Introduction
Asthma is a complex and heterogenous, yet very common lung disease,
affecting approximately 14% of all children worldwide1, 2. Although both non-pharmacologic and
pharmacologic strategies are mainstays of therapy, pharmacologic means
of asthma management often provide suboptimal control of symptoms. This
has led to considerable investigation into the immune mechanisms
underlying asthma, to identify more specific therapeutic targets,
particularly for those with symptoms resistant to inhaled therapy with
corticosteroids. Yet another rationale for these investigations has been
the need for novel biomarkers that may identify sub-groups of patients
at risk for poor disease control and/or exacerbations.
Asthma has historically been considered a primarily T-helper type 2
(Type 2) cytokine-driven disorder, characterized by
eosinophil-predominant airway inflammation, elevated IgE synthesis,
airway hyperreactivity, and mucus hypersecretion 3.
This Type 2 inflammatory phenotype tends to respond well to standard
pharmacological interventions, which primarily rely on combined inhaled
therapy with corticosteroids and bronchodilators. Additionally, a
variety of more specific anti-Type 2 therapies targeting IgE,
interleukin (IL)-4, IL-5, and IL-13 have been successful in treating
patients with the eosinophil-predominant endotype and severe clinical
disease 4-6. However, there is considerable evidence
that up to 60% of patients with severe asthma are partially resistant
to corticosteroids and other anti-Type 2 therapies, and these may
display a clinically distinct endotype, characterized primarily by
neutrophilic airway inflammation and increased Type 1 and Type 17
cytokine expression 4, 7. Despite the latter, while
IL-17A immunomodulation has been used effectively in the treatment of
certain Type 17-driven inflammatory conditions 8, the
two trials of anti-IL-17A therapies published so far have not proven
utility in treating patients with moderate-to-severe asthma, possibly
due to the lack of stratification of specific immunological endotypes9, 10. For this reason, there is an unmet medical need
to identify additional moleular targets for treating the Th17 endotype
in patients with severe asthma.
The cytokine IL-26 is a 36 kDa homodimeric protein that belongs to the
IL-10 family 11. Although it was originally described
as an exclusive Type 17 cytokine, it has since been demonstrated that
IL-26 is produced in structural as well as a variety of both
myeloid-derived cell types, including both Type 1 and Type 17 cells11-15. In the lung, IL-26 is constitutively expressed
by bronchial epithelial cells, lung fibroblasts, alveolar macrophages,
and CD4+ and CD8+ T cells16-19. At the local level, it acts by stimulating the
production of a variety of pro-inflammatory cytokines in alveolar
macrophages 16, while simultaneously inhibiting the
production of the same cytokines from bronchial epithelial cells,
thereby indicating an intriguing cell-specific responsiveness to IL-2619. At the systemic level, IL-26 is likely to be
expressed primarily by blood neutrophils, for which it enhances
chemotaxis while inhibiting chemokinesis, and downregulate enzymes such
as myeloperoxidase and elastase 20. Moreover, IL-26
exerts directs bactericidal activity, and experimental evidence
indicates that this is achieved as a direct molecular effect via
membrane pore formation and the formation of complexes with
extracellular DNA that act as a ligand for Toll-like receptors (TLRs)20,21.
Our group has previously reported that IL-26 concentrations in BAL
samples from adults with asthma are decreased compared to control
subjects without asthma 24. However, among adults with
asthma, we found that BAL IL-26 levels are clearly higher in those with
uncontrolled asthma as compared to those with controlled disease.
Similarly, amongst children with asthma, IL-26 concentrations in induced
sputum were enhanced in those with uncontrolled disease as compared to
those with controlled disease 25. Conversely, other
investigators found that systemic IL-26 levels are increased in adult
patients with asthma as compared with non-asthmatic control subjects,
regardless of disease severity or atopic status 22.
Additionally, these investigators identified IL-26 single nucleotide
polymorphisms (SNPs) associated with either increased or decreased risk
of developing asthma. Moreover, in a smaller case-control study, the
same investigators demonstrated that IL-26 concentrations are elevated
both locally in sputum as well as systemically in a cohort of adult
women with severe uncontrolled asthma as compared with non-asthmatic
control subjects 5. Avramenko and colleagues observed
that exhaled IL-26 concentrations are enhanced in both non-obese and
obese asthmatics compared with control subjects without asthma23. Moreover, they observed that obese subjects with
asthma have enhanced systemic IL-26 concentrations as compared with
control subjects, whereas non-obese subjects with asthma do not have
clearly enhanced systemic IL-26 concentrations compared to control
subjects without asthma. While there are differences in the populations
assessed in these studies, the differences in local and systemic IL-26
concentrations in subjects with asthma suggest that are
compartment-specific mechanisms regulating the production of IL-26.
Taken together, these previous findings suggest that IL-26 expression is
altered in patients with asthma and motivate further study, given the
limited conceptual understanding of the role of IL-26 in asthma.
The aim of the current study was to determine how systemic IL-26
concentrations relate to allergen sensitization, asthma severity, and to
concentrations of the archetype Type 17 cytokine IL-17A, in children. To
address this, we analyzed a cohort of children with (n=60) and without
(n=17) sensitization to dog allergen. Most subjects in the
allergen-sensitized group reported one or more clinical manifestations
of allergic inflammation, plus asthma. Serum concentrations of IL-26 and
IL-17A were measured and compared to subjective and objective
demographic characteristics to test our hypothesis, namely that systemic
IL-26 and IL-17A levels are altered in allergen-sensitized children,
particularly in those with asthma.