Investigation Into The Mechanism Of The Role Of Rhinosinusitis-derived Staphylococcal Enterotoxin B In The Pathogenesis Of Allergic Disorders

Objective: To determine a possible association between the rhinosinusitis derived Staphylococcus enterotoxin B (SEB) and the pathogenesis of food allergy (FA). Inasmuch as anatomic position of the sinus, chronic sinusitis-derived SEB may follow the secretion and to be swallowed down to the gastrointestinal tract and induce lesions to the intestinal mucosa. The present study aimed to take insight into the role of SEB in an association between chronic rhinosinusitis (CRS) and asthma and to determine the contribution of the CRS-derived SEB to the pathogenesis of asthma. Methods: A group of patients with both chronic rhinosinusitis (CRS) and FA was treated with sinus surgery for their CRS. Antigen skin prick test, analyses of serum specific IgE, IL-4, IL-13, IFN-γ and oral antigen challenge were performed before and after the sinus surgery. Peripheral blood mononuclear cells (PBMCs) were separated and cultured. PBMCs reaction to the stimulation of specific antigen and SEB was observed. Sinus wash fluid (SWF, containing SEB) was collected from a group of patients with both chronic sinusitis (CS) and ulcerative colitis (UC). A group of mice were sensitized to ovalbumin (OVA) in the presence of SWF. The sensitized mice were challenged with the specific antigen OVA. The inflammatory status of the colonic tissue was determined with histology, serology and electron microscopy. Using horseradish peroxidase (HRP) as a tracer, another group of mice was stimulated with SWF for 2 hours. The HRP activity was detected in the colonic tissue with enzymatic approaches and electron microscopy. 38 patients with both CRS and asthma underwent functional endoscopic sinus surgical treatment. Serum specific IgE and cytokines, clinical symptoms of CRS and asthma were evaluated before and after the surgery. The peripheral blood mononuclear cells (PBMCs) were separated and cultured. The Th2 reaction in the cultured PBMCs in the presence or absence of specific antigen and SEB was observed.Results: Two months after the sinus surgery, the FA clinical symptoms in response to oral antigen challenge and the antigen skin prick test in the patients with CRS-FA antenuated significantly. Marked decreases in serum IL-4, IL-13 and specific IgE were observed. Th2 response was provoked in the cultured PBMCs with the specific antigens and SEB. SEB was required in maintaining the Th2 response in these PBMCs. Epithelial hyperpermeability in colonic epithelium was induced by stimulating with SWF. The HRP activity in the colonic mucosa was almost 11 times more in the SWF treated group (3.2 ± 0.6 μg/g tissue) than the control group (0.3 ± 0.1 μg/g tissue). Mice were sensitized using a mixture of SWF and OVA (serum OVA-specific IgE was detected with a highest titer as 1:64). Challenge with OVA induced extensive inflammation in the colonic mucosa by showing (1) marked degranulation in mast cells (MC, 46.3 ± 4.5%) and eosinophils (Eo, 55.7 ± 4.2%); (2) inflammatory cell infiltration (MC = 145.2 ± 11.4; Eo = 215.8 ± 12.5; mononuclear cell = 258.4 ± 15.3/mm~2 tissue); (3) increased myeloperoxidase (MPO) activity (12.9 ±3.2 U/g tissue) and inflammatory scores (1.8 ± 0.3); (4) mucosal surface ulcers; (5) edema in the lamina propria; (6) bacterial translocation and abscess formation in the subepithelial region. The patients with both CRS and asthma obtained satisfactory results in the improvement of clinical symptoms and lung function tests after sinus surgery. The preoperatively elevated Th2 cytokines, IL-4 and IL-5, normalized postoperatively. The Th2 response was generated with the cultured PBMCs stimulated with specific antigen. SEB is required for sustaining the Th2 response. Conclusion: SEB plays certain roles in the pathogenesis of FA by augmenting and/or maintaining the Th2 reactions. Sinusitis is one of the sources of SEB that may be discharged to the nasal cavity and swallowed down the gastrointestinal tract to disturb the intestinal immune homeostasis. Introducing Sinusitis-derived SEB-containing SWF to the gastrointestinal tact compromised colonic mucosal barrier function increasing epithelial permeability to luminal macromolecular protein in mice. The SWF facilitated colonic mucosal sensitization to luminal antigen. Challenging the sensitized colonic mucosa with specific antigen OVA induced inflammation, induced a condition similar to human ulcerative colitis. The present study indicates that bacterial superantigen SEB plays a crucial role in sustaining the Th2 response of the low airway hypersensitivity related to sinusitis.