3.4 Discussion
3.4.2 Further Work:
variety of clinical manifestations, with the majority being either bronchiolitis or pneumonia which further supports the literatures re-evaluation of hRV as an important pathogen in lower respiratory infection. When analysing for the novel group, hRV-C, we found it to be commonly detected in 29% of hRV infections. Demographically there were no significant differences in hRV group but clinically we found hRV-C to be associated more commonly with EVW/ asthma compared to hRV-A. This is an important finding as studies involving asthma exacerbations have reported higher prevalence’s of hRV-C100 206
. Our findings appear to support the current literature and highlight the novel subtype of hRV- C as an important pathogen in paediatric asthma and wheeze.
3.4.2 Further Work:
Since its relatively recent discovery in 2006 much interest has been generated by hRV-C. We reported our findings in paediatric ARI, demonstrating hRV to be frequently detected in children with LRTI and demonstrating hRV-C to be more frequently associated with EWV/asthma than hRV-A.
Further work is needed to confirm these findings of the association of hRV- C with asthma. Although significant, the numbers of children with the diagnosis of EVW/asthma in our cohort was low. To date no research has been conducted on this pathogen in the UK and this would provide an ideal setting for a large investigation to confirm our results. The lack of a control group is especially interesting, other studies have reported hRV to be detected in high
levels in asymptomatic patients174. Further work could possibly accommodate this also.
Our findings in context with current literature highlight hRV-C to be associated with asthma pathogenesis. Recent discoveries have allowed hRV- C to be cultured for experimentation208. It would be of great interest to analyse why there is an association with asthma, in cell or animal models.
4
An investigation into the role of Interleukin 17
in RSV infection
4.1 Introduction
Infection with RSV commonly occurs in infancy, with the majority of children being infected by 2 years of age. In the developed world, 1-2% of all infants having sufficiently severe infection to require hospitalisation, most commonly with bronchiolitis137. Hospitalisation with RSV infection in infancy has been linked to respiratory dysfunction in later life, with the prevalence of wheezing being increased in children up to 13 years of age37 38.
T-Helper (Th) cells are important in the pathogenesis of RSV bronchiolitis. Originally they were classified into T-helper 1 and T-helper 2 cells (Th-1 and Th-2) according to their secreted cytokine profile. The response of Th-1 cells are characterised by expression of cytokines the Interferon gamma (IFN-γ) and Tissue necrosis factor alpha (TNF-α)209
. In contrast Th-2 cells express the cytokines IL-4, IL-5, IL-9 and IL-13209. The immune response to respiratory viral infections normally favours a response from the Th-1 subclass of T-helper cells31. However in the case of RSV bronchiolitis elevated levels of the cytokine IL-4 have been described, suggesting a role for these cells in disease pathogenesis31.
Findings that children with atopic asthma in later life have elevated levels of Th-2 cytokines, such as IL-13, led to the hypothesis that an imbalance of Th-1/Th-2 cells is involved in asthma pathogenesis and may be linked to the
action of RSV in infancy210. IL-13 has a pleotrophic effect with an important role in airway hyper-responsiveness and airway remodelling of asthma211. IL- 13 has been found in high levels during RSV infection and is a suggested target of bronchiolitis therapy212 213. Limited success of Th-2 targeted drugs further suggested cells other than Th-1/Th-2 to be involved in airway pathology214 215.
In recent years a novel group of T helper cells were discovered that did not match the classical Th-1 or Th-2 classification. This distinct group of CD4+ T helper cells secreted the pro-inflammatory cytokine IL-17 and so were termed Th-17 cells. Th-17 cells have shown to be important in the pathology of many diseases including Crohn’s disease, sarcoidosis, rheumatoid arthritis and atherosclerosis216. Experiments involving mouse and human models have also shown that IL-17 plays a role in both bacterial and viral infections and provides an important link between the innate and adaptive immune response216. The first discovered cytokine, IL-17A has now shown to be one of a family of six which have been classified IL-17A-F217. The cytokines IL-17A and IL-17F are produced primarily by activated CD4+ T cells and are the most researched217 218
. The receptors for both of these IL-17 cytokines are present on the epithelial cells of the lung218 219. A raised response to metacholine challenge has also been shown to correlate with levels of IL-17 in the sputum, suggesting that IL-17 is involved in airway hyper-responsiveness220. However, in the case of RSV bronchiolitis elevated levels of the cytokine IL-4 have been described, suggesting a role for these cells in disease pathogenesis31.
IL-17 has shown to be important in both neutrophil recruitment and acute inflammation, causing expression of the cytokines IL-8 and IL-6 from
airway epithelial cells221. The presence of IL-17 has also been shown to increase the effect of other inflammatory cytokines. Synergy has been demonstrated with IL-1β and TNF-α causing significant increase in pro- inflammatory cytokines when IL-17 was present222 223. Both of these findings highlight IL-17 as an important cytokine in acute inflammation, a key feature of RSV infection of the airways in the lungs of infants. It also raises questions over the role of IL-17 in RSV infection. To date no study has measured the response of airway epithelial cells to RSV infection in the presence of IL-17.
In this chapter, the effects of both IL-13 and IL-17(specifically IL-17A) and IL-13+IL-17 together have been examined on airway epithelial cells in the context of RSV infection. An immortalised airway epithelial cell line (BEAS- 2Bs) has been used as the model in which to assess these effects with the inflammatory cytokines IL-6 and IL-8 used as outcome measures.