NP is a severe chronic inflammatory disease involving the pnasal sinuses that is frequently associated with asthma and aspirin sensitivity. NP in combination with aspirin-induced asthma (AIA) represents the most severe form of airway inflammation within the group of patients with NP. The pathophysiology of NP is not fully understood, and is most likely to be multifactorial. Over the years, this disease has frequently been linked to staphylococcal colonization and, particularly, to bacterial products such as enterotoxins from Staphylococcus aureus.
Staphylococcal species are the most prevalent bacteria that have been isolated from the nasal mucus of white patients with NP. An increased colonization rate of S. aureus has been demonstrated in patients with NP (63.6%), but could not be demonstrated in patients with chronic rhinosinusitis without polyps (27.3%) as compared with control subjects. In patients with NP and comorbid asthma or aspirin sensitivity, colonization rates were further increased, up to 80% . S. aureus has also been detected in the submucosal space by peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH) in patients with NP, and especially in subgroups of NP with aspirin sensitivity [16, 17].
These are both potential reservoirs for superantigen release in the sinuses. Th2-polarized inflammation with a resultant eosinophilic inflammatory milieu has also been linked to the presence of S. aureus biofilms. This may occur both dependently and independently of the superantigen pathway, implying a direct link between microorganism and host . A different form of colonization by Staphylococcus aureus, through biofilms, has received attention recently.
A biofilm is a group of adherent bacteria irreversibly anchored to a surface and enclosed in a matrix of exopolysaccharide [19, 20].
Fungal elements associated with bacteria within biofilms of CRS patients have been demonstrated, an association that could lead to enhanced virulence of bacterial biofilms .
Biofilm-grown bacteria can be very resistant to fluctuations in moisture, pH and temperature. They are also highly resistant to antibiotic therapy, which may explain chronic infections refractory to clinical management [19, 20].
Foreman et al. confirmed the hypothesis that biofilms would be present in NP patients as a nidus from which planktonic S. aureus and superantigens are released into the pnasal sinuses .
Staphylococcus aureus biofilms in NP patients have been shown to result in eosinophilic inflammation and significantly higher levels of IL-5 and ECP. Staphylococcal superantigen-specific IgE was associated with a Th2-skewed response and a significantly elevated total IgE, IL-5 and ECP. The presence of Staphylococcus aureus biofilms was also associated both with worse symptoms and worse Lund-Mackay scores in patients with NP.
Biofilms have also been detected in control groups composed of patients who underwent septoplasty surgery due to nasal obstruction .
The mechanisms of this increased bacterial colonization in NP are unclear, but recent data suggest that a defect in the phagocytic system in NP might contribute to increased S. aureus colonization .
The pathogenic impact of S. aureus in NP has been mainly attributed to virulence factors secreted by S. aureus, such as staphylococcal enterotoxins. However, screening for staphylococcal superantigens genes showed no correlation with the presence or severity of NP. This suggests that the specific immune response of the host to S. aureus colonization, rather than the panel of enterotoxin genes present, determines the pathophysiology of NP [24, 25].
Staphylococcus aureus enterotoxins (SEs) elicit a massive inflammatory reaction resulting in a polyclonal activation of T and B-lymphocytes independent of the specific adaptive immune response. Clonal expansion of the corresponding V-β signature region of TCRs might play a major role in the pathogenesis of NP. A significant, specific TCR-Vβ expansion linked to the presence of serum IgE to staphylococcal toxins was observed in NP tissue, suggesting a superantigen reaction .
SEB stimulation in cultured nasal polyps increases levels of IFN-γ and IL-4, but not of IL-10. It also upregulates mRNA expression of T-bet and GATA-3, but not that of Foxp3 or RORγt, which indicates that SEB is able to affect Treg activity and cause Treg insufficiency. SEB stimulation also increases levels of various pro-inflammatory factors, including IL-2, IL-6, and IL-8, in cultured nasal polyps; these, in turn, also affect Treg activity [27, 28].
A second mechanism by which the local inflammatory response can be upregulated is specific IgE directed against S. aureus enterotoxins. IgE antibodies to S. aureus enterotoxins were present in 28% of polyp samples, with rates as high as 80% in the subgroup of patients with asthma and aspirin sensitivity, as compared with 15% in control individuals and 6% in patients with CRSsNP, respectively . The presence of specific IgE against S. aureus enterotoxins was also coincident with higher levels of interleukin IL-5, eotaxin and ECP. Consistent with the increase in IL-5 and other Th2 cytokines, a significant increase in local IgE, IgA and IgG antibodies can be observed in polyp patients. Nasal polyp homogenates in which S. aureus enterotoxin–IgE antibodies were detectable had significantly greater concentrations of IgG, IgG4 and IgE than did those without S. aureus enterotoxin-specific IgE, positively correlating with IgE and the number of plasma cells, whereas the IgG2 fraction was significantly lower. These changes were not reflected in the serum of patients, confirming the notion of a local impact of superantigens – via direct action on B cells or indirectly via T-cell derived cytokines – on immunoglobulin synthesis. S aureus superantigens can also induce the formation of polyclonal IgE directed against multiple inhalant allergens. These polyclonal IgE antibodies in NP are functional and able to activate mast cells ex vivo upon allergen challenge; apart from typical inhalant allergens, SEB may also serve as an allergen per se or as an indicator for superantigen impact on mucosal inflammation by maintaining a continuous activation of mast cells [29, 30].
Patients with NP typically exhibit an upregulation of proinflammatory cysteinyl leukotrienes and a downregulation of prostaglandin E2, which is considered an anti-inflammatory metabolite. NP patients who exhibit an immune response to S. aureus have an upregulated production of cysteinyl leukotrienes, leukotriene B4 and lipoxin A4 as compared with tissue from nasal polyp patients who were negative for S. aureus enterotoxin-specific IgE .
Nevertheless, a direct mechanism by which enterotoxins can modify prostanoid metabolism and related functions has yet to be identified.
The presence of specific IgE to staphylococcal enterotoxins is not only associated with a more severe and persistent inflammatory response, but is also linked to clearly identified clinical phenotypes of NP. Rates of both staphylococcal colonization and specific IgE to Staphylococcus are increased in NP patients if co-morbid asthma and aspirin intolerance are present .
Recently, the presence of IL-5 and IgE antibodies to S. aureus enterotoxin (SE-IgE positivity) in human NP patients was shown to be associated with an increased risk of comorbid asthma, suggesting a decisive role of staphylococcal superantigens in amplifying and aggravating airway disease .