Protein Glycosylation: An Emerging Regulator of Allergic Diseases

Type 2 (T2) inflammation is central to allergic disorders. Glycosylation, a post-translational modification, is emerging as a pivotal regulator in T2 inflammation and associated allergic diseases. This review synthesizes current knowledge on glycosylation patterns of key T2 inflammation players, including cytokines, immunoglobulins (e.g., IgE, IgG4) and their receptors, STAT6, mucins, and CTLA-4. We detail how site-specific glycosylation fine-tunes cytokine-receptor interactions, alters signaling pathways, and stabilizes proteins, thereby dictating their bioactivity. Moreover, we examine the enzymatic machinery orchestrating these glycosylation events and the regulatory factors modulating their activity in the context of T2 inflammation. By leveraging these mechanistic insights, we highlight how glycosylation aberrations contribute to food allergy, eosinophilic esophagitis, asthma, allergic rhinitis, and atopic dermatitis, while allergen immunotherapy exploits glycosylation reprogramming (e.g., sialylated IgG4 induction) to restore immune tolerance. Furthermore, we explore the diagnostic and prognostic potential of glycosylation patterns in predicting disease severity and allergen immunotherapy responsiveness, while underscoring the therapeutic promise of targeting glycosylation enzymes or glycan-immune receptor interactions to mitigate T2 inflammation-driven pathologies. A deeper understanding of glycosylation dynamics in T2 inflammation not only enhances our grasp of disease pathogenesis but also opens new avenues for innovative therapeutic interventions.