Page 169 - ADULT-ONSET ASTHMA PREDICTORS OF CLINICAL COURSE AND SEVERITY

atopic asthma runs via epithelial cells and dendri c cells, where T helper 2 lymphocytes are primed either directly by Il-25 and Il-33 or via naïve T helper cells. Clonal expansion of Th2 cells and ac va on of mast cells via IgE leads to produc on of Il-4, Il-5 and Il-13, which recruit and ac vate eosinophils. In pa ents with non-atopic asthma eosinophilic airway in amma on also exist, but this is probably ini ated via innate lymphoid cell (ILC-2) instead of Th2 cells. S muli to the airway epithelial like smoke, pollutants and viruses, directly ac vate these cells via Il-25 and Il-33. These cells have been shown to be a major source of Il-5 and Il-13, important cytokines for eosinophil ac va on and survival. The crucial role of Il-5 in asthma has been shown by the extraordinary e ect of blocking the cytokine with an bodies: it reduces the exacerba on rate and prednisone maintenance dose in prednisone dependent asthma pa ents.26 Whether all cytokines involved in the in ammatory cascade play a crucial role in the clinical disease is ques onable, as a recent trial with an an -Il-13 an body did not show clear improvement of disease outcomes. 27
Would there be be er biomarkers for in amma on in asthma? Or are the currently used biomarkers able to di eren ate properly or is this an oversimpli ca on of reality? The immunology underlying asthma is complex with several interac on and crossing pathways leading to airway in amma on. Perhaps other cells or molecules in these pathways could serve as more accurate biomarkers. For example serum perios n has been shown to be a good predictor of response to an -IL-13 therapy, although the associa on with sputum eosinophilia was weak.28 Another approach could be to look at gene sets associated with ac va on of a certain in ammatory pathway, such as Th2 High gene set consis ng of a set of genes associated with Th2 ac va on.29 Furthermore measurement of markers in exhaled breath has poten al to discriminate between di erent in ammatory phenotypes.30 These alterna ve biomarkers might prove to be useful for the development of new therapeu c compounds and selec on of pa ents who will bene t most of these therapies.
BIOMARKERS OF AIRWAY INFLAMMATION IN ASTHMA PATIENTS WITHOUT EOSINOPHILIA.
Part 1 of this thesis mainly focuses on eosinophilic in amma on as expression of type-2 in amma on. However, more than half of all adult asthma pa ents do not have type-2 in amma on (chapter 3). This is a large and important subgroup, as non-type-2 in amma on is associated with poor response to regular asthma therapy31 and clinical deteriora on.32 33 Ac va on of Th1 and Th17 cells, via s muli like cigare e smoke and diesel exhaust, produces Il-1, TNF-α, Il-17 and Il-8. These cytokines and chemokines induce in ux of macrophage and neutrophilic in amma on in the airways. Neutrophils might play an important role; especially in smokers as we have shown in Chapter 8 where neutrophils in blood are associated with frequent asthma exacerba ons. Measurement of neutrophils as such might therefore serve as biomarker for exacerba ons in smoking asthma pa ents.
In addi on, perhaps processes leading to non-eosinophilic in amma on could serve as a
SUMMARY AND GENERAL DISCUSSION
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