DISCUSSION
In this study, we show that levels of the chemokines CCL18, CXCL10 and
CXCL11 in early life and childhood may predict outcomes of allergic
disease later in childhood and adolescence. To our knowledge, this is
the first study to show that childhood circulating CCL18 levels may
affect allergy-related outcomes longitudinally until adolescence.
The main finding was that the dually Th2/Treg regulated chemokine CCL18
predicted development of both asthma and sensitisation, with consistent
effects over time. Being constitutively expressed in the lung and
lymphoid tissues during homeostatic conditions, CCL18 exhibits both
chemotactic and immunoregulatory properties.17 It
promotes tolerogenic differentiation of dendritic cells, which in turn
may polarise T cells into Tregs, and may polarise memory T cells into
FoxP3+ T cells in vitro . In allergic subjects, however, the
tolerogenic effects of CCL18 are seemingly abrogated, despite being
upregulated in allergic conditions such as atopic
dermatitis10,27,28 and asthma.17Described being due to less efficient binding of the protein on immune
cells, this possibly could partly explain the loss of tolerance in
allergic individuals. Furthermore, CCL18 induces production of collagen
both in the skin and lung, implying a role in remodelling of the airways
typically seen in asthmatic subjects.17 As alveolar
macrophages are the main producers of CCL18 in the lung, where its
expression is constitutive, it is tempting to speculate that these
levels are augmented in asthmatic individuals owing to dysregulation of
these cells. However, as our measurements were performed in plasma
samples, and CCL18 may originate from one of many bodily sources, we
cannot draw conclusions on tissue specific effects of the observed
elevation without performing functional studies. Furthermore, whether
heightened CCL18 responses in asthmatic and sensitised children
constitute causative mechanisms of allergy induction, or compensatory
immune dampening responses, remains to be elucidated. We further
examined chemokine expression within allergy clusters previously derived
from our cohort.20-23 Indeed, CCL18 levels at age 8
were higher in the multiple early allergic sensitisation cluster.
Moreover, children with asthma exacerbations had higher levels of CCL18
at age 8 compared to children without wheeze. Taken together, this
suggests that increased CCL18 levels later in childhood may reflect
allergic disease severity, although further studies should elaborate on
this matter.
Interesting findings also appeared for the Th1-associated chemokines
CXCL10 and CXCL11. Elevated levels of CXCL10 in infancy and childhood
associated with present and future development of asthma, in line with
results from children with wheezing at age 3, who subsequently developed
asthma at age 6.16 Additionally, CXCL10 levels are
increased in viral-induced asthma29,30, suggesting
that viral infections may induce Th1-chemokine responses in asthmatic
individuals. On the contrary, low cord blood CXCL10 levels associated
with sensitisation in infancy and adolescence. Similarly, decreased
CXCL11 levels in early life associated with later development of
sensitisation. This corroborates findings from our previous studies,
where SPT-positive children had lower levels of CXCL11 at birth and 24
months.10 As sensitisation is a Th2-driven process,
and Th1-responses were lessened in sensitised children, diminished
neonatal Th1-responses seemingly paves way for development of
sensitisation in these children. Additionally, reduced cord blood CXCL11
levels associated with asthma at age 16 and translated into a predicted
lower risk with high CXCL11 levels at birth, supporting previous results
where children with the highest quartile CXCL11 levels at birth did not
become sensitised throughout the first two years of
life.10 No long-term effects of CXCL10 and CXCL11 on
allergy development could be demonstrated in this study. Possibly, the
function of Th1 cells, and their expression of IFN-γ, may become
attenuated due to immunoregulatory effects of the highly expressed CCL18
on Tregs, although the findings may also constitute altered patterns of
expression in allergic conditions. Collectively, this indicates that
although these chemokines are induced by the same cytokine, downstream
effects seem to be differentially regulated both in terms of allergy
outcome and how levels reflect temporal development of disease.
There are both limitations and strengths to the present study. We
evaluated circulating chemokine levels but did not have the opportunity
to evaluate functional aspects of the same mediators in different
tissues. This would have added mechanistic insights into the findings
presented here. Also, the generalisability of these data may be limited,
as children in the cohort originate from the Greater Manchester region,
with rather homogenous populations. A strength of this study includes
the substantial sample size, as few studies have surveyed circulating
chemokines at this magnitude. Furthermore, the consistency of the
methodologies used compared to previous studies provides another
advantage. Moreover, by performing both cross-sectional logistic
regression and longitudinal GEE models we have taken into account
different temporal perspectives throughout childhood, which is a
strength of this study.
In conclusion, we have shown that elevated levels of CCL18 throughout
childhood precede the development of asthma and sensitisation, findings
that remained solid longitudinally. The Th1-associated chemokines CXCL10
and CXCL11 also predicted development of sensitisation and asthma, with
differential regulation at different time points in life. This motivates
further investigations of chemokines as biomarkers for allergy
development, with putative clinical utility in the prediction of
allergic outcomes.