Factors associated with preschool wheeze developing into school-age asthma

Preschool wheeze affects one third of all toddlers up to the age of three years and half of the children before six years of age. Approximately one third of these children will develop asthma in school age, and several risk factors have been proposed. However, as of today, it is not possible to reliably predict which children, with preschool wheeze, will develop asthma. All four studies in this thesis are based on the Gene Expression in Wheezing and Asthmatic Children (GEWAC) study, a longitudinal case-control study in which 156 cases and 102 healthy controls, ages 6-48 months, were included. The cases were recruited from the pediatric emergency department at Astrid Lindgren’s Children’s Hospital in Stockholm, when seeking care for an episode of acute wheeze. They came to a revisit after approximately 3 months and were followed annually up to the age of 7 years and a follow-up at age 11. The age-matched healthy controls were recruited from the same hospital at the surgical day-care ward and came to a follow-up at ages 7 and 11 years. The study protocol included nasopharyngeal swabs for viral detection at inclusion, blood sampling, questionnaires, physical examination, measurements of lung function and fractional exhaled nitric oxide (FeNO). Study I consisted of 113 children with an episode of preschool wheeze (cases) and 52 healthy controls who came to the 7-year follow-up. The prevalence of asthma at age 7 was 70.8 % among cases and 1.9 % in healthy controls. Rhinovirus-induced preschool wheeze was more common among cases with asthma in comparison to cases without asthma at age 7 years (48.1 % vs. 21.9 %, p = 0.011; OR 3.3, 95 % CI 1.3-8.5) and this association remained after adjustment for infection with other viruses (OR 3.8, 95 % CI 1.4-10.5). Cases with asthma at age 7 years were admitted to hospital more often because of respiratory difficulties (p = 0.024) and spent more time hospitalized (p = 0.01) during the year after inclusion in the study. In study II we evaluated 107 cases and 46 healthy controls at the 11-year follow-up. We found that 62.6 % of cases and 13.0 % of healthy controls had asthma at age 11 years. Earlylife factors associated with asthma at age 11 years, among cases, were rhinovirus-induced wheeze (OR 2.4, 95 % CI 1.02-5.6) and allergic sensitization at 2 years of age (OR 2.9, 95 % CI 1.05-8.1). However, in multivariate logistic regression only allergic sensitization at age 2 years (adjusted OR 3.0, 95 % CI 1.02-8.7) and parental heredity for asthma and/or allergy (adjusted OR 3.4, 95 % CI 1.1-9.9) were associated with asthma at age 11 years. Cases with both rhinovirus-induced wheeze at inclusion and allergic sensitization at age 7 years had a higher prevalence of asthma at age 11 years, in comparison to cases with rhinovirus-induced wheeze at inclusion but without allergic sensitization at age 7 years (92.9 % vs. 57.1 %, p = 0.03). In study III we measured 92 inflammatory-related plasma proteins during an episode of acute preschool wheeze in 145 cases and compared them to 101 healthy controls. With unsupervised clustering we found that the ten most differentially expressed inflammatoryrelated proteins could almost entirely separate cases from healthy controls. Seven proteins exhibited a higher expression in cases (OSM, IL-10, IL-6, CXCL10, FGF21, AXIN1 and SIRT2) and three proteins had a lower expression (TNFSF11, TNF-b and CASP8), in comparison to healthy controls. These proteins are implicated to be involved in airway epithelial dysfunction, airway remodelling, viral defence, and type 2 inflammation. Among the ten proteins, three (FGF21, SIRT2 and IL-10) were still differentially expressed between cases and controls at the revisit 3 month later. Finally, in study IV we investigated sensitization to multiple allergen molecules longitudinally and its relation to asthma development at 7 years using the multiplex ImmunoCAP ISAC measuring 112 allergen molecules. In this study 72 cases were included and 43 healthy controls. Sensitization to each additional allergen molecule from preschool age to 7 years was associated with asthma at 7 years (OR 1.2; 95 % CI 1.01-1.5). The median number of sensitizing molecules increased from 3 (1-14) at inclusion to 10.5 (1-21) at 7 years of age among sensitized cases with asthma at 7 years of age (p = 0.038). No significant increase was seen in cases without asthma (p = 0.26). Lastly, the number of sensitizing allergen molecules at 7 years was associated with asthma at the same age (OR 1.2; 95 % CI 1.02-1.42). In summary, we found rhinovirus-induced wheeze to be associated with asthma at both 7 and 11 years of age, although probably acting as an unveiling factor in children already predisposed to asthma development. We highlighted the importance of allergic sensitization in asthma development with molecular spreading and polysensitization being involved in disease development. Finally, we found ten inflammatory-related plasma proteins that could contribute to the understanding of why preschool wheeze is a risk factor for asthma development

Cartilage-specific autoimmunity in animal models and clinical aspects in patients – focus on relapsing polychondritis

Relapsing polychondritis is an autoimmune disease in which an inappropriate immune response destroys cartilage. Cartilage of the ears, larynx and nose rather than spine and joint cartilage is affected by a chronic relapsing and erosive inflammation. Several animal models for relapsing polychondritis have been published in which immunization with various cartilage proteins induces a variety of chondritis symptoms that mimic those seen in patients. In this review we describe the collagens, matrilin-1 and cartilage oligomeric matrix protein as potential autoantigens able to trigger the tissue-specific immune response seen both in patients and in animal models for relapsing polychondritis and related autoimmune diseases

Managerial competencies of female and male managers in the Swedish construction industry

The construction industry is one of the most male dominated industries around the world, not only when it comes to workers, but also as regards managers. Only 5% of the managers in the Swedish construction industry are women. The managerial competencies of individuals working as managers in the Swedish construction industry are researched to get a clearer understanding of the situation, and to investigate if this lack of balance between male and female managers has to do with differences in managerial competence. The management development questionnaire provided by Human Resource Development Press was sent to 143 managers in the Swedish construction industry and 112 respondents (44 women and 68 men) assessed themselves in 20 competencies, resulting in a response rate of 78%. The Mann-Whitney U test showed that female and male managers possess equal managerial competencies in 17 of the 20 competencies. Male managers rated themselves as having better managerial competency than females in two of the 20 competencies, namely ‘resilience’ and ‘decision making’. Female managers rated themselves as having better managerial competency than males in ‘sensitivity’, which follows the social norm of what is expected of a woman. It was also found that both groups scored high in decision making, reflecting traditional virtues of construction managers as decisive and active. The most important result is not the differences but the many similarities between women and men working as managers in the construction industry. Thus, it is concluded that female managers are as competent as male managers in the Swedish construction industry

The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis

For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future

A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis