Abstract
Background : The impact of physical activity on immune response
is a hot topic in exercise immunology, but studies involving asthmatic
children are scarce. Our aims were to examine whether there were any
differences in the level of physical activity and daily TV attendance,
to assess its role on asthma control and immune responses to various
immune stimulants.
Methods: Weekly physical activity and daily television
attendance were obtained from questionnaires at inclusion of the
PreDicta study. PBMC cultures were stimulated with phytohemagglutinin
(PHA), R848, poly I:C and zymosan. A panel of cytokines was measured and
quantified in cell culture supernatants using luminometric multiplex
immunofluorescence beads-based assay.
Results: Asthmatic preschoolers showed significantly more TV
attendance than their healthy peers (58.6% vs. 41.5% 1-3h daily and
only 25.7% vs. 47.2% ≤ 1h daily) and poor asthma control was
associated with less frequent physical activity (PA) (75% no or
occasional activity in uncontrolled vs. 20% in controlled asthma; 25%
≥ 3 times weekly vs. 62%). Asthmatics with increased PA exhibited
elevated cytokine levels in response to polyclonal stimulants,
suggesting a fitness and readiness of circulating immune cells for type
1, 2 and 17 cytokine release compared to subjects with low PA and high
TV attendance. Low physical activity and high TV attendance were
associated with an increase in proinflammatory cytokines.
Proinflammatory cytokines were correlating with each other in in
vitro immune responses of asthmatic children, but not healthy controls.
Conclusion: Asthmatic children show more sedentary behavior
than healthy subjects, while poor asthma control leads to a substantial
decrease in physical activity. Our results suggest that asthmatic
children profit from regular exercise, as elevated cytokine levels in
stimulated conditions indicate an immune system prepared for responding
strongly in case of different types of infections.
Keywords: asthma; cytokines; immune modulation; physical
activity; PreDicta
Introduction
Asthma affects more than 300 million people worldwide, and it is
estimated that this number will increase to over one billion by
2050.1 It is more prevalent in children, where it lies
among the top 20 chronic diseases for the global ranking of
disability-adjusted life years1,2 with up to 25% of
children affected in Western urban areas.3 The global
burden of asthma in children and adolescents increased significantly
over the last decades, while previously countries affected at lesser
extent in Africa, South America and Asia started to catch up on these
numbers.1,4 Multiple factors are thought to play a
role in this world-wide increase in asthma prevalence including allergen
exposure and sensitization, environmental influences, viral infections,
urbanization, diet and sedentary lifestyle with physical
inactivity.5,6 Asthma attacks often appear during
physical activity (PA),7 termed “exercise-induced
asthma” (EIA) affecting 70-90% of asthmatic
children.3
PA is beneficial both for growth and the psychological development of
children.8-10 Whereas the World Health Organization
(WHO) recommends for children and adolescents aged 5 to 17 years to be
moderately to vigorously active for a minimum of 60 minutes
daily,10,11 specific guidelines for children suffering
from asthma are lacking.12 Although it is agreed that
it is essential for asthmatic children to participate in
sports,7 fear of EIA might prevent the practice of
regular PA in children, particularly the ones with severe and/or
uncontrolled asthma.3,13 This self-limiting cycle of
inactivity has led to the common perception that asthmatics are more
physically inactive in comparison to healthy
individuals.3
Asthma pathogenesis is a consequence of epithelial barrier
dysfunction,14 and research has shown that there are
several underlying pathophysiological mechanisms (endotypes) that can
lead to variable clinical presentations
(phenotypes).15-17 An imbalance of both Th1/Th2 cells
and Th17/Treg cells can play a crucial role in its
development.18-20 Type 2 inflammation is considered to
be the major driver in the most common phenotype, allergic
asthma,21 and seems to be the result of a complex
cross-talk between airway epithelium, innate and adaptive
immunity.19 PA is known to impact both the innate and
adaptive immune responses in various ways: For example, moderate
exercise was found to lead to an acute increase in the absolute numbers
of natural killer (NK) cells and NK cell
cytotoxicity.22,23 As for the adaptive immune
response, increased and intensified training loads were shown to lead to
a reduction of T cell functionality in well-trained individuals, with
lower numbers of circulating type 1 T cells, reduced T cell
proliferation responses and B cell immunoglobulin
synthesis.22 While Walsh et al. describe in their
position statement on immune function and exercise a resulting temporary
inhibition of Th1 cytokine production in trained individuals without
asthma, studies examining the impact of aerobic exercise in murine
asthma models reported an enhancement of Th-1 and Treg responses and
lower levels of Th-2 cytokines.22,24,25
The “Post-infectious immune reprogramming and its association with
persistence and chronicity of respiratory allergic diseases” (PreDicta)
study, was designed to prospectively evaluate asthma persistence in
preschoolers in association with microbial exposures and immunological
responses.26 PreDicta has demonstrated differential
immune responses to viruses in asthma,27,28 as well as
evolution of airway inflammation at that age.29 The
objective of the present study was i) to evaluate whether there were any
differences in the level of PA and sedentary behavior between asthmatic
and non-asthmatic children, ii) to assess the impact of asthma control
on PA and iii) to examine the influence of PA and long time TV
attendance on the immune system in asthmatic children. We have
investigated multiple cytokine levels in response to four different
immune stimuli: by phytohemagglutinin (PHA) that mimics polyclonal
innate immune activation, by polyinosinic-polycytidylic acid (poly I:C)
and R848 (resiquimod) that both mimic respiratory virus stimulation and
by zymosan (zymo) that mimics fungal stimulation in PBMC cultures. R848
is an imidazoquinoline compound with potent antiviral activity that
functions through the Toll-like receptor (TLR)7/TLR8 myeloid
differentiation primary response protein (MyD88)-dependent signaling
pathway.30 Poly I:C is a synthetic analog of
double-stranded RNA that induces the production of pro-inflammatory
cytokines by the activation of NF-κB through TLR3.31Zymosan is a glucan binding to TLR2 and dectin1 found on the surface of
yeasts.32
Methods