No description available.

No description available.

No description available.

Thesis (Ph.D.)--University of Western Australia, 2007.

Introduction. The atopic diseases of asthma, eczema and hayfever are immunologically mediated diseases initiated and perpetuated by T-helper (Th) cells of the Th2 phenotype, in affluent countries the prevalence of atopic diseases has increased dramatically in the last 40 years. This increase has been attributed to declining dietary intake of naturally occurring antioxidants. Epidemiological data and in vitro studies demonstrating that antioxidant deficiency is associated with Th2 differentiation support this 'antioxidant' hypothesis. The 'hygiene' hypothesis attributes the recent increase in atopic disease to declining childhood infections. This proposal originated from the observation of an inverse association between atopic disease and birth order. There is increasing interest that in utero influences play a critical role in determining the development of childhood atopic disease. There are reports that Th-cells from genetically susceptible neonates and neonates who subsequently develop atopic disease exhibit altered in vitro proliferative and cytokine responses. A proposed in utero influence is the sensitisation of fetal Th- cells by allergens and this concept is supported by indirect evidence. This thesis describes a prospective study designed to test the hypothesis that maternal allergen exposure and dietary antioxidant intake during pregnancy influence fetal Th-cell differentiation and the subsequent development of childhood atopic disease. Methods. Advantage was taken of a prospective cohort study of 2,000 pregnant women. Cord blood samples were obtained from a random sample of the neonates at birth. Cord blood mononuclear cells (CBMC) were stimulated with mitogen, control antigens and allergens. CBMC proliferative responses were quantified and CBMC interleukin-4 (IL-4) and interferon-y (IFN-y) secretion was measured by the celELISA method. These responses were related to antenatal data collected prospectively relating to the pregnancy. In a small number of samples the CD45 isoform of the responding CBMC was determined to investigate whether in utero allergen sensitisation of fetal Th-cells occurs. CBMC responses were also related to respiratory symptoms and atopic disease during the first year of infant life. Results. CBMC responses from 223 cord blood samples were characterised. CBMC culture conditions were optimised and the celELISA successfully detected secreted IFN-y and IL-4. CBMC proliferative responses were detected in 27-91% of cord blood samples, IL-4 responses in 18-31% and IFN-y responses in 19-88%. CD45 isoform analysis indicated that in utero sensitisation of timothy grass specific Th-cells occurs in 38% of pregnancies. CBMC proliferative responses were positively associated with a family history of atopic disease and maternal smoking. CBMC proliferative responses were negatively associated with birth order and maternal dietary vitamin E intake during pregnancy. CBMC IFN-gamma and IL-4 cytokine responses were positively associated with each other and a family history of atopic disease. CBMC IFN-gamma responses were negatively associated with birth order. Wheezing illness in the first year tended to be associated with increased CBMC proliferative responses at birth. Conclusions. Previously identified risk factors for atopic disease, which have been considered to be manifestations of post-natal influences, exert significant antenatal influences. The accepted adverse effects of maternal smoking on children's respiratory health may be a consequence of in utero influences. This study demonstrates a major in utero component to the association between birth order and atopy, contradicting the widely held assumption that it is a consequence of the protective effect of childhood infections. The maternal influence of dietary vitamin E intake raises the possibility of preventing childhood allergy by modifying the maternal diet during pregnancy. This study also provides the most direct evidence to date of the in utero sensitisation of Th-cells by allergens.

Background: Over the latter half of the last century, a dramatic increase in the prevalence of asthma has been observed. Over this same period there has been a substantial increase in the prevalence of obesity, this giving credence to the hypothesis that obesity and asthma may be causally associated. Aim: The main aims of this thesis were to: i) estimate the prevalence of asthma, allergic rhinitis, and atopic eczema in primary schoolchildren in Madinah, Saudi Arabia; ii) investigate the association between childhood obesity and prevalence of asthma; and iii) investigate possible mechanisms that might explain any associations observed. Methods: I undertook a pilot study aimed at testing the feasibility of conducting a large-scale descriptive epidemiological study of asthma and associated allergic disorders. This was followed by a two-stage cross-sectional survey, which was conducted to investigate the prevalence of asthma, allergic rhinitis, and atopic eczema in a sample of 5,188 schoolchildren, aged 6-8 years using an Arabic, validated version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Finally, I undertook an analytical study investigating the relationship between obesity and asthma. The cross-sectional study allowed for the identification of cases (i.e. those with a history of symptoms suggestive of asthma) and controls (i.e. those without a history suggestive of asthma). A sample of 632 cases and controls were recruited into a matched case-control study. Conditional logistic regression analysis, with appropriate adjustment for a range of potential confounders, was undertaken to explore the association between measures of obesity (in particular, body mass index (BMI)) and asthma. The possible aetiological roles of atopy and airway obstruction were studied by investigating the impact of sensitisation to common aeroallergens and measurements of lung function on the association between body mass index (BMI) and asthma. Results: In the pilot study, I found that the asthma, allergic rhinitis, and atopic eczema were very prevalent in children in Madinah and that further epidemiological studies were therefore likely to be feasible. The overall prevalence of children with a history of symptoms suggestive of asthma was 23.6% (95% CI: 21.3, 26.0); the prevalence among boys was estimated at 24.4% (95% CI: 22.0, 26.9) and among girls at 21.9% (95% CI: 17.4, 27.1), respectively. After adjustment for a number of possible confounders, BMI was found to be a significant predictor of the odds of asthma in both boys (OR=1.11; 95% CI: 1.03, 1.19) and girls (OR=1.38; 95% CI: 1.23, 1.56). When sensitisation to allergens was included in the analyses, the effect of BMI on the risk of asthma was no longer evident in boys (OR=1.09, 95% CI: 0.99-1.19) or girls (OR=1.25; 95% CI: 0.96-1.60). When the effect of lung function measures were factored into the model, the association however persisted: boys: OR=1.10 (95% CI: 1.02, 1.18) and girls OR=1.37 (95% CI: 1.22, 1.54). Conclusions: Asthma and related allergic disorders are very common in primary schoolchildren in Saudi Arabia. BMI is associated with symptoms suggestive of asthma in primary schoolchildren. This effect does not appear to be mediated through respiratory obstruction, but may, at least in part, be mediated through increasing the risk of allergic sensitisation. Prospective and more detailed gender-specific mechanistic studies are now needed to further investigate this association.

No description available.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

Lung surfactant protein D (SP-D) is a soluble pattern recognition and innate immune molecule, which has been shown to be protective against lung infection, allergy, asthma and inflammation. SP-D is composed of an N-terminal collagen region and a homotrimeric, C-terminal carbohydrate binding domain (CRD). A recombinant form of trimeric CRD region (rhSP-D) has been shown to offer protection against asthma and inflammation in murine models by bringing down IgE levels, eosinophilia, and causing T helper cell polarisation from a pathogenic Th2 to a protective Th1 phenotype. Thus, rhSP-D can provide a therapeutic effect by dampening asthmatic symptoms in mice. The therapeutic mechanisms include inhibition of allergen-IgE binding and histamine release by sensitized mast cells, downregulation of allergen/antigen-specific IgG and IgE antibodies, pulmonary and peripheral eosinophilia, a shift from Th2 to Th1 cytokine response, interference with airway remodelling processes, and apoptosis- induction in sensitised eosinophils from allergic patients. The majority of the ex vivo and in vivo studies where a therapeutic effect of rhSP-D has been reported can not be explained by hitherto described candidate receptor involvement, especially CD91-calreticulin complex that requires collagen region for its cellular response. Thus, it is pertinent to examine at the cellular and molecular level how a trimeric lectin domain of human SP-D modulates immune cells. This was achieved by firstly expressing, purifying and characterising the recombinant rhSP-D and examining the interaction of rhSP-D with various immune cells such as macrophages, which are potent antigen presenting cells and play a crucial role in the maintenance of the inflammatory and humoral response to allergens. The highlight of this study is the demonstration that rhSP-D interferes with the co-operative binding of allergen-IgE complexes to B cells, and also downregulates expression of CD23, a low affinity IgE receptor (FcεRII), found on B cells. This suggests that inhibition of IgE-facilitated antigen presentation may represent a mechanism whereby SP-D suppresses Th2-driven allergic inflammation. In addition, this study is also the first to establish the calcium-dependent interactions between rhSP-D, CD23 and CD21. The possibility of formation of a trimolecular complex on the B cell surface may account for the suppression of IgE in therapeutic murine models since rhSP-D may interfere with CD21-CD23 mediated IgE production by primed B cells.

Asthma is a heterogeneous condition characterised by variable airflow obstruction, airway inflammation and hyper-responsiveness. Fungal sensitisation has been associated with asthma severity; and airways colonisation by the pathogenic fungus Aspergillus fumigatus has been associated with a progressive lung function decline in allergic bronchopulmonary aspergillosis. Interest in the home environment as a source of fungal exposure is increasing; however, there are still no accepted guidelines or standardised methods for the quantification of indoor fungal levels. We sought to i) investigate typical airborne fungal spore concentrations in homes and to compare exposure levels in asthma patients grouped according to either A. fumigatus sensitisation or sputum culture; ii) fully characterise the fungal biota capable of colonising the airways in patients with asthma; and iii) define the clinical characteristics of fungal colonisation. Aspergillus/Penicillium-type conidia exhibited indoor predominance and independence of season, and were highest in old, terraced, non-insulated properties. A. fumigatus was the predominant fungus isolated from sputum and IgE sensitisation to A. fumigatus was associated with reduced post-bronchodilator FEV1 in patients with asthma. Sputum culture of filamentous fungi was also associated with reduced lung function, with predominant fungi comprising Aspergillus and Penicillium species; notably Penicillium piceum and species of Aspergillus section Nigri. Higher levels of airborne A. fumigatus were detected in homes of asthmatics with a positive sputum culture for A. fumigatus. In conclusion, sensitisation to A. fumigatus and airways colonisation by fungi are associated with reduced lung function in moderate to severe asthma; and this study provides a direct link between home exposure and airways colonisation.