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.

1. I have described a population of children and young adults with asthma in primary and secondary care, in terms of relevant history, medication use and exacerbations. 2. My thesis presents observations reported for the first time that asthmatic children and young adults homozygous for the Arg16 allele on the ß2 adrenergic receptor gene (ADRB2), on frequent doses of on demand short-acting ß2-agonists are at greater risk of asthma exacerbations.I have shown an increase in the risk of exacerbations per copy of Arg16 allele in children and young adults with asthma on the regular long-acting ß2-agonist salmeterol. 4. I have shown that there is an increase in risk of exacerbations per copy of Arg16 allele in children and young adults with asthma on frequent (once daily or more) as required doses of inhaled salbutamol. This effect is not observed on participants with asthma who are not exposed to ß2-agonist on a daily basis. 5. I have shown that the Arg16Arg variant status may be associated with worse airway obstruction, as measured by the FEV1/FVC ratio.6. I have shown that the individuals with FLG null alleles have a significantly increased risk of exacerbations requiring hospital admissions, courses of oral steroids, or experiencing school absences

Background: Exposure of skin to UVB radiation (290-320 nm) modulates the immune system, with most studies showing a suppression of Th1-driven immune responses. Investigations into the effects of UVB exposure on allergic respiratory responses have been limited. This study investigated the systemic effects of UVB on Th2-associated immune responses using two different murine models of allergic respiratory inflammation. The mechanism of immune regulation was also examined. Methods and Results: Two murine models of asthma were used: the papain model and the ovalbumin (OVA) model using papain and OVA, respectively, as the allergens. In the papain model, C57BL/6, histamine receptor-1 knockout (H1RKO) and histamine receptor-2 knockout (H2RKO) mice were exposed to a single 4 kJ/m2 dose of UVB (twice a minimal oedemal dose) on shaved dorsal skin three days prior to intranasal sensitisation with papain, a cysteine protease homologue of the house dust mite (Dermatophagoides pteronyssinus) allergen Der p 1. Sensitisation and boost each consisted of five daily intranasal doses of 1 µg papain whilst the challenge consisted of three daily intranasal doses of 100 µg papain. Asthmatic symptoms were assessed 24 h after the final challenge dose. H1RKO mice demonstrated enhanced papain-specific inflammatory responses in the lung-draining lymph nodes (LDLNs) whilst the responses of H2RKO mice closely mimicked those of C57BL/6 mice. UVB irradiation three days before sensitisation reduced in vitro papain-specific proliferation of LDLN cells from C57BL/6 and H1RKO mice but not H2RKO mice 24 h after challenge. The regulatory effect of UVB was transferred by adoptive transfer of 5 x 106 unfractionated LDLN cells from UVB-irradiated, papain-sensitised and -challenged C57BL/6 and H1RKO donor mice into naïve recipients of the corresponding strain that were ii subsequently sensitised and challenged with papain. Additionally, UVB exposure suppressed papain-induced IL-5 and IL-10 production in vitro by LDLN cells from H1RKO mice but not from C57BL/6 mice or H2RKO mice. The results of this study demonstrate systemic immunomodulation of responses to intranasally delivered antigen by UVB irradiation and the induction of regulatory cells in the LDLN following UVB exposure. Furthermore, these results implicate a role for the H2R in UVB-induced suppression of antigen-specific responses in the draining lymph nodes.

Thesis (Ph. D.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains v, 59 p. Includes abstract. Includes bibliographical references (p. 38-51).

Les granulocytes, neutrophiles et éosinophiles, sont des cellules effectrices de l'immunité innée. La régulation de la vie des granulocytes par le mécanisme de mort programmée cellulaire quest lapoptose procure un équilibre judicieux entre leur fonction de cellules effectrices dans la défense de lorganisme et le renouvellement sécurisé de ces cellules potentiellement dangereuses. Lapoptose spontanée constitue un processus nécessaire pour le maintien de lhoméostasie des cellules immunes, telles que les granulocytes. Mon travail de doctorat a permis didentifier de nouveaux mécanismes régulateurs de l'apoptose des granulocytes. La première étude démontre le rôle important des céramides de type C16 et C24 en tant que messagers secondaires dans la transmission du signal de mort dans les neutrophiles vieillissants. En effet, nous montrons que ces céramides, générées par la voie de synthèse de novo, s'accumulent spontanément dans les neutrophiles et précèdent l'apparition des signes de l'apoptose précoce ainsi que l'activation des caspases-8, -9 et -3. L'inhibition ou l'accélération pharmacologiques de cette accumulation ralenti ou accélère l'apoptose des neutrophiles, respectivement. Laccumulation des céramides C16 et C24 est également inhibée par le traitement des neutrophiles avec du GM-CSF, une cytokine proinflammatoire et anti-apoptotique. Par contre, nos résultats montrent que la mort induite par l'activation du récepteur Fas ne dépend pas de la synthèse de céramides par la voie de novo. Au cours de la seconde étude, nous avons identifié un mécanisme spécifique dans la régulation de l'apoptose des éosinophiles. Nous montrons que les éosinophiles expriment spontanément CD40 à leur surface et que lengagement de CD40 s'oppose à la mort des éosinophiles via l'induction de la protéine inhibitrice de l'apoptose cytoplasmique-2 (c-IAP2). En outre, nous apportons les évidences de l'existence d'un mécanisme similaire in vivo, en particulier dans l'inflammation allergique des voies respiratoires.

Asthma, a huge burden on millions of individuals worldwide, is one of the most important public health issues in many countries. As genetic and   environmental factors interact, asthma may be programmed very early in life, perhaps even in utero. The aim of this thesis was to assess the impact of gestational age, cord blood immunoglobulin E (IgE), a family history of asthma, migration, and pertussis immunization in early life on the development of asthma in child and adult populations. As a proxy for asthma disease, dispensed asthma medication was used as the main outcome variable based on data from the Swedish Prescribed Drug  Register. Data from other national registers were used to control for  confounders. Three of our studies were based on national cohorts, and one on a local birth cohort that was initiated in 1974–75. Gestational age had an inverse dose-response relationship with dispensed asthma medication in 6– to 19-year-olds. Odds ratios for dispensed asthma medication increased with degree of prematurity compared with children born in term. Furthermore, asthma medication was more likely to be dispensed among children and adolescents born early term after 37–38 weeks’ gestation than among those at the same age who were born in term. Elevated cord blood IgE and a family history of asthma in infancy were associated with a two- to threefold increased likelihood of dispensed asthma medication and self-reported allergen-induced respiratory symptoms at the age of 32–34 years, but the predictive power was poor. Age at migration had an inverse dose-response relationship with dispensed asthma medication at the age of 6–25 years in adoptees and foreign-born children with foreign-born parents. International adoptees and children born in Sweden to foreign-born parents had three- to fourfold higher rates of asthma medication compared with foreign-born children who were raised by their foreign-born birth parents. No association was found between pertussis immunization in early infancy and dispensed asthma medication in 15-year-olds. The type of vaccine or vaccine schedule did not affect the outcome. Fetal life is a vulnerable period. This thesis strengthens the evidence that every week of gestation is important for lung maturation. Cord blood IgE, however, did not predict the risk of asthma in adults. Furthermore, the study of migrating populations demonstrated that environmental changes at any age during childhood may affect the risk of asthma. Another, important public health message from this thesis is that vaccination against pertussis in early childhood can be considered safe with respect to the long-term development of asthma.

No description available.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / Typescript. Vita. Includes bibliographical references (leaves 111-120). Also available on the Internet.

Thesis (Ph. D.)--Lehigh University, 2003. / Includes vita. Includes bibliographical references (leaves 121-138).

Thesis (Ph. D.)--University of Chicago, Committee on Immunology, August 2003. / Includes bibliographical references. Also available on the Internet.