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].