Chronic rhinosinusitis with nasal polyps — Identification of immune cells principally involved in pathogenesis

A research group led by Assistant Professor Masanori Kidoguchi and Professor Shigeharu Fujieda of the Faculty of Medical Science, University of Fukui, and Associate Professor Atsushi Kato of Northwestern University, U.S., announced on April 24 that they have identified type 2 innate lymphoid cells (ILC2) as the main cause of inflammation in chronic rhinosinusitis with nasal polyps. They analyzed the nasal polyp tissues of patients by state-of-the-art single-cell RNA sequencing. They also identified four different subsets of ILC2, the proportion of which was strongly associated with disease severity and subjective symptoms. Their findings are expected to contribute to the development of new treatment methods. The results were published in The Journal of Allergy and Clinical Immunology, the journal of the American Academy of Allergy, Asthma and Immunology, on April 7.

Eosinophilic rhinosinusitis is associated with formation of multiple polyps (nasal polyps) in the nasal cavity, causing severe nasal congestion and olfactory dysfunction. It is designated as an intractable disease and is often accompanied by bronchial asthma and otitis media. The patients suffer a recurrence rate of about 40%, even after their polyps are removed.

In recent years, steroids and certain molecular-targeted drugs have been used for its treatment, but other drugs have not proved effective. The disease is triggered by allergy, often induced by type 2 inflammation involving excessive production of cytokines such as IL-5 and IL-13. Several types of cells are known to secrete these cytokines, but it has been unclear which of these is principally involved in excessive cytokine production in the disease.

Therefore, the research group precisely isolated immune cells from nasal polyp tissues and peripheral blood collected from patients during surgery and compared their cytokine production levels ex vivo. In the nasal polyp tissues, ILC2s were found to produce cytokines at particularly high levels, accounting for about 60% and 70% of IL-5 and IL-13 productions, respectively. ILC2s are known to respond to stimuli including those derived from epithelial cells, even in the absence of specific antigens, and release vast amounts of cytokines that cause allergic inflammation.

Approximately 11,000 isolated ILC2s were then subjected to single-cell RNA sequencing to comprehensively analyze gene expression in individual cells.

Overall, ILC2s in nasal polyps were highly activated compared to ILC2s in the peripheral blood. It was also found that ILC2s in nasal polyps can be classified into four different subsets based on their activation states.

The four subsets were: "migratory ILC2," which shows relatively low activation and expresses receptors related to tissue migration; "transitional ILC2," which shows moderate activation and expresses distinctive immunomodulatory molecules; "inflammatory ILC2," which is highly activated and produces large amounts of inflammatory cytokines including IL-5 and IL-13; and "exhausted-like ILC2," which is induced to express inhibitory receptors that suppress cell function under chronic inflammatory stimulation.

Analyzing the relations among these subsets suggested that ILC2s progress continuously through these subtypes in the order of migratory, transitional, inflammatory and exhausted-like subtypes under chronic inflammation conditions. The association between the abundance of individual subsets and the severity score based on CT imaging was also examined.

The results showed that the higher the CT severity score, the greater the combined number of transitional, inflammatory and exhausted-like ILC2 subsets. Inflammatory and exhausted-like ILC2s were also found to be strongly associated with the international severity score (SNOT-22), which represents the patient's subjective assessment of symptoms, sleep dysfunction and psychological dysfunction.

In the future, the group plans to validate the efficacy of antibodies raised against the cytokines known to be involved in exacerbation of the disease and address the development of new antibody drugs.

Kidoguchi said, "By stopping the progression of ILC2s through the subtypes revealed in this study, there may be a chance to overcome this intractable rhinosinusitis. We expect our findings to contribute to the development of personalized medicine."

Journal Information
Publication: The Journal of Allergy and Clinical Immunology
Title: Heterogeneity and clinical relevance of group 2 innate lymphoid cells subsets in nasal polyps
DOI: 10.1016/j.jaci.2026.03.021