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