Deregulated Immune Response in Early Life and The Development of Asthma

Abstract

The prevalence of non-communicable diseases (NCDs) such as diabetes, asthma and mental disorders have been rising worldwide during the last decades. Those NCDs are suggested to be based on a common reason, as they can all be explained as the “altered reactivity” of the human body to the mismatched total modern environment. Among all forms of NCDs, childhood atopic diseases including asthma, allergic rhinitis and food allergy have attracted a lot of attention and have been extensively studied as they manifest during early life and may serve as an indicator of the altered immune system and forerunner of other forms of NCDs. This PhD study aimed to investigate potential early life immune mechanisms underlying the development of asthma and other forms of allergic disorders. We hypothesized that a deregulated immune response to specific microorganisms in early life may result in inefficient removal of these infectious agents and subsequently result in exaggerated immune activity, in continuous or recurrent infections, and in development of asthma or allergic sensitization. The hypothesis was studied by using data based on ex vivo stimulated cytokine release from peripheral blood mononuclear samples collected at 6-month-of age from children followed consecutively from birth to school age for collection of environmental exposure and clinical data. Immune response data were based on stimulation of immune cells with whole airway bacteria or pathogen associated components activating different adaptive or innate immune responses. From examining cytokine production in response to three selected airway bacteria, we identified a reduced IL-2 production to link with increased levels of total IgE at the age of 6 years. Moreover, we also found that reduced IL-2 in combination with elevated IL-5 associated with increased risk of allergic rhinitis at the age of 7 years. These results provided evidence to support an association between a deregulated immune response against certain bacteria in early life and later allergic sensitization. We also identified an IL-23-biased innate immune response against viral and bacterial derived nucleic acids to underline the association between asthma risk SNPs and childhood asthma. This result suggested that the link between the 17q21 asthma risk and asthma development is partly mediated via a deficient innate immune response to intracellular pathogens in early life. This result did not only provide evidence to support the hypothesis about deregulated innate immune function, but also pointed to a mechanism for how the 17q21 locus variants may increase the risk of developing childhood asthma. Altogether, we here provide evidence for two different deregulated immune mechanisms in infants which couple pathogenic colonization in the airways in early life to later asthma development or allergic sensitization at school age.