Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti–IL-5 or anti–IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin−/−) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4+ T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin−/− mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease

CFTR Cl− channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis

BACKGROUND & AIMS: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. METHODS: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. RESULTS: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. CONCLUSIONS: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity

Polymorphisms in the IL18 gene are associated with specific sensitization to common allergens and allergic rhinitis

Background: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene. IL-18 enhances IL-4/IL-13 production and induces IgE production that is directly associated with the pathogenesis of atopic disorders. Objective: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy. Methods: Among a white population of 105 families, the oldest child was examined with regard to atopic phenotypes and single-nucleotide polymorphisms (SNPs) within the IL18 gene. Results: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6). Three SNPs are located in promoter 2, and one (-133[c/g]; nuclear factor 1 site) was significantly associated with high serum IgE leveis (P = .001; odds ratio, 3.96) and specific sensitization to common allergens (P = .005; OR, 4.12). In addition, previously identified SNPs in exon 1 (+113[t/g] and +127[c/t]) and in promoter 1 (-137[g/c], GATA3 site) of the IL18 gene were significantly associated with high IgE levels (P ≤ .005; OR, 3.27-3.90) and specific sensitization (P = .02 to .008; OR, 3.27-3.83). The SNP +127(g/t) in exon 1 was also a susceptibility locus for seasonal allergic rhinitis (P = .008; OR, 3.22). Conclusion: IL18 might be responsible for the linkage effects seen in the chromosomal region 11q22, which has been found previously with the phenotype "sensitization to mite allergen." Thus a suspected direct role of IL18 in the pathogenesis of atopy has been strengthened by the presence of 8 common SNPs in the promoter regions of IL18

Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia

Human airway epithelia express Ca-activated Cl channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K channels in CaCC-mediated Cl secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K channels, and by clotrimazole, an inhibitor of Ca-activated hSK4 K channels. The K channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca-activated Cl secretion in native human airway epithelia requires activation of Ca-dependent basolateral K channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease

Role of K(V)LQT1 in cyclic adenosine monophosphate-mediated C1- secretion in human airway epithelia

Ion transport defects underlying cystic fibrosis (CF) lung disease are characterized by impaired cyclic adenosine monophosphate (cAMP)-dependent CI conductance. Activation of Cl secretion in airways depends on simultaneous activation of luminal CI channels and basolateral K channels. We determined the role of basolateral K conductance in cAMP-dependent Cl secretion in native human airway epithelium obtained from non-CF and CF patients. CF tissues showed typical alterations of short-circuit currents with enhanced amiloride-sensitive Na conductance and defective cAMP-mediated Cl conductance. In non-CF tissues, Cl secretion was significantly inhibited by the chromanol 293B (10 μmol/liter), a specific inhibitor of K(V)LQT1 K channels. Inhibition was increased after cAMP-dependent stimulation. Similar effects were obtained with Ba (5 mmol/liter). In patch-clamp experiments with a human bronchial epithelial cell line, stimulation with forskolin (10 μmol/liter) simultaneously activated Cl and K conductance. The K conductance was reversibly inhibited by Ba and 293B. Analysis of reverse-transcribed messenger RNA from non-CF and CF airways showed expression of human K(V)LQT1. We conclude that the K channel K(V)LQT1 is important in maintaining cAMP-dependent Cl secretion in human airways. Activation of K(V)LQT1 in CF airways in parallel with stimulation of residual CF transmembrane conductance regulator Cl channel activity or alternative Cl channels could help to circumvent the secretory defect

Early-life antibiotic use is associated with wheezing among children with high atopic risk: a prospective European study

<div><p></p><p><i>Background</i>: Little is known about the relationship between antibiotic use and asthma in the children with a higher risk of allergic sensitization. We examine the association between the use of specific therapeutic antibiotics in the first year of life and development of wheezing by 36 months among children with a higher risk of allergic sensitization. <i>Methods</i>: A multi-center prospective cohort study was conducted among children at high risk for allergic sensitization. A validated questionnaire was used to prospectively collect information on antibiotic use and potential risk factors for wheezing from parents or guardians of 606 children from three European countries at 6, 12, 24 and 36 months of age. Multivariate linear and logistic regression models were used to adjust for potential confounders and effect modifiers and to estimate the association of antibiotic use with the development of early childhood wheezing. <i>Results</i>: Of the antibiotics assessed, only macrolide use in the first year of life was associated with increasing risk for wheezing by 36 months, after adjusting for gender, socioeconomic status, breast feeding >6 months, tobacco smoke exposure, family history of asthma, and respiratory infection (RR = 1.09; 95% CI 1.05–1.13). To avoid a bias by indication, we analyzed children with and without respiratory infection separately. Similar associations were observed for macrolides use in children who had no respiratory infection. <i>Conclusions</i>: In European children with a familial risk for allergic sensitization, we found a positive association between macrolide use in the first year of life and wheezing until 36 months old which was independent of the effect of respiratory infection.</p></div

Association of allergy-related symptoms with sensitisation to common allergens in an adult European population

BACKGROUND:Atopy is an important risk factor for asthma and allergic diseases. However, the relationship between atopy and allergic symptoms is not fully understood, and may not be the same for different allergy related symptoms and in differing environmental conditions.OBJECTIVE:To study the differences in the association of allergy-related symptoms and atopy, in an adult population from five European countries.METHODS:A prospective, multi-national study was conducted. Centres included Isle of Wight (UK), Vienna (Austria), Freiburg (Germany), Athens (Greece), and Kaunas (Lithuania). We used five questions derived from the ISAAC (International Study of Asthma and Allergy in Children) and other validated questionnaire, to evaluate the presence of allergic symptoms in a selected adult population. Atopy was assessed by SPT or IgE measurement to 3 core allergens (dust mite, cat and grass pollen) in all centres and 1-2 additional allergens relevant to each area (parietaria, olive, birch pollen, tree pollen mix, dog).RESULTS:Of 3985 subjects, 2478 (62%) responded positively to one or more core ISAAC questions. Sensitisation rate was high in Austria and UK and relatively low in Greece. Dust mite and cat were important allergens for asthma, odds ratio (OR): 2.24, 95% confidence interval (CI): 1.63-3.08 and OR: 2.31, CI: 1.69-3.14, respectively. Grass pollen was strongly associated with hay fever in all centres (OR: 3.62 CI: 2.81-4.66) and with birch pollen in Austria (OR: 3.57, CI: 2.09-6.09) and with parietaria in Greece (4.61 (2.99-7.12). In the comparative analysis, using UK as a reference, Lithuanians had a 10-20-fold reduced risk of asthma and hay fever, but were twice more likely to report chronic itching. The risk of dust mite allergy was 3- and 10-fold lower in Lithuania and Greece, respectively, whereas the risk of cat and grass pollen allergy was one and half times higher in Austria.CONCLUSION:The risk of allergic symptoms and sensitisation and their association vary widely in different European countries