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Background: Recent findings indicate that Staphylococcus aureus and its products may be involved in the modification of nasal polyposis. The purpose of this study was to investigate the presence of S. aureus enterotoxin genes and the agr subtype in bacterial DNA of S. aureus strains isolated from the middle meatus of nasal polyp and control patients., Methods: S. aureus strains were isolated from nasal polyp patients and controls. The strains were screened using PCR for their agr subtype, classic superantigens (SEA, SEB, SEC, SED or TSST-1), the egc cluster (SEG, SEI, SEM, SEN, and SEO and other enterotoxins (SEE, SEH, SEJ, SEK, and SEL) distinct from the egc locus., Results: Seventy-five percent of S. aureus strains had at least one enterotoxin in their DNA. The egc gene cluster was identified in 27 (67.5%) strains. At least one classic enterotoxin gene was present in 42.5% of the strains. Interestingly, there were no differences in enterotoxin genes between S. aureus strains isolated from controls compared with nasal polyposis patients. In controls, an equal distribution among the four agr groups was found, while 73% of the NPs strains belonged to agr groups I and II., Conclusion: In this study we found no significant difference between strains from nasal polyp patients and controls in the presence of enterotoxin genes. However, in NPs, a higher number of strains belonged to agr I or II, which are associated with strains causing enterotoxin-mediated disease.

Background: Increasing evidence points toward a modifying role of Staphylococcus aureus and its products in the pathogenesis of nasal polyposis., Objective: The aim of this study was to investigate cytokine and mediator production after stimulation with S aureus-derived proteins enterotoxin B, protein A, and lipoteichoic acid in nasal polyp and control inferior turbinate tissue., Methods: Tissue fragments were stimulated with RPMI (negative control), enterotoxin B, protein A, and lipoteichoic acid for 30 minutes and 24 hours. Supernatants were measured by multiplex for proinflammatory cytokines (IL-1beta, TNF-alpha) and T-cell and subset-related cytokines (IFN-gamma, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13). Histamine, TGF-beta1, cysteinyl leukotrienes, and prostaglandin D(2) were analyzed by ELISA., Results: Thirty minutes of protein A stimulation resulted in a significant increase of histamine, leukotrienes, and prostaglandin D(2). Enterotoxin B stimulation over a period of 24 hours induced a significant increase of IL-1beta, TNF-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-10, and IL-13 in both groups, with this increase significantly higher in nasal polyps compared with controls., Conclusion: We here show that S aureus products have various effects on mucosal tissues: surface protein A induces mast cell degranulation, whereas enterotoxins induce the release of cytokines, with a T(H)2-skewed pattern in nasal polyps, supporting the stimulatory role of superantigens in the development of this inflammatory disease.

Nasal polyps represent a severe eosinophilic inflammation of the upper airways which is characterized by poor impact of therapeutic intervention and frequent recurrences. Based on distinct cytokine, mediator and cell profiles, chronic sinonasal disease in Caucasians can be differentiated into several subgroups such as chronic rhinosinusitis without nasal polyps, chronic rhinosinusitis with nasal polyps, and nasal polyps in cystic fibrosis patients,. In Caucasians, nasal polyps showed a Th2 polarisation with high IL-5 concentrations, while chronic rhinosinusitis without polyps was characterized by a Thl polarisation with high levels of IFN-gamma. In the Caucasian nasal polyps we found that significantly more nasal polyp patients are colonized with S. aureus and that colonization increased in patients with concomitant asthma and aspirin sensitivity. Although there was no major difference in the presence of enterotoxin genes in S. aureus strains derived from nasal polyp or control patients, we found an increased immune response to S. aureus enterotoxins in nasal polyps, which resulted in a more pronounced eosinophilic inflammation and higher total IgE production in those polyps affected. We suggest that S. aureus superantigens amplify the inflammation in about 50% of nasal polyps, resulting in a strong Th2 polarisation, eosinophil activation, and an overproduction of IgG4 and IgE. These findings imply new therapeutic approaches apart from the currently used topical and systemic steroid therapy for nasal polyposis. In three double blind placebo controlled studies it was shown that firstly, oral corticosteroids only led to a short term reduction of polyp size. Secondly that a low dose of doxycycline treatment for 20 days had a sustained clinically relevant effect on polyp size for more than 3 months and thirdly we also showed a significant effect on polyp size by selective antagonizing IL-5 with a monoclonal antibody.

Background: Staphylococcus aureus-derived enterotoxins (SEs) have been implicated in the pathogenesis of airway inflammatory diseases, especially nasal polyposis. However, the exact role of these molecules in the regulation of eicosanoid synthesis in this pathology remains unexplored. We studied the possible impact of SE-induced immune responses on the eicosanoid production in nasal polyp (NP) patients., Methods: Tissue sample homogenates from NP patients, with (NP-SEs[+]) and without detectable IgE-antibodies to SEs (NP-SEs[-]; ImmunoCap system), were assayed for IL-5, myeloperoxidase, leukotriene CJD4/E4 (LTC4/D4/E4), LTB4, lipoxin A4, total IgE, and eosinophil cationic protein., Results: Inflammatory makers, eicosanoids, and total IgE were significantly increased in NP-SEs(+) compared with NP-SEs(-) tissues, with the exception of myeloperoxidase, which was similar in both groups. Eicosanoid concentrations correlated to IL-5 and eosinophil cationic protein; however, only cys-leukotriene levels correlated with IgE-antibodies to SEs, independently of allergy and asthma., Conclusion: Eicosanoid synthesis is up-regulated in polyp tissue of patients with immune response to SEs and seems to be related to the inflammatory reaction induced by these enterotoxins.

Nasal polyps in adults, characterized by abundant eosinophils, local overproduction of immunoglobulin E, and often associated with asthma, have been appreciated as an eosinophilic inflammation, potentially of allergic origin, but unrelated to a bacterial impact. Evidence accumulates, however, that Staphylococcus aureus colonizes chronic rhinosinusitis with, but not without polyps, with significantly increased prevalence. The germs release enterotoxins, which act as superantigens and induce a topical multiclonal IgE-formation as well as a severe, possibly steroid-insensitive eosinophilic inflammation. Recently, S. aureus could be demonstrated to reside intraepithelially, and potentially to release superantigens into the tissue from within the epithelial cells. An immune defect, either in the innate or adaptive immunity, might be responsible for this phenomenon. Follicle-like structures and lymphocyte accumulations, specifically binding enterotoxins, can be found within the polyp tissues, giving rise to local IgE formation. The superantigen-induced immune response also leads to a modulation of the severity of the eosinophilic inflammation, and may be linked to lower airway co-morbidity in polyp patients. Interestingly, IgE antibodies to enterotoxins can be found in the majority of aspirin-sensitive polyp tissues, associated with a substantial increase in ECP and IL-5. The possible role of S. aureus enterotoxins in polyp disease in Europe, the US and Asia has meanwhile been supported by several studies, demonstrating the presence of IgE antibodies to enterotoxins and inflammatory consequences in nasal polyp tissue. First studies also point to an involvement of S. aureus derived enterotoxins in lower airway disease, such as severe asthma and exacerbated COPD, clearly suggesting a clinical need for diagnosis and treatment of the germ and its related effects. Therapeutic approaches are so far empirical, and need further study, also serving to proof the clinical relevance of the concept.

Although the etiology of nasal polyposis is still not revealed, insights in the pathogenesis have largely expanded over the last years. Usually nasal polyps occur in adults, are bilateral and are characterized by a manifest tissue eosinophilia. Deposition of plasma-proteins (albumin), potentially driven by subepithelial eosinophilic inflammation, seems to be an early and key pathogenic factor in the development of nasal polyps. Accumulation and activation of eosinophils is favoured by low TGF-beta1 concentrations and overproduction of IL-5 and eotaxin. In nasal polyps high IgE concentrations are measured. Our findings indicate that this IgE is produced locally. Total IgE and the expression of specific IgE is unrelated to skin prick tests, but correlates with the degree of eosinophilia. In addition, we demonstrated the organisation of secondary lymphoid tissue in nasal polyps and a polyclonal hyper-immunoglobulinemia E, associated with the presence of IgE specific to Staph. aureus enterotoxins (SAE), colonization with Staph. aureus and increased eosinophilic inflammation in a relevant subgroup of NP patients (about 50%). In about half of the nasal polyps we thus find a local immune response against SAE. SAE can hereby act as conventional allergens, triggering T- en B-cells to produce sIgE against SAE. On the other hand, SAE can also act as superantigens and induce polyclonal B-cell activation and hyper-immunoglobulinemia. In addition, the presence of IgE antibodies to SAEs seems to be associated with the severity of asthma and nasal polyposis disease. Nasal and oral corticosteroids are currently the standard treatment for NP. This treatment however, is not always sufficient and oral corticosteroids have several side effects. Often surgery is required, which in turn is not free of complications and recurrencies. Increasing insights in the pathophysiology of NP opens perspectives for new pharmacological treatment options, with eosinophilic inflammation, IgE and Staph. aureus as potential targets.