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.