By Helene Wolsk
Chariman: Bente Klarlund Pedersen
Opponent: Harald Renz
Opponent: Tine Brink Henriksen
From the moment of birth, the airway immune system is exposed to airborne pathogens and other environmental triggers. The failure of the immune system to mediate a balanced immune response in the airways towards such irritants is thought to be fundamental for development of asthma and allergy, which are the most common chronic childhood diseases. Even though it is broadly believed that early life subclinical immune changes precede the clinical manifestation of asthma and allergy, there are few published studies on that topic. In particular, no longitudinal studies have been performed, where the airway topical immune signature in neonates has been combined with outcomes of asthma and allergy later in childhood. In this thesis, I present a method to assess the unstimulated upper airway immune signature in neonates and explore if early environmental exposures affect the immune signature in healthy neonates and whether such airway immune profile is related to later development of asthma and allergy. My hypotheses were that early exposures, including presence of airway viruses and siblings at birth, have immune programming effects; and that the neonatal immune signature would predict development of allergy and asthma-related diseases in childhood.
In paper I, we describe the method, which is the foundation of this thesis. The mucosal lining fluid
sampling method has the advantage of being non-invasive and undiluted.
This has enabled us to measure in vivo and unstimulated levels of cytokines and chemokines longitudinally – from the neonatal period and into childhood.
In paper II, we explore the effect of viruses on the immune signature in asymptomatic neonates.
We found that asymptomatic neonates with picornavirus in the airways had a topical up-regulation of 20 key immune mediators related to the Type 1, Type 2, Type 17 and regulatory (Treg) immune pathways. This indicates that early exposure to picornavirus may have an early immune programming effect in asymptomatic neonates.
In paper III, we explore the effect of siblings on the neonatal immune signature at the time of birth.
We observed that the presence of siblings mediated a Type 1/Type 17-related immune-stimulatory effect in the airways of asymptomatic neonates,
independent of presence of pathogenic bacteria and viruses. This indicates that presence of siblings in the home exert early immune modulatory effect.
Furthermore, we found that the effect was attenuated by the time since previous pregnancies. Hence, this may indicate an in utero immune priming of the fetal immune system.
In paper IV, we examine the association between the neonatal immune signature and later development of asthma, allergy and lower respiratory tract infections between 0-5 years of age. For allergic sensitization, we found evidence of an airway immune signature characterized by a down regulation of TGF-β1, whereas asthma-related disorders, were characterized by a down-regulation of mediators important for neutrophilic recruitment (CXCL8, IL-1β and TNF-α). Hence, the immunological basis for the subsequent chronic inflammatory component of asthma and allergy seems to originate in pre- and perinatal life.
In conclusion, we observed that neonatal environmental exposures are mirrored in the airway immune profile; and that distinct immune profiles are evident in children with subsequent development of asthma and allergy.
The mucosal lining fluid method, which is the backbone of this thesis, holds promising implications for studying the longitudinal airway immune response through childhood. This will aid our understanding of how changes in the compositions of the airway immune response are associated with, and possibly precede diseases such as asthma and allergy.