INTRODUCTION
Worldwide, allergic diseases affect development and well-being of many children and adolescents, while also posing a considerable socioeconomic burden.1 Allergic diseases are heterogenous and may present with similar symptoms but different underlying causes, the features of which are just beginning to be characterised.2 Both sensitisation and asthma are considered heterogeneous traits, with distinct clusters being unveiled using unsupervised machine learning techniques.3,4While numerous immune biomarkers have been investigated as potential determinants of heterogeneity and development of allergic phenotypes, thus far none has proven unequivocal utility in a clinical setting.
Allergic inflammation depends on chemokine-facilitated recruitment of immune cells to the allergic reaction site.5 The Th2-associated chemokines CCL17 and CCL22 are expressed by the thymus, and may be induced by IL-4 and IL-13 in several cell types including T cells.6,7 Development of allergic symptoms and sensitisation early in life is preceded by elevated cord blood levels of CCL17 and CCL22, respectively.8,9 Similar findings from sensitised children with allergic symptoms8,9, and children developing recurrent wheeze10 and asthma9, further corroborate involvement in allergic immune responses.
The Th1-associated chemokines CXCL10 and CXCL11 are induced by IFN-γ11, and are mainly expressed by the thymus, peripheral blood leukocytes, epithelial and endothelial cells.12,13 Increased levels of CXCL10 and/or CXCL11 have been observed in both viral-induced14 and moderate-to-severe asthma.15 Multiple studies have also revealed elevated early life Th1-associated chemokine levels predicting outcomes such as wheezing and asthma.10,16In contrast, sensitised children revealed lower circulating levels of CXCL11 at birth and 2 years of age10, suggesting diverse mechanisms of action in allergy development.
CCL18 is under dual regulation of both Th2 and Treg cells, as it may be induced by IL-4, IL-13 as well as IL-10.17 This contrasts to CCL17 and CCL22, which are inhibited by IL-10.17,18 Being produced primarily by tissue resident antigen presenting cells, CCL18 is also constitutively expressed in the lung and circulation.17 At steady state, CCL18 is mainly a regulatory chemokine, which is up-regulated in allergic conditions such as allergic rhinitis, atopic dermatitis and asthma.17 Indeed, we have previously showed elevated levels of CCL18 in children developing eczema and recurrent wheeze in the first years of life.10
We hypothesised that allergy-related chemokines, namely CXCL10, CXCL11, CCL17, CCL22 and CCL18, precede the development of different allergic phenotypes throughout childhood. To this end, we measured circulating levels of these chemokines at three time points throughout childhood (at birth, 1 year and 8 years of age) in a population-based birth cohort19, and related these chemokines to allergic outcomes from infancy to age 16 years. Furthermore, we ascertained the relationship between these chemokines and previously described clusters of allergic diseases derived using machine learning in this cohort.20-23