Immunopathogenic endotypes of asthma: from type 2 and non-type 2 inflammation to precision therapeutic strategies

Asthma is a chronic heterogeneous airways disease with multifactorial origins that plagues millions of people around the globe and has a huge global burden in terms of the recurrent exacerbations, diminished quality of life, and enormous costs of care- up to 10% of severe cases cannot be treated by steroids- so far. This extensive revision clarifies its immunopathogenesis, which involves a dynamic interaction between T2-high endotypes (supported by Th2/ILC2 cytokines IL-4/5/13 that promotes the eosinophilic inflammation, IgE-mediated allergy, hypersecretory mucus, and reversible obstruction) and T2-low (supported by Th1/Th17 cytokines IFN-7) phenotypes, which result in neutrophilic, remodeling prone, and cortic Indirectly, mixed severe asthma is supported by bidirectional T1-T2 crosstalk whereby TNF enhances ILC2 survival by TNFR2, IL-33 alarmins promote IL-5/13, and epithelial pro-inflammatory cascades, thus supporting therapeutic failures and the future of precision medicine. Depending on type of inflammation, eosinophilic (anti-IL-5 (mepolizumab) and mixed inflammation (dupilumab/tezepelumab) and high IgE (omalizumab) biomarkers are pivotal in stratifying phenotypes, predicting exacerbation, and informing targeted biologics, including anti-IL-5 (mepolizumab) and dupilumab/tezepelumab, respectively. This synthesis heralds a paradigm shift of empirical symptom control to personalized interventions, reduction of exacerbations, lessening of overtreatment, and the identification of new targets in multi-omics era to overcome the unmet needs of severe, steroid-resistant asthma.