Thymic Stromal Lymphopoietin and its downstream networks in severe asthma
thesisposted on 08.11.2013, 15:28 by Aarti Parmar
TSLP is a cytokine implicated in the pathophysiology of asthma through a TSLP-OX40L-T cell axis and a TSLP-mast cell axis. Whether these pathways operate in human asthma is unknown. The objective was to investigate whether mucosal TSLP protein expression relates to asthma severity, and distinct immunological pathways. GMA-embedded bronchial biopsies from subjects and patients with mild, moderate and severe asthma were immunostained for TSLP, OX40/OX40L, CD83, IL-4, IL-13, and inflammatory cells. TSLP and IL-13 release were measured in supernatants from epithelial cells co-cultured with human lung mast cells (HLMC). There was considerable heterogeneity in TSLP, IL-13 and IL-4 immunostaining across the asthmatic subjects. TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, in particular severe asthma which correlated with the severity of airflow obstruction. IL-13 staining was increased in non-epithelial cells within the epithelium in severe asthma of which lineage-negative CD45+ cells represented a substantial proportion. Asthmatic subjects with elevated IL-13 immunostaining in the lamina propria also had elevated levels of IL-4 and TSLP expression. Recombinant TSLP attenuated FcεRI-dependent HLMC degranulation and TSLP production, and HLMC rapidly degraded TSLP. In summary, TSLP expression is elevated in severe asthma despite high-dose corticosteroid therapy. Although the TSLP-OX40L-T cell pathway within asthmatic bronchial mucosa was not detected, it is possible that it operates in secondary lymphoid organs. The close approximation of airway stroma and mast cells suggests the TSLP-mast cell axis maybe active in asthmatic bronchial mucosa, but my in vitro data suggests that TSLP may inhibit HLMC activation. The interaction of TSLP with CD45+ lineage-negative innate lymphoid cells group 2 maybe the most important pathway contributing to increased IL-13 expression in subset of patients with asthma, including severe disease. Targeting TSLP may only be efficacious in the subset of asthma characterised by increased Th2 inflammation.