The alarmin-ILC2 axis as a candidate mechanism for persistent olfactory dysfunction in allergic rhinitis

Area of Science:

• Immunology
• Neuroscience
• Otorhinolaryngology

Background:

• Allergic rhinitis (AR) is an underrecognized cause of olfactory dysfunction (OD).
• Smell loss in AR is often attributed to nasal obstruction, but persistent hyposmia suggests other mechanisms.
• Sensorineural pathways may contribute to OD in AR patients unresponsive to decongestion.

Purpose of the Study:

• To hypothesize a novel type 2 neuroimmune pathway contributing to olfactory dysfunction in allergic rhinitis.
• To propose specific molecular and cellular players involved in allergen-induced olfactory cleft inflammation.
• To identify potential injury modules affecting olfactory sensory neurons and sustentacular cells.

Main Methods:

• This study presents a hypothesis based on indirect evidence from animal models and human nasal studies.
• It proposes a mechanistic model for allergen-induced epithelial stress and subsequent immune activation in the olfactory cleft.
• The hypothesis integrates findings from murine models, ex vivo preparations, and CRSwNP studies.

Main Results:

• The proposed pathway involves alarmins (IL-33, TSLP, IL-25) activating group 2 innate lymphoid cells (ILC2s).
• This immune response may lead to olfactory sensory neuron injury via eosinophils and sustentacular cell dysfunction.
• Candidate injury modules include IL-13/STAT6-biased basal cell fate, IL-5/eosinophil-mediated neuron damage, and IL-4/IL-13-driven sustentacular cell dysfunction.

Conclusions:

• The hypothesis provides a framework for understanding persistent olfactory dysfunction in allergic rhinitis.
• It generates falsifiable predictions for future research on olfactory cleft biomarkers and immune responses.
• This model guides future studies on non-invasive biomarkers, tissue analysis, and organoid experiments.