Tregs represent a subset of CD4+ cells that suppresses the functions of other lymphocytes and are characterized by surface expression of CD4 and CD25 and nuclear expression of the transcription factor FOXP3. Recently, many functions of FOXP3 and its influence on the immune system have been elucidated. Tregs influence the development and expression of atopy and the allergic response.9-11
Adaptive FOXP3+ Tregs are essential for establishing mucosal tolerance and for suppressing IL-4 production.17
Decreased expression of FOXP3 has been reported in asthma and allergic rhinitis,12,18
although there have been no studies to compare FOXP3 expression in nasal polyps and allergic nasal mucosa or to define the role of Tregs in NP pathogenesis. In the present study, we compared the levels of FOXP3 expression in allergic nasal mucosa and nasal polyps and demonstrated lower expression of FOXP3 in nasal polyps.
Recently, NPs were characterized by a polarized Th2 reaction and eosinophilic inflammation and high IgE levels, irrespective of atopic status. We have recently reported that high-level expression of TSLP correlates strongly with the numbers of eosinophils in nasal polyps and also IgE, irrespective of atopic status.8
In the present study, we demonstrate decreased numbers of FOXP3+ cells in nasal polyps, as compared to allergic nasal mucosa. These lower numbers of FOXP3+ cells observed in patients with NP may result in unopposed overexpression of Th2 cells and the increased migration and activation of dendritic cells, eosinophils, and mast cells.
High IgE concentrations have been found in nasal polyps, indicating that IgE is produced locally.19-21
Suh et al.20
also reported a polyclonal hyper-immunoglobulinemia E, associated with the presence of IgE specific for S. aureus
enterotoxins (SAE), colonization with S. aureus
, and increased eosinophilic inflammation in a relevant subgroup (about 50%) of nasal polyp patients. These authors also reported a strong correlation between the levels of IgE in nasal polyps and the presence of nasal eosinophils. Our recent study demonstrates that the high levels of IgE seen in nasal polyps are in good correlation with the number of TSLP+ cells in nasal polyps as well as between TSLP and eosinophils, irrespective of atopic status.8
Moreover, the levels of TARC/CCL17 and macrophage-derived chemokine (MDC) were also high in the nasal polyps.8
In the present study, we also found lower numbers of CD4+FOXP3+ cells in the nasal polyps than in the allergic nasal mucosa, irrespective of atopic status.
It has been suggested that S. aureus
secretes exotoxins that may act as superantigens and upregulate the variable beta region of lymphocytes in chronic hyperplastic sinusitis with NP.7
Recently, Van Bruaene et al.22
reported lower expression of FOXP3 mRNA in chronic rhinosinusitis. In the present study, we compared the levels of expression of FOXP3 in the nasal mucosa of patients with AR and NP, as well as in the nasal polyps from atopics and non-atopics. While the numbers of Tregs in the nasal mucosa of patients with AR are reported to be low, we detected a decrease in the number of CD4+
Tregs in both the atopic and non-atopic nasal polyps. In this context, Pérez Novo et al.23
recently assessed the effect of S. aureus
enterotoxin B (SEB) on T-cell activation in patients with nasal polyps and asthma, and its possible link to aspirin hypersensitivity. SEB significantly increased the levels of IFN-γ, IL-4, TNF-α, IL-5, and IL-2 in the supernatants of both NP polyp groups with asthma but with and without aspirin sensitivity compared with controls. The baseline level of FOXP3 was significantly decreased in both NP-asthma groups. After incubation with SEB, FOXP3 was significantly up-regulated in the control group, but not in the NP-asthma groups. These researchers concluded that although SEB induces both Th1 and Th2 pro-inflammatory responses in patients with NP and asthma, regardless of the presence of aspirin hypersensitivity, the nature of this response may be linked to the basal deficiency of FOXP3 observed in the NP-asthma patients. Therefore, the deficiency of FOXP3 may lead to the enhanced Th2 inflammation in the NP of atopics and non-atopics and the high level of IgE, irrespective of the atopic status.
These data suggest that the suppressive function of Tregs may be partially inhibited. This might partially explain the more pronounced Th2-type inflammation and eosinophilic inflammation in nasal polyps, as compared to the allergic nasal mucosa. Furthermore, there is no reported statistically significant difference between the lymphocyte subpopulations of atopic and non-atopic patients.24,25
Taken together, the present findings indicate that the deficiency of Tregs in nasal polyps may play an important role in enhancement of the severity of Th2 inflammation in nasal polyps and the persistence and progression of NP. Furthermore, these results point to increasingly important roles for T cells in chronic rhinosinusitis with nasal polyposis.