By Nilofar Følsgaard, MD, PhD
Chairman: Kjeld Schmiegelow
Opponent: John O. Warner
Opponent: Carsten Heilmann
Asthma and wheezing together with the other atopic disorders; allergy, eczema and rhinitis are the most common chronic diseases in children with major impact on quality of life for patients and significant socioeconomic costs due to health care utilization. The airway mucosa is constantly exposed to environmental factors such as microorganisms, airborne allergens and pollutants. Depending on the composition of this exposome, specific types of immune cells become activated releasing a fingerprint of cytokines and chemokines in the airway mucosa. The immune competence of the new-born child determines the penetration and impact of the exposome. The ability to mediate a balanced and appropriate immune response is fundamental for managing healthy airways while inappropriate release of inflammatory mediators may have unfavorable long-term consequences such as asthma. Genetic predisposition to atopic diseases is well-recognized, with estimated heritability as high as 60% in asthma. Atopic hereditary disease linkage in the offspring seems stronger for maternal than paternal atopic disease. But it is not known how parental atopic disease may affect early immunity in the target organ, the airways. COPSAC has recently reported an association between abnormal bacterial colonization with M. catarrhalis, S. pneumoniae, H. influenzae of the upper airways of neonates and later development of asthma. This led to the hypothesis that the interaction between genetics and this microbiome in very early life may cause immune modulation towards an atopic trajectory.
In this PhD thesis we aim to explore the immune profile of the airway mucosal lining fluid of 700 neonates from the COPSAC2010 cohort by discovering how heritability and colonization of the airways with pathogen bacteria M. catarrhalis, S. pneumoniae, H. influenzae and S. aureus affects the expression of immune mediators in 4 week old infants.
In paper I, we explore the effect of atopic heredity on the immune expression, showing that children of mothers with atopic disease express down-regulation of nearly all their chemokines and cytokines in the airway mucosa. There was no paternal linkage to the mucosal immune response pattern, suggesting maternal programming of the fetus or neonate is causing an aberrant local airway immune profile in the newborn child. Furthermore our results suggest an association between maternal atopic disease and the expression of cytokines reflecting activity of the innate and adaptive (Th2) immune systems in the infant.
In paper II, we looked at colonization of the airways with 4 specific pathogenic bacteria (M. catarrhalis, H. influenzae, S. pneumoniae and S. aureus) and investigated the specific immune signature this asymptomatic colonization induces. Even though these neonates did not exhibit any symptoms of infection, colonization with M. catarrhalis, H. influenzae and S. aureus triggered a sizable species specific topical immune response, indicating an immune-regulating function of these bacteria that may induce a chronic atopic inflammatory response.
In conclusion, maternal atopic disease influences the immune expression in the airways of the new born child by inducing a general down regulation of the mediators in children of atopic mothers. Colonization of the airways of asymptomatic neonates with pathogenic bacteria induces species specific and significant stimulations of the immune profile of the airway mucosa indicating that particularly M. catarrhalis and H. influenzae are not just innocent bystanders but may likely induce a chronic inflammatory response. In these studies we have shown for the first time that known perinatal milieu factors influence airways of the newborn child directly and alter the immune expression in a target organ for atopic disease.