference in IgG-IC level among the four groups (p > 0.05), while IgA-IC levels of aspirin-sensitive asthma were higher than those of other groups (p = 0.0035). Patients with nasal polyp had significantly higher IgG-IC than those without it (p = 0.02). No differences were found according to medication and symptom scores, and presence of atopy, rhino-sinusitis, urticaria or concurrent sensitivity to sulfite (p > 0.05). Insignificant correlation was found between IgG-IC level and asthma duration, total IgE level, or circulating eosinophil count., Conclusion: These findings suggest a possible contribution of IgG-IC to the development of nasal polyp in ASA-BA. Further study will be needed to clarify the role of IgA-IC in the pathogenesis of ASA-BA.

Appreciable numbers of aspirin-sensitive asthmatic patients have chronic steroid-dependent severe asthmatic symptoms. We report four cases of aspirin-sensitive asthmatics who had mild to severe asthmatic symptoms, whose methacholine PC20 level ranged from 0.6 to 22 mg/ml at the first visit. The aspirin sensitivity was confirmed by lysine-aspirin bronchoprovocation. After anti-asthmatic medications and avoidance of salicylate-containing agents, airway hyperresponsiveness and respiratory symptoms disappeared for two to 30 months. These results suggest that early detection and careful avoidance of salicylate-containing agents may have a beneficial effect resulting in the resolution of airway hyperresponsiveness in aspirin-sensitive asthmatic patients.

Inhalation of aerosolized lysine-aspirin (L-ASA) has been described as an alternative diagnostic method in aspirin-sensitive asthma. To further understand the pathogenetic mechanism of aspirin-sensitive asthma, we performed L-ASA (Inyesprin) bronchoprovocation test (BPT) in 51 asthmatic patients (45 non-atopic and six atopic asthma). Twenty-six patients showed significant bronchoconstriction after the inhalation of L-ASA. Bronchoprovocation test produced immediate asthmatic responses in 13 cases as well as dual asthmatic responses in four cases, whose late onset asthmatic response was noted at 4-7 h after L-ASA inhalation. We conclude that L-ASA bronchoprovocation might be a useful method for the diagnosis and investigation of aspirin-sensitive asthma. However, L-ASA inhalation can also induce late onset asthmatic responses.

Non-acetylated salicylates have been recommended for use as alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) in aspirin and/or tartrazine-sensitive patients. We experienced a case of an aspirin-sensitive asthmatic patient who developed a broncho-obstructive reaction after taking 100 mg of sodium salicylate. The result of this study suggests that sodium salicylate may cross-react with aspirin in aspirin-and tartrazine-sensitive patients.

Aspirin and food additives are known to induce bronchoconstriction, angioedema or urticaria in susceptible patients. To evaluate the incidence of hypersensitivity to aspirin and food additives, 36 subjects with bronchial asthma, 33 of whom were non-allergic asthmatics and 3 were allergic asthmatics who had a history of aspirin sensitivity, were challenged orally with six compounds: acetylsalicylic acid (ASA), sodium bisulfite, tartrazine, sodium benzoate, 4-hydroxy benzoic acid, and monosodium L-glutamate. Significant bronchoconstrictions were found in 15 (41.7%) of the 36 subjects tested. Eight of the 15 subjects showed positive asthmatic responses to the aspirin, two showed asthmatic responses to the food additives, and five responded to both aspirin and the food additives. It is suggested that ASA and food additives could be causes of clinically significant bronchoconstriction in moderately severe non-allergic asthmatic patients.

Background Eosinophil activation is the key feature of upper and lower airway inflammation in aspirin-exacerbated respiratory disease ( AERD). Objective To investigate the mechanism of eosinophil activation and identify novel inflammatory mediators using proteomics. Methods Thirty-two asthmatic subjects were enrolled: 18 AERD patients who showed positive responses to the lysine-aspirin nasal provocation test (L- ASA NPT) and 14 aspirin-tolerant asthma ( ATA) patients who showed negative responses to the L- ASA NPT (control group). Nasal lavage fluid ( NLF) was collected before (baseline), at 10, 30 and 60 min (early response), and at 3 h (late response) after the L- ASA NPT. Eosinophil cationic protein ( ECP) and cysteinyl leucotriene (Cys LT) levels were measured using an Immuno CAP system and ELISA respectively. To identify proteins involved in AERD, comparative proteomics was applied using NLFs collected before and after L- ASA NPTs in AERD patients. The clinical relevance of identified novel proteins was evaluated by ELISA using NLFs from the AERD and ATA groups. Results Eosinophil cationic protein and Cys LT levels both increased significantly during the early response in AERD. ECP levels increased until the late response in AERD, while Cys LT levels were not significantly increased during the late response. Proteomic analysis showed up-regulation of apolipoprotein A1 (ApoA1), α2-macroglobulin (α2M) and ceruloplasmin ( CP), with significant increases in NLF of AERD patients, which was significantly higher in AERD patients with chronic rhinosinusitis. Significant correlations were noted between ECP and Cys LT, ApoA1, α2M and CP levels during the early response in AERD patients. Conclusion Eosinophil activation occurred in early and late responses after L- ASA NPT in upper airway mucosa of AERD patients, where ApoA1, α2M and CP as well as Cys LT may be involved in eosinophilic inflammation. [ABSTRACT FROM AUTHOR]

To cite this article: Palikhe NS, Kim S-H, Cho B-Y, Ye Y-M, Choi G-S, Park H-S. Genetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease. Allergy 2010; 65: 338–346. Introduction: CRTH2 is expressed on the surface of eosinophils and has been shown to mediate PGD2-induced eosinophil migration in vitro. Eosinophilic infiltration in the upper and lower airways is the key feature of asthma. Considering the fact that eosinophil infiltration is prominent in the upper and lower airways of aspirin exacerbated respiratory disease (AERD) compared to aspirin-tolerant asthma (ATA) patients, we hypothesized that activation of eosinophils via dysregulation of the CRTH2 gene may play an important role and be an important marker for AERD. Methods: The three study groups – 107 with AERD, 115 with ATA and 133 normal healthy controls (NC) – were recruited from Ajou University Hospital, South Korea. Two polymorphisms of the CRTH2 gene at -466T>C and -129C>A were genotyped using primer extension methods. Results: AERD patients had significantly higher serum eotaxin-2 levels than did those with ATA ( P = 0.034). A significant difference in the genotype frequencies of CRTH2 -466T>C was detected between AERD and ATA patients ( P < 0.05). The serum eotaxin-2 level was significantly higher in AERD patients carrying the TT genotype of CRTH2 -466T>C than those with the CT and CC ( P < 0.05). In vitro functional study demonstrated that the -466T allele had lower luciferase activity ( P < 0.001) and lower mRNA expression with higher production of eotaxin-2 ( P = 0.003) in human lung epithelial cells. EMSA showed that CRTH2 -466T produced a specific band with a higher affinity than CRTH2 -466C had. Conclusion: The CRTH2 -466T>C polymorphism increases serum and cellular eotaxin-2 production through lowered CRTH2 expression, leading to eosinophilic infiltration in AERD patients. [ABSTRACT FROM AUTHOR]

Objective: Although the pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, mast cell activation has been noted in patients with AIU. Tumour necrosis factor (TNF)-α, a potent pro-inflammatory cytokine, is released by human skin mast cells and other inflammatory cells in patients with urticaria. To investigate the role of TNF-α promoter polymorphisms in the development of AIU, we performed an association study of TNF-α promoter polymorphisms with AIU phenotype. Methods: Two hundred thirty-nine patients with AIU consisting of 120 patients with aspirin intolerant chronic urticaria (AICU) and 119 with aspirin-intolerant acute urticaria (AIAU), and 524 normal controls were enrolled. AIU was confirmed by oral aspirin challenge test. Five SNPs in the TNF-α gene (-1031T>C, -863C>A, -857C>T, -308G>A, -238G>A) were genotyped by a single-base extension method. Haplotype analyses were done. Results: The genotype frequencies of TNF-1031T>C and TNF-863C>A were significantly higher in the AIU patients than in the normal controls in both co-dominant ( P = 0·014, P = 0·007) and dominant ( P = 0·007, P = 0·004) models. The frequency of TNF-ht2[CACGG] containing a genotype in the AIU group was significantly higher in the normal controls with both co-dominant ( P = 0·004, Pc = 0·02) and dominant models ( P = 0·002, Pc = 0·01). Conclusions: These findings suggest that the two promoter polymorphisms of TNF-α at -1031T>C and -863C>A may contribute to the development of AIU. [ABSTRACT FROM AUTHOR]

Urticaria/angioedema is a common aspirin-induced allergy; however, its pathogenic mechanism is not understood.In order to uncover the genetic mechanism, we studied the associations of the human leucocyte antigen (HLA) genotypes in patients with aspirin-induced urticaria compared with aspirin-intolerant asthma and normal control in a Korean population.Ninety-four aspirin-induced urticaria patients presenting urticaria/angioedema-induced by both ASA and NSAID (50 had underlying chronic urticaria) and showing positive responses on oral aspirin challenge test, 76 aspirin-intolerant asthmatics with positive responses on lysine–aspirin bronchoprovocation test, and 185 normal healthy controls were enrolled. HLA-DRB1, DQB1, and DPB1 genotypings were performed by direct DNA sequencing analysis.The allele frequencies of HLA-DRB1*1302 (18.1%) and HLA-DQB1*0609 (10.1%) in aspirin-induced urticaria were significantly higher than in aspirin-intolerant asthma (5.3%,P=0.0004; 2.0%,P=0.0024) and in normal controls (8.1%,P=0.0005; 3.2%,P=0.0008), and they remained significant after correcting for multiple comparisons. The patients with these two HLA markers had a significantly younger age than patients without, while no associations were found in with respect to atopic status, a history of previous allergic diseases, total IgE level, or presence of underlying chronic urticaria (P>0.05, respectively). In haplotype analysis, the HLA-DRB1*1302-DQB1*0609-DPB1*0201 was significantly higher in the aspirin-induced urticaria (8.0%) than in the aspirin-intolerant asthma (0.7%,P=0.0014) and normal controls (2.0%,P=0.0006).These findings suggest that the HLA-DRB1*1302-DQB1*0609-DPB1*0201 may be a strong genetic marker to determine the aspirin-induced urticaria phenotype. [ABSTRACT FROM AUTHOR]

Nasal polyps infiltrated with eosinophils are commonly found in chronic asthmatic patients, more frequently in those with aspirin-intolerant asthma (AIA) than aspirin-tolerant asthma (ATA). Some studies have suggested a contribution of superantigens derived from Staphylococcus sp to nasal polyposis and eosinophilia, but their relative importance in AIA and ATA subjects is unknown. We investigated whether local production of specific IgE to staphylococcal enterotoxins A and B (SEA and SEB) and relationships with markers of eosinophilic inflammation differ in the nasal polyps of AIA and ATA subjects. Fifteen AIA subjects with positive responses to lysine–aspirin bronchoprovocation and 15 ATA subjects underwent polypectomy. Immunoassays were used to quantify eosinophil cationic protein (ECP), IL-5, mast cell tryptase, soluble IL-2 recepters (sIL-2R), total IgE, and specific IgE for SEA and SEB. ECP levels in nasal polyp homogenates were higher in AIA subjects than in ATA subjects ( P<0.02), with no significant differences in tryptase, IL-5 or sIL-2R. Total IgE, and specific IgE to both SEA and SEB, were detectable in some nasal polyps from both subject groups, but median levels were markedly higher in AIA subjects than in ATA subjects ( P=0.04, 0.01, 0.05, respectively). Levels of specific IgE to SEA and SEB correlated significantly with levels of ECP and IL-5, but not those of tryptase or sIL-2R. These findings suggest that staphylococcal superantigens may drive local eosinophilic inflammation in nasal polyp tissue, and that this is exacerbated in subjects with AIA. [ABSTRACT FROM AUTHOR]

Aspirin (ASA)-sensitive asthma is characterised by a typical sequence of symptoms, including intense eosinophilic inflammation of nasal and bronchial tissues. It is more commonly found in non-atopic, middle-aged female asthmatic patients with chronic rhino-sinusitis and/or nasal polyps. The lysine-aspirin bronchoprovocation test has become a widely used diagnostic test. When ASA-sensitive asthma is confirmed, complete avoidance of ASA/non-steroidal anti-inflammatory agents (NSAIDs) is crucial in preventing life-threatening adverse reactions. The basic principle of pharmacotherapy is step-wise treatment based upon anti-inflammatory therapy. Corticosteroids are the mainstay of therapy and anti-leukotriene agents may be indicated for treatment of the underlying disease. ASA desensitisation may reduce inflammatory mucosal disease symptoms, particularly in the nasal passage. [ABSTRACT FROM AUTHOR]

The article focuses on a study done to evaluate the use of the human leukocyte antigen (HLA) allele marker for differentiating two aspirin (ASA) hypersensitivity phenotypes, the ASA intolerant urticaria (AIU) and the ASA intolerant asthma (AIA). The study suggests that two HLA allele markers, HLA-DPB1*0301 for AIA and DRB1*1302-DQB1*0609 for AIU, can be used for differentiating two phenotypes of ASA hypersensitivity.