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Balancing immune responses in lung pathology

Asthma UK Fellow

Dr Tara Sutherland
Tel: +44 (0)161 306 6052




Our research

For a long time, asthma was largely considered a single, T-helper 2 (Th2) driven inflammatory disease, with eosinophils being the characteristic effector cell population.

However, it is now clear there is a heterogeneity of asthma phenotypes with a complex array of T cell responses, innate and adaptive responses, as well as a variety of effector cells all contributing to pathology.

Chitinase-like protein family and severe asthma

In severe asthmatics inflammation is generally defined by neutrophilic or mixed neutrophil/eosinophil airway infiltrates, along with increased IL-17 and airway remodelling. Severe asthma with neutrophil predominance or mixed phenotype has proved challenging to treat, with the patients often becoming unresponsive/resistant to steroid treatments.

Unlike eosinophilia and adaptive Th2 responses, the contribution of neutrophils, innate immune responses and IL-17 to chronic allergic airway inflammation and remodelling is poorly understood.

We have recently shown that the chitinase-like protein (CLP) family can drive alveolar neutrophil recruitment through increased IL-1/IL-18 expression and expansion of an innate population of IL-17-producing gamma delta T cells.

Chitinase-like protein family expression and TH2 pathology

Considering CLP expression is strongly associated with Th2 pathology and type 2 inflammatory diseases are not normally characterised by neutrophilia, this was a rather surprising finding and provides a potential link between type 2 responses in allergic inflammation and enhanced neutrophilia.

It is unlikely that simply increased IL-17 and neutrophil numbers in the lungs alone explain the degree of pathology in severe asthma. Rather, mounting evidence would suggest that IL-17 and/or neutrophils might exacerbate type 2 pathology.

Indeed, further to effects on neutrophilia, CLPs also alter the production of type 2 cytokines during lung inflammation. As a consequence of increased pro-fibrotic IL-13 levels and also through direct, as yet undefined actions, CLPs will promote repair/remodelling of lung tissue, a dominant trait of severe asthma.

Therefore, we believe CLPs are key regulators of both innate and adaptive immune responses, pushing the boundaries of asthma pathology.

Using a range of technologies including bio-imaging, multi-parameter flow cytometry, molecular techniques, in vivo and in vitro models, we aim to investigate the key initiating immune mechanisms that influence the development of allergic airway inflammation and ask questions about the relationship between IL-17/neutrophils and Th2 pathology.

We will also investigate whether CLPs may be the missing link that tips the balance of type 2 airway inflammation towards a more severe phenotype with neutrophil dominance and chronic remodelling of the airways.