Toward mechanistic endotyping in allergic rhinitis: a State-Place-Time framework for appraising nasal tissue evidence

Allergic rhinitis (AR) heterogeneity is usually described by sensitization, symptom burden, or inflammatory profiles, but these descriptors do not establish which mechanism operates in a particular nasal mucosa. This critical narrative review proposes a State-Place-Time framework that evaluates cellular programs together with their anatomical setting and exposure-related response phase. The framework distinguishes descriptive tissue states from candidate mechanistic modules, measurable mechanistic endotypes, and clinically actionable endotypes. These are operational definitions for this review, rather than a validated classification. Five overlapping examples are examined: IgE-FcϵRI effector activity, late-phase type 2 amplification, barrier-repair dysfunction, separable sensory, vascular, and secretory outputs, and putative stromal maintenance. An author-derived conceptual matrix summarizes human evidence, spatial localization, timing/recurrence, matched perturbation, accessible measurement, and clinical utility; it does not provide an evidence score or patient assignment rule. Human intervention supports IgE-pathway dependence, but this does not establish a validated nasal tissue endotype for treatment selection. Late-phase cytokine responses and epithelial abnormalities are supported by human observations and functional systems, while their stability and predictive utility remain incompletely established. Stromal maintenance remains a hypothesis, with important limits from nasal polyposis sampling and inferred communication. The framework complements existing clinical and inflammatory classifications by identifying missing links and testable alternatives. Progress toward clinical use requires reproducibility within patients, analytical and external validation, and incremental value beyond routine assessment; treatment-selection claims additionally require evidence of differential treatment benefit.