IgE in Non-Atopic Asthma

Abstract

Introduction Previous studies suggest that IgE switching and synthesis occur in the bronchial mucosa of “non-atopic” asthmatics, suggesting a role for IgE in asthma regardless of conventional atopic status. To investigate this, I addressed the following hypotheses: (1) allergen-specific IgE is manufactured in the bronchial mucosa of “non-atopic” asthmatics but does not appear in the periphery; (2) naturally occurring IgE-specific IgG-autoantibodies may involve IgE in asthma pathogenesis in an allergen-independent manner; (3) anti-IgE therapy improves lung function and bronchial mucosal inflammation in non-atopic asthmatics in vivo. Methods (1) ImmunoCAP and ImmunoCAP ISAC microarrays were used to detect, quantify and specify IgE in the bronchial mucosa of both atopic and non-atopic asthmatics; (2) bespoke assays were developed to detect and quantify IgE-specific IgG autoantibodies in the sera of atopic and non-atopic asthmatics, and positive sera examined for their ability to activate IgE-sensitised human blood basophils in the presence and absence of allergen using a basophil activation test, and to inhibit allergen binding to specific IgE on a rat basophilic cell line stably expressing human FcεRI; (3) a randomised, double-blind, proof of concept study was performed to address the hypothesis that omalizumab therapy improves lung function and reduces bronchial mucosal IgE expressing cells (utilising immunohistochemistry) in a group of severe, non-atopic asthmatics. Results I found that (1) although the median total IgE concentration in bronchial mucosal homogenates was significantly elevated in both non-atopic and the atopic asthmatics compared with controls, allergen component-specific IgE species were detectable only in the atopic, and not the non-atopic asthmatics; (2) IgG autoantibodies binding to both free and FcεRI-bound IgE were detectable in patients with atopic and non-atopic asthma as well as controls: some were able to activate IgE-sensitised basophils, whereas others inhibited allergen-induced basophil activation, at least partly by inhibiting binding of IgE to specific allergen; (3) omalizumab, but not placebo therapy of a group if non-atopic asthmatics for 20 weeks was associated with significant improvement in absolute and % predicted FEV1 despite substantial reduction of existing anti-asthma treatment, along with a significant reduction in the median total IgE+ cells (p<0.001) in the bronchial mucosa. Conclusions IgE is elevated in the bronchial mucosa of asthmatics termed ‘non-atopic’ by conventional criteria. Although not allergen-specific, it may play a role in the pathogenesis of bronchial mucosal inflammation in asthma, for example as a result of the effects of auto-anti-IgE antibodies. Blockade of IgE binding to its receptors has the propensity to improve lung function in non-atopic asthmatics.

Date of Award	2019
Original language	English
Awarding Institution	King's College London
Supervisor	Christopher Corrigan (Supervisor) & Hannah Gould (Supervisor)