From nasal cytology to cellular endotyping: mast cell-eosinophil interactions and overlapping inflammation in...

Allergic rhinitis is traditionally defined by allergen sensitization and type 2 inflammation, yet increasing evidence indicates that this framework does not fully capture the biological heterogeneity of the nasal mucosa. The local inflammatory landscape reflects a dynamic interaction among epithelial cells, innate and adaptive lymphoid populations, mast cells, eosinophils, stromal elements, and vascular components, and may diverge substantially from systemic biomarkers. Recent single-cell and multi-omic studies have further revealed disease-associated alterations in epithelial differentiation, stromal activation, and cell-cell communication, reinforcing the concept of the nasal mucosa as an integrated immunological ecosystem. Within this context, mast cell-eosinophil interactions appear particularly relevant, as their coexistence and degranulation may characterize inflammatory states that differ from isolated eosinophilia. Nasal cytology provides a clinically accessible morphological readout of this local cellular architecture and has shown that allergic rhinitis does not correspond to a single cytological expression. In some patients, established allergic sensitization coexists with recognized non-allergic cellular rhinitis entities, including non-allergic rhinitis with eosinophils (NARES), non-allergic rhinitis with mast cells (NARMA), and non-allergic rhinitis with eosinophils and mast cells (NARESMA), giving rise to the concept of overlapping rhinitis. This phenomenon challenges a binary allergic versus non-allergic classification and may contribute to difficult-to-treat disease and incomplete therapeutic responses. Although these nosological entities are clinically and cytologically defined, they should not be considered synonymous with molecular endotypes. Their future value may instead lie in a cytology-informed endotyping strategy integrating morphology with local biomarkers, proteomics, transcriptomics, and single-cell approaches. This Review discusses the cellular players and interactions shaping allergic rhinitis, the biological and clinical relevance of overlapping inflammation, and the potential role of nasal cytology as an interface between clinical phenotyping and molecular endotyping.