Introduction
Chronic rhinosinusitis (CRS) is a chronic inflammatory disease in the nose and paranasal sinus characterized histologically by the infiltration of inflammatory cells, especially eosinophils, with high prevalence, worldwide1-3. Based on the extent of tissue eosinophilia, CRS can be classified into eosinophilic chronic rhinosinusitis (ECRS) and non-eosinophilic (Non-eCRS) subtypes4,5. Compared with Non-eCRS, ECRS is associated with worse disease severity, a higher risk of comorbid asthma, and a higher ratio of recurrence and revision surgery6-8. There are significant geographic and ethnic differences in the tissue eosinophilic infiltration, ECRS is predominant in Western white patients and less common in East Asians9-11. However, it has been reported that the proportion of ECRS has increased over time in Korea and China12,13. Thus, identifying specific mediators that drive the development of eosinophils and modulating their functions, in particular of ECRS, will be important for developing novel treatment strategies and improving treatment outcomes.
CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF-R) family14. Although the primary function was initially restricted to B and T lymphocytes, CD40 has been explored more extensively because of its broad expression on non-lymphocytic cell types15-19. It has been reported that eosinophils isolated from allergic subjects express CD40 by Yuichi Ohkawara et al., which is biologically functional. Interestingly, they also found that CD40 was detected in nasal polyp tissues but not in normal nasal mucosa (inferior turbinate), and primarily in eosinophils. At the same time, they demonstrated that CD40 expression in eosinophils could be upregulated by exposure to IgA immune complexes and downregulated by interleukin (IL) -10 and the synthetic steroid budesonide20. These observations suggest that the CD40-CD40 ligand (CD40L) pathway may contribute to the development of eosinophil-mediated inflammation. It is therefore reasonable to speculate that the CD40-CD40L signal pathway may be involved in the regulation of eosinophils function in CRS.
CRS without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are the 2 phenotypes of CRS according to the presence or absence of nasal polyp (NP)1,3. CRSwNP is often characterized by the local production of polyclonal IgE idiotypes21-25. As for the induction and regulation of IgE synthesis, a two-signal model is accepted. The first signal is provided by cytokines IL-4 or IL-13, which are secreted by T cells, mast cells, and basophils. The second signal is CD40-CD40L interaction, which is well established as a key signal for the induction of isotype switching in B-cells26-29. Interestingly, inducible co-stimulator (ICOS) ICOS-ICOSL ligation can promote the expression of CD40L, which in turn strengthens CD40-CD40L interaction to provide a co-stimulatory signal for B cell activation. And one very recent study has shown that ICOS co-stimulation induces CD40L expression by human T cells30,31. Nevertheless, the role of ICOS-ICOSL and its interaction with CD40-C40L in CRS has not been investigated.
Therefore, in the current study, we investigated patients with CRS for their CD40 and C40L levels, as well as ICOS and ICOSL levels. We characterized the clinical relevance of CD40-CD40L and ICOS-ICOSL, especially with eosinophils, in CRS, and we explored potential mechanisms that underlie their role in the pathogenesis of CRS.