The role of the interleukin-6 pathway in asthma (2018)

Asthma is a chronic airway disease with high prevalence worldwide. Symptoms n including wheeze, cough, shortness of breath and chest tightness n can be life-threatening and long-lasting. Yet, asthma remains without cure, and the need for improved treatments is clear. In a genome-wide association study (GWAS) performed in 2011,na variant (rs4129267) in the interleukin-6 (IL-6) receptor gene (IL6R) was reported to associate with asthma risk. That study showed that asthmatics are more likely to carry the rs4129267:T allele that correlates with increased serum levels of the soluble IL-6 receptor (sIL-6R), which in turn appears to extend the inflammatory effects of IL-6 through a pathway called trans-signalling. Subsequently, a variant in high linkage disequilibrium with rs4129267:T was shown to associate with poor lung function and severe asthma. Together with functional studies that implicated the IL-6 pathway in asthma, these findings suggested that anti-IL-6R therapynnspecifically inhibition of IL-6 trans-signallingnnmight represent a new treatment option for asthma.nThe goal of this thesis was to study that hypothesis and to understand the significance of the IL-6 pathway in asthma. Specifically, four main questions were addressed:n1.nnnnWhat characterises asthma patients likely to benefit from anti-IL-6R therapy?n2.nnnnIs IL-6 trans-signalling more likely to be promoted by some allergen types?n3.nnnnAre there other genes that associate with IL-6 signalling that are also risk factors for asthma?n4.nnnnCan asthma symptoms be attenuated by a drug that blocks IL-6 signalling?To address the first question (Chapter 2), sputum IL-6 and sIL-6R levels were tested for association with relevant clinical information available for 33 asthmatics. Sputum levels of IL-6 and sIL-6R were largely independent of levels measured in matched serum samples. On the other hand, sputum levels of IL-6 and sIL-6R associated with the total number of immune cells measured in the same samples. High sputum levels of IL-6 and sIL-6Rnnwhich promotes IL-6 trans-signallingnnwere more likely to be observed in patients with neutrophilic and mixed granulocytic sputum inflammatory subtypes.To assess whether some allergen types were more likely to trigger airway inflammation that is associated with IL-6 trans-signalling (Chapter 3), the frequency of sputum subtypes observed after allergen challenge was studied in 129 asthma patients exposed to different allergen types. Overall, baseline sputum inflammatory subtypes shifted towards eosinophilic and mixed granulocytic inflammation after allergen inhalation. However, no difference was observed in the frequency of sputum inflammatory subtypes between the different allergen types used in the allergen challenge.In Chapter 4, data from gene expression studies and asthma GWAS were analysed to study gene networks associated with IL-6 signalling in asthma. Specifically, genes co-expressed withnIL6Rwere screened for nearby variants that associated both with the expression of that gene and asthma risk. Five such genes were identified, including one which had not previously been implicated in disease pathophysiology:nSTOML2.nThis gene plays a key role in mitochondrial function and T-cell activation. Follow-up analyses (Chapter 5) of thenSTOML2risk variant showed that it has a stronger effect in early-onset asthma, while it also associates with the risk of hay fever.nFinally, two approaches were used to determine if tocilizumabnna drug that blocks IL-6 classic and trans-signalling and is approved to treat rheumatoid arthritisnnrepresents a promising new treatment for asthma.nFirst, data from a proof-of-concept clinical trial were analysed to assess the effect of a single dose of tocilizumab on allergen-induced asthma exacerbations (Chapter 6). Eleven participants with mild asthma completed the trial. Lung function, airway hyperresponsiveness, pathology results and inflammatory cells and mediators were compared between the tocilizumab and placebo groups. Overall, the drug did not inhibit allergen-induced airway responses. One participant with mixed‑granulocytic sputum, rs4129267:TT genotype and treated with tocilizumab did not develop a late asthmatic response, but this should not be over-interpreted. Second, using data from the Australian Pharmaceutical Benefits Scheme (Chapter 7), individuals who were treated regularly with tocilizumab and were also likely to suffer from asthma were identified (Nn= 88). Then, in these individuals and a group of matched controls (N = 440), the number of asthma-related prescriptions was compared one year before against one year after the onset of tocilizumab treatment. Results showed no significant differences in the number and frequency of inhaled corticosteroids, suggesting that regular tocilizumab is unlikely to have an effect in asthma symptoms.In summary, (1) IL-6 trans-signalling was associated with mixed-granulocytic sputum; (2) different allergens were unlikely to influence sputum inflammatory subtype; (3)nSTOML2nwas identified as annIL6R-associated gene with suggestive association with early-onset allergic disease; and (4) tocilizumab treatment did not reduce allergen-induced bronchoconstriction, nor the frequency of asthma-related prescriptions.n