2.1. Type 2 (T2)-High asthma:
Much of the currently available knowledge regarding the contribution of epithelial cells to asthma comes from investigating this endotype. Eosinophilic, T2high airway inflammation is present in around 50% of adults with asthma and 37% of severe asthma, and atopy is present in 50–60% of adults and children with asthma [26, 27]. T2high asthma phenotypes include three groups namely, early-onset allergic asthma, late-onset eosinophilic asthma, and aspirin-exacerbated respiratory disease. The airway epithelium is a dynamic orchestrator of the immune responses in T2highasthma. It responds rapidly to external stimuli with release of cytokines such as IL-25, IL-33 and TSLP, which are central regulators of T2 immunity and drive a broad array of allergic responses [28]. (Figure 1). They are described as “alarmins”, alerting the immune system to external insults and regulating tissue restoration and repair after injury.
While IL-33 and IL-25 mainly activate ILC2s, TSLP also primes antigen-presenting cells (APCs), typified by dendritic cells (DCs), to promote type 2 immunity by activating T cells and B cells [24]. Tuft cells are the main producers of IL-25 in the airways, suggesting a specific role of this cell type in the control of T2 immune mechanisms [29]. IL-33 and its receptor (IL1RL1 or ST2) are both related genetically to atopic asthma particularly in children [30]. Recent data suggests that a TSLP/ILC axis may also mediate steroid resistance in asthma [31]. After allergen sensitization and consequent activation of DCs, these alarmins activate ILC2s and adaptive Th2 cells releasing IL-4, IL-5 and IL-13. Of note, ILC2s produce 10-fold more IL-5 and IL-13 compared with activated Th2 cells [32] suggesting that ILC2s are main source of these cytokines in the airway and explaining the relative paucity of ILC2 cells in the human asthmatic respiratory tract. IL-5 is a vital cytokine for the survival and maturation of eosinophils, and also supports the development of mast cells and basophils. IL-4 drives B-cell isotype switching, IgE synthesis, Th2 cell differentiation and production of downstream cytokines including IL-5 and IL-13. In addition, IL-13 and IL-4 promote goblet cell overexpression, increased mucus secretion, as well as airway hyperresponsiveness [24].
The expression of these epithelial-derived T2 cytokines is significantly increased in the airways of asthmatics and related to the severity of the disease. This suggests that they may be useful biomarkers of asthma and also therapeutic targets. The expression of IL-33 in the sputum and blood of asthmatics was higher than that of healthy controls and positively correlated with asthma severity [33, 34]. An asthma patient who has IL-25 mRNA levels that are above the 95th percentile in normal control AECs is defined as “IL-25high”. These asthmatics are more sensitive to skin allergy testing and exhibit higher eosinophilia, higher IL-13 and greater airway hyperresponsiveness to methacholine challenge supporting the concept that they have a more severe T2 asthma phenotype [35]. In a phase 2 study, the neutralizing antibody against TSLP (tezepelumab, AMGl57) demonstrated a significant reduction in the annual asthma exacerbation rate compared with placebo in patients with severe uncontrolled asthma [36]. This antibody is now in a phase 3 multicenter, randomized, double-blind, placebo controlled, parallel group trial (NAVIGATOR, NCT03347279). A humanized anti–IL-33 IgG1 antibody Etokimab has completed phase I and phase IIa trials whilst antibodies against IL-25 are under development but have not yet entered clinical trials [28].