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Asthma Pathogenesis (asthma + pathogenesis)
Selected AbstractsThe importance of environment on respiratory genotype/phenotype relationships in the InuitALLERGY, Issue 2 2010P. V. Candelaria To cite this article: Candelaria PV, Backer V, Khoo S-K, Bizzintino JA, Hayden CM, Baynam G, Laing IA, Zhang G, Porsbjerg C, Goldblatt J, LeSouëf PN, The Greenlandic Study Population Group. The importance of environment on respiratory genotype/phenotype relationships in the Inuit. Allergy 2010; 65: 229,237. Abstract Background:, Genetic and environmental influences and their interactions are central to asthma pathogenesis. This study aimed to investigate the effects of different macro-environments on asthma genotype,phenotype associations in two geographically separated populations with common ancestry. Methods:, To accomplish this, two unselected populations of Inuit were recruited, one living in Greenland (n = 618) and the other in Denmark (n = 739). Subjects were genotyped for CD14 C-159T, SCGB1A1 A38G, ADRB2 Arg16Gly and Gln27Glu. The resulting genetic data were analysed for relationships with asthma-related parameters including lung function, ever asthma, atopy, rhinitis and dermatitis. Results:, The results showed contrasting magnitude and direction of genetic associations between the two geographically separate Inuit populations. In Greenland, the ADRB2 16Arg allele was associated with male-specific lower lung function, but in Denmark the same allele was associated with male-specific higher lung function. This allele was also associated with higher incidence of ever asthma in Denmark but not in Greenland. The SCGB1A1 38A allele was associated with lower rhinitis prevalence in Greenland but not in Denmark. Conclusions:, These associations suggest that environment interacts with candidate asthma genes to modulate asthma pathogenesis in the Inuit. [source] IgE cross-reactivity between Ascaris and domestic mite allergens: the role of tropomyosin and the nematode polyprotein ABA-1ALLERGY, Issue 11 2009N. Acevedo Background:, Analysis of cross-reactivity between the nematode Ascaris ssp. and dust mites, two important allergen sources in the tropics, will contribute in understanding their influence on asthma and atopy. The objective of this study was to investigate immunoglobulin E (IgE) cross-reactivity between Ascaris and two domestic mites in the tropics. Methods:, Sera from 24 asthmatic patients were used in ELISA and immunoblotting IgE-binding inhibition assays using Ascaris, Blomia tropicalis and Dermatophagoides pteronyssinus extracts and the recombinants Blo t 10, ABA-1 and Blo t 13 as competitors. Identification of Ascaris allergens was confirmed by mass spectrometry (LC-MS/MS). Results:, We detected at least 12 human IgE-binding components in Ascaris extract. Blomia tropicalis and D. pteronyssinus inhibited 83.3% and 79% of IgE-binding to Ascaris, while Ascaris inhibited 58.3% and 79.3% to B. tropicalis and D. pteronyssinus respectively. Mite tropomyosin inhibited 85% of IgE-binding to Ascaris. Affinity-purified human IgE to rBlo t 10 identified an allergen of 40 kDa in Ascaris extract, further confirmed as tropomyosin by LC-MS/MS. We found no evidence of IgE cross-reactivity between rABA-1 and any allergen component in mite extracts, including rBlo t 13. Conclusions:, There is cross-reactivity between Ascaris and mites, determined by several allergens including tropomyosin and glutathione- S -transferase. In addition to its potential impact on asthma pathogenesis, Ascaris infection and mite allergy diagnosis relying on the determination of specific IgE could be affected by this cross-reactivity. ABA-1 has no cross-reactive counterpart in mite extracts, suggesting its usefulness as a more specific marker of Ascaris infection. [source] Age and sex as factors of response to RSV infections among those with previous history of wheezingPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 5 2006Yoko Nagayama Although enhanced immune reaction caused by the respiratory syncytial virus (RSV) in allergen-sensitized animal model has been reported, RSV illnesses in children already sensitized or having recurrent wheezing episodes have not been completely studied. In addition, the reason for male dominances in RSV infection at young ages was also inconclusive. Therefore, gender analysis in recurrent wheezing children with RSV infection can shed light on asthma pathogenesis. We studied the clinical features and the laboratory data of RSV infections in children who had recurrent wheezing histories. The subjects with RSV infection consisted of 98 boys and 58 girls. The children under 4 yr of age were 123 (78.8%) in number. Children with pneumonia were 78 and those with febrile episode were 119. Children above 1 yr of age were highly sensitized with mite antigen (75/96, 78.1%). The clinical symptoms and signs differed according to their ages. Children in each age group behaved differently in their immune reaction to RSV. Above all, 3-yr-old children deteriorated clinically during acute RSV infection, accompanied by transient elevated C-reactive protein (CRP) and suppressed blood eosinophil counts. Clinical features differed in several points between boys and girls. In general, the white blood cell count and the CRP levels were higher in girls in every age group. Blood eosinophil counts at the acute illness were significantly higher in boys than girls aged 2 and 3< yr. Age and gender comparison in already sensitized children might suggest a clue to asthma pathogenesis. [source] Adjuvant effects of ambient particulate matter monitored by proteomics of bronchoalveolar lavage fluidPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2010Xuedong Kang Abstract Ambient particulate matter (PM) from air pollution is associated with exacerbation of asthma. The immunological basis for the adjuvant effects of PM is still not well understood. The generation of ROS and the resulting oxidative stress has been identified as one of the major mechanisms. Using a new intranasal sensitization model in which ambient PM is used as an adjuvant to enhance allergic inflammation (Li et al., Environ. Health Perspect. 2009, 117, 1116,1123), a proteomics approach was applied to study the adjuvant effects of ambient PM. The enhanced in vivo adjuvant effect of ultrafine particles correlates with a higher in vitro oxidant potential and a higher content of redox-cycling organic chemicals. Bronchoalveolar lavage fluid proteins from normal and sensitized mice were resolved by 2-DE, and identified by MS. Polymeric immunoglobulin receptor, complement C3, neutrophil gelatinase-associated lipocalin, chitinase 3-like protein 3, chitinase 3-like protein 4, and acidic mammalian chitinase demonstrated significantly enhanced up-regulation by UFP with a polycyclic aromatic hydrocarbon content and a higher oxidant potential. These proteins may be the important specific elements targeted by PM in air pollution through the ability to generate ROS in the immune system, and may be involved in allergen sensitization and asthma pathogenesis. [source] Anti-bacterial IgE in the antibody responses of house dust mite allergic children convalescent from asthma exacerbationCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2009B. J. Hales Summary Background Atopic sensitization to the house dust mite (HDM) is associated with altered antibody responses to the nasopharyngeal colonizing bacterium Haemophilus influenzae and children admitted to the emergency department for asthma exacerbation have reduced IgG responses to HDM allergens. Objective To investigate anti-bacterial and anti-allergen antibody responses during convalescence from asthma exacerbation and differences found in exacerbations associated with and without viral infection. Results IgE antibodies to the P6 bacterial antigen increased in 60% of sera during convalescence and for many children achieved titres as high as IgE titres to allergens. In contrast IgE anti-HDM titres declined during convalescence. The anti-bacterial IgE titres were the same in subjects with and without virus infection while the anti-HDM IgE declined more rapidly in virus-infected subjects. IgG titres to the major HDM allergens showed no consistent increase and the overall IgG anti-HDM titres even declined in subjects without a virus infection. Anti-bacterial IgG antibodies in contrast to IgE did not change. Patients with frequent episodic or persistent asthma had similar IgE anti-bacterial titres to patients with infrequent asthma during the acute phase, although they had reduced IgG titres to both the bacteria and the HDM. Conclusions During the period following an acute exacerbation of asthma there was a marked and specific increase in anti-bacterial IgE compared with a reduced IgE response to HDM. This provides further support for the concept of T-helper type 2 responses to bacterial antigens playing a role in asthma pathogenesis. [source] Effects of 4 months of smoking in mice with ovalbumin-induced airway inflammationCLINICAL & EXPERIMENTAL ALLERGY, Issue 12 2007B. N. Melgert Summary Background The effects of smoking on asthma pathogenesis are complex and not well studied. We have shown recently that 3 weeks of smoking attenuates ovalbumin (OVA)-induced airway inflammation in mice and that 4,6 months of smoking induces emphysema in mice without airway inflammation. Effects of combined long-term smoking and OVA exposure have not been investigated so far. Objective To study whether long-term smoking affects progression of allergic airway inflammation and/or enhances the development of emphysema in mice. Methods Mice were sensitized to OVA and challenged with saline or OVA aerosols for 6 months. From 2 months onwards, mice were also exposed to air or smoke. Lung tissue was analysed for extent of inflammation, emphysema, remodelling and for cytokine levels, and serum for OVA-specific IgE levels. Results Chronic OVA exposure of 6 months resulted in a T helper type 2 (Th2)-type inflammation with increased levels of IL-4, IL-5, IL-6 and infiltration of eosinophils, CD4+ T cells, macrophages and plasma cells. Smoking induced a Th17-type of airway inflammation, characterized by neutrophils, macrophages, B cells and increased levels of IL-17, IL-6, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and monocyte chemoattractant protein-1. Concomittant smoking and OVA exposure resulted in inflammation similar to OVA exposure alone. OVA exposure increased IgE levels compared with saline exposure, and smoking did not further increase these levels. Conclusion We did not find evidence for increased inflammation, IgE levels or emphysema in mice with allergic airway inflammation after 4 months of smoking compared with non-smoking. However, a 4-month exposure to smoke alone did enhance neutrophilic airway inflammation characterized by high pulmonary IL-17 levels. A Th2 inflammatory environment due to OVA exposure may be one explanation as to why no further detrimental effects of smoking on allergic airway inflammation were found. [source] Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2007N. E. McCarthy Summary Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid-naïve, allergen-challenged and allergen-naïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA-DR+ (negative for markers of other cell lineages) were predominantly myeloid and comprised ,0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4+ naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05,P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c,CD123high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies. [source] The topical glucocorticoids beclomethasone dipropionate and fluticasone propionate inhibit human T-cell allergen-induced production of IL-5, IL-3 and GM-CSF mRNA and proteinCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2001N. Powell T-cell production of eosinophil-active cytokines (IL-5, IL-3, GM-CSF) is thought to be fundamental to asthma pathogenesis. Inhaled aeroallergens may be one important stimulus for T-cell cytokine production in asthma. To compare the potency and efficacy of the topical anti-asthma glucocorticoids beclomethasone dipropionate (BDP) and fluticasone propionate (FP) in inhibiting allergen-driven peripheral blood T-cell proliferation and production of IL-3, IL-5 and GM-CSF mRNA and protein. Peripheral blood mononuclear cells from six atopic asthmatics sensitized to house dust mite (HDM) were cultured in the presence of HDM and serial dilutions of BDP or FP in vitro. Cellular proliferation (7 days) and culture supernatant cytokine concentrations (6 days) were measured by uptake of tritiated thymidine and ELISA, respectively. Cytokine mRNA expression (24 h) was measured in three subjects using a quantitative PCR technique. Both BDP and FP inhibited allergen-induced T-cell proliferation, expression of IL-3, IL-5 and GM-CSF mRNA, and secretion of the corresponding proteins in a concentration-dependent fashion. FP was considerably more potent, but not more efficacious, in exerting these actions. Both BDP and FP have the potential markedly to inhibit allergen-induced T-cell production of asthma-relevant cytokines. This activity is effected at the level of T-cell proliferation and cytokine gene transcription. These properties may be key features of the anti-asthma activity of these drugs. The greater potency of FP in vitro may be responsible for its greater clinical potency. [source] Function of Siglec-8 on human eosinophilsCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 2004E. Nutku Summary Eosinophil recruitment and activation are regarded as central to the pathophysiology of allergic diseases, including asthma. An improved understanding of the mechanisms involved in these responses is therefore of great relevance to asthma pathogenesis and the development of new therapeutics. As part of ongoing efforts to discover novel eosinophil-specific molecules, we recently cloned Siglec-8 (formerly called sialoadhesin family member-2) from a human eosinophil cDNA library. Siglecs (sialic acid binding Ig-like lectins) are a family of transmembrane, I-type lectins characterized by an N-terminal V-set Ig domain that binds sialic acid. We now know that Siglec-8 is expressed only on human eosinophils, basophils and mast cells, giving it a unique expression pattern on effector cells of allergic disease. We have determined that in eosinophils, Siglec-8 exists in two isoforms, one of which contains two putative cytoplasmic tyrosine-based signalling motifs, including an ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence. Because of the ITIM sequence, we hypothesized that Siglec-8 ligation would inhibit eosinophil functions. Initial studies found that incubation of eosinophils with Siglec-8 binding monoclonal antibodies under cross-linking conditions caused rapid and profound caspase-dependent apoptosis, and this response could not be rescued by the survival-promoting cytokine interleukin (IL)-5. In fact, IL-5 enhanced the ability of Siglec-8 cross-linking to induce eosinophil apoptosis. Activation via Siglec-8 could potentially be used to inhibit eosinophil survival in vivo, providing a novel strategy for reducing or inhibiting these cells in allergic and other diseases. [source] | ||||||||||