2.2. Non-T2high (T2low) asthma:
The mechanisms that contribute to pathogenesis of T2lowasthma are not yet clear but existing knowledge suggests that epithelium may also play a role in these cases by the activation of IL-17 and IFN-γ pathways. There is an imbalance between Th17/Treg cells which may play an important role in steroid-resistant, severe neutrophilic asthma and T2low asthma has been associated with the activation of Th1 and/or Th17 cells [24].
Th17 cytokines play vital role in T2low disease with increased levels of IL-17A and IL-17F in the bronchial walls of severe asthmatics. This is associated with neutrophilic infiltration, airway hyper-responsiveness (AHR), and steroid resistance. In mouse models, blockade of T2 cytokines or corticosteroid treatment increased Th17 inflammation suggesting that treatment of T2high asthma may allow the emergence of Th17high asthma [37]. Studies also show that IL-17 stimulates AECs to enhance MUC5AC production.
At present, it is believed that enhanced IFN-γ expression is mainly confined to severe asthma. Raundhal and colleagues [38] recently reported that IFN-γ-induced downregulation of secretory leukocyte protease inhibitor (SLPI) in AECs causes an increase in AHR in severe asthma. Elevated IFN-γ is associated with high airway resistance, increased inflammatory infiltration, and corticosteroid resistance [24]. However, the specific mechanism(s) for these effects has not yet been clarified.