Elucidating the roles of secretory immunoglobulins in asthma under homeostatic and infectious conditions

Abstract

Secretory immunoglobulin A (SIgA) as well as its exclusive epithelial transport molecule, the polymeric immunoglobulin receptor (pIgR), are crucial elements of respiratory mucosal immunity whose absence or downregulation are linked to an increased susceptibility to bacterial infections. While the crucial role of pIgR and SIgA for mucosal antibacterial defense aswell as their relevance for intestinal immunity are well understood, little is known so far regarding their regulation throughout the entire respiratory tract and related possible implications for airway mucosal immunity. Thus, the overarching goal of this thesis was to dissect airway secretory immunity during homeostatic, inflammatory and infectious conditions. In the first part of this study, the impact of different endogenous vs. exogenous (environmental) factors on airway associated antibacterial and secretory immunity was assessed using different murine models. These initial analyses revealed that sitespecific differences regarding basal Pigr gene expression are depending on microbial colonization as well as on yet unknown intrinsic effects. Moreover, secretory immunity in the upper respiratory tract (URT) and lower respiratory tract (LRT) can be partly modulated by exogenous (microbial-derived) as well as endogenous (host-derived) stimuli. Allergic asthma was previously shown to reduce PIGR-mediated secretory immunity in the LRT and to increase the susceptibility to bacterial pneumonia. The URT, e.g. the nasal cavities, represents both entry site and natural reservoir of several pathogenic bacteria, as well as site of allergic sensitization to aeroallergens during asthma development. It is conceivable, that allergic asthma is associated with altered secretory immunity in the URT, which in turn might affect infection with respiratory bacterial pathogens as well as microbial composition in general. Following this hypothesis, the second part of this thesis focused on analysing secretory immunity as well as pneumococcal colonization of the respiratory tract of asthmatic and non-asthmatic mice under homeostatic conditions and in reaction to intranasal treatment with an endogenous molecule (IFN-g). To this end, two different murine models of house dust mite (HDM)-induced allergic asthma were established and characterized in detail. High-dose, mid-term HDM treatment led to a stable phenotype of allergic asthma. IFN-g treatment improved antipneumococcal immunity in the URT of non-asthmatic mice. This effect was not reproducible in asthmatic mice, indicating that IFN-g stimulation exerts no effect on host antibacterial defense in the astmathic URT and shows that this cytokine has a context-dependent role on antipneumococcal immunity in healthy vs. pre-diseased individuals. Ultimately, the third and final part of this thesis addressed the impact of allergic asthma on secretory immunity and microbiota composition in the human URT in frame of a clinical cohort study. These analyses revealed, that neither asthma nor the presence of allergy affects PIGR-mediated secretory immunity in the URT. Yet, asthma was partly associated with elevated nasal IgG2 levels and increased microbial diversity. However, there was no correlation between these two parameters. Thus, asthma-associated alterations in nasal microbiota composition seem to be independent of secretory and antibacterial immunity.