Figures
- FIGURE 1
Signalling pathways following interleukin (IL)-17 binding its cognate receptor, IL-17R. Both stimulatory (blue arrows) and inhibitory (red arrows) regulatory pathways are shown. ASF: alternative splicing factor; MAPK: mitogen-activated protein kinase; GCSF: granulocyte colony-stimulating factor; AMP: antimicrobial peptide.
- FIGURE 2
Flow diagram exploring the putative links between elevated interleukin (IL)-17A levels and severe asthma. As is commonly supposed, IL-17A may drive a particularly severe form of the disease (1), or the reciprocal may be true that severe asthma results in elevated IL-17A levels, through for instance, the disruption and damage to the epithelial cell layer that is commonly seen in asthmatic airways (2). Given that, by definition, all people with severe asthma are on high-dose inhaled corticosteroids (ICS), it is possible that through ICS-induced suppression of local inflammation there is a predisposition to infection that causes an appropriate increase in IL-17A to combat that infection (3). Alternatively, IL-17A may induce corticosteroid resistance in the epithelium, requiring higher doses of ICS for the same effect (4). IL-17R: interleukin-17 receptor.
- FIGURE 3
Human airway bronchoalveolar lavage T-helper (Th)17 cell frequencies in health and asthma. Frequencies of live CD3+CD4+ interleukin (IL)-17-secreting (Th17) cells were measured using intracellular cytokine staining after ex vivo stimulation in peripheral blood mononuclear cells and bronchoalveolar lavage fluid (BALF) obtained from 60 patients with asthma and 24 healthy subjects [99]. In one individual in this cohort, Haemophilus influenzae was identified as a highly abundant pathogen by deep sequencing of BALF. This finding was also confirmed on routine culture of the same sample. This 63-year-old man exhibited marked neutrophilia in sputum (71%) and BALF (68%) and his Th17 frequency in the same BALF sample (red) of 11.3% of CD4+ T-cells was strikingly elevated above the group median (2.6%), representing the highest frequency observed in the study, consistent with a direct, local Th17 cell response to the pathogen in the airways. In the 12 months prior to the study, the subject had experienced 20 exacerbations requiring oral steroids. After initiation of long-term antibiotics following the culture result, they experienced a 1.1-point fall in asthma control score and suffered only one steroid-treated exacerbation in the next 18 months.
Tables
- TABLE 1
Human T-helper (Th) cell subtypes
Type Co-stimulatory cytokine Transcription factors Effector cytokines Target Th1 IL-12 T-bet, STAT1 IFN-γ, TNF, IL-2 Intracellular bacteria, viruses and mycobacteria Th2 IL-4 STAT6, GATA3 IL-4, IL-5, IL-13 Extracellular parasites Th17 IL-23 STAT3, RORγt IL-17A, IL-17F, IL-21, IL-22 Extracellular bacteria and fungi IL: interleukin; STAT: signal transducer and activator of transcription; IFN: interferon; TNF; tumour necrosis factor; RORγt: retinoic acid receptor-related orphan receptor γt.
