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.