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Certain proteases derived from house dust mites and plants are considered to trigger initiation of allergic airway inflammation by disrupting tight junctions between epithelial cells. It is known that inhalation of proteases such as house dust mite-derived Der p1 and/or papaya-derived papain caused airway eosinophilia in naïve mice and even in Rag-deficient mice that lack acquired immune cells such as T, B and NKT cells. In contrast, little is known regarding the possible involvement of proteases derived from Aspergillus species (fungal-associated proteases; FAP), which are ubiquitous saprophytic fungi in the environment, in the development of allergic airway eosinophilia. Here, we found that inhalation of FAP by naïve mice led to airway eosinophilia that was dependent on protease-activated receptor-2 (PAR2), but not TLR2 and TLR4. Those findings suggest that the protease activity of FAP, but not endotoxins in FAP, are important in the setting. In addition, development of that eosinophilia was mediated by innate immune cells (ILCs) such as innate lymphoid cells, but not by acquired immune cells such as T, B and NKT cells. Whereas IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) are involved in induction of FAP-induced ILC-mediated airway eosinophilia, IL-33—rather than IL-25 and/or TSLP—was critical for the eosinophilia in our model. Our findings improve our understanding of the molecular mechanisms involved in induction of airway inflammation by FAP.

TSLP induces Th2 cytokine production by Th2 cells and various other types of cells, thereby contributing to Th2-type immune responses and development of allergic disorders. We found that house dust mite (HDM) extract induced TSLP production by nasal epithelial cells, suggesting that TSLP may be involved in development of HDM-induced allergic rhinitis (AR). To investigate that possibility in greater detail, wild-type and TSLP receptor-deficient (TSLPR−/−) mice on the C57BL/6J background were repeatedly treated intranasally with HDM extract. The frequency of sneezing, numbers of eosinophils and goblet cells, thickness of submucosal layers, serum levels of total IgE and HDM-specific IgG1, and levels of IL-4, IL-5 and IL-13 in the culture supernatants of HDM-stimulated LN cells were comparable in the two mouse strains. Those findings indicate that, in mice, TSLPR is not crucial for development of HDM-induced AR., Highlights • TSLP is involved in Th2-type immune responses. • HDM can induce TSLP production by nasal epithelial cells. • TSLP receptor is not crucial for development of HDM-induced AR.

IL-17A, IL-17F, and IL-25 are ligands for IL-17RA. In the current study, we demonstrated that IL-25–deficient mice—but not IL-17A–, IL-17F–, IL-17A/F–, IL-23p19–, or retinoic acid-related orphan receptor (ROR)-γt–deficient mice—showed significant suppression of 1) the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, 2) airway hyperresponsiveness to methacholine, and 3) OVA-specific IgG1 and IgE levels in the serum during OVA-induced Th2-type/eosinophilic airway inflammation. The IL-25 deficiency did not affect lung dendritic cell migration or Ag-specific memory–Th2 cell expansion during Ag sensitization. Adoptive transfer of T cells, mast cells, or bone marrow cells from IL-25–deficient mice revealed that induction of Th2-type/eosinophilic airway inflammation was dependent on activation of lung epithelial cells and eosinophils by IL-25 produced by airway structural cells such as epithelial cells but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells. Therefore, airway structural cell-derived IL-25—rather than Th17 cell-derived IL-17A and IL-17F—is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase of Th2-type/eosinophilic airway inflammation. It is not required for Ag-specific Th2 cell differentiation in the sensitization phase.

The usefulness of BG as a marker has been reported in patients with pulmonary aspergillosis. However, no data have demonstrated the behavior of BG in sino-orbital IA. We encountered a case of sino-orbital IA and demonstrated changes in the BG level, radiological images, and pathological features.A 63-year-old Japanese woman suffered from invasive sino-orbital aspergillosis. The serum BG level measured immediately before surgery was 37.2pg/mL (normal value3.4pg/mL). Endoscopic sinus surgery revealed some necrotic tissue extending from the ethmoid sinus to the orbit. The infiltrating Aspergillus was revealed in the pathological examination. The BG level decreased to the normal value. However, CT revealed a high-density area; this may indicate that an aspergillosis lesion remained slightly in the orbit.(1--3)-beta-d-Glucan (BG) is a useful marker for diagnosing Aspergillus and evaluating the therapeutic effect of the treatment administered.

Objectives We aimed to analyze the factors influencing caloric response and vestibular evoked myogenic potential (VEMP) in vestibular schwannoma. Subjects The subjects comprised 130 patients with unilateral vestibular schwannoma pathologically diagnosed by surgery. Method Caloric response and the amplitude and latency of VEMP were measured and analyzed based on the nerve of origin, localization, and size of the tumor. The tumors were classified into 3 types based on localization: intracanalicular, intermediate, and medial; and into 4 grades based on size: 9 mm or less, 10 to 19 mm, 20 to 29 mm, and 30 mm or greater. Results : Abnormal rates of caloric response and VEMP in patients with tumors arising from the superior vestibular nerve were not significantly different from those in patients with tumors of the inferior vestibular nerve. In the intermediate and medial type-but not in the intracanalicular type-a significant difference in tumor size was observed between patients with normal caloric response and those with canal paresis as also between patients with normal VEMP and those with abnormal VEMP. In patients with tumors that maximally measured 10 to 19 mm or of the intermediate type, the p- and n-wave latencies of VEMP were significantly prolonged compared with those in the normal opposite ear. Conclusion 1) The nerve of origin of tumors cannot be predicted based on caloric response and VEMP. 2) In the intermediate and medial types, caloric response and the VEMP amplitude are significantly diminished in association with an increase in tumor size. 3) Prolonged VEMP latencies seem to be not only caused by tumor compression to the brainstem or vestibular spinal tract but also by tumor compression isolated to the inferior vestibular nerve.

Dichotic sound discrimination is influenced by either visual or vestibular stimulation. This study investigated the effect of simultaneous gaze and vestibular inputs on dichotic sound discrimination. The subjects (n = 12) closed their eyes or gazed at a red target light placed at a distance of 50 cm from their eyes, and the ITD discrimination test was simultaneously performed in either the supine or in the right lateral decubitus position, in which gravitational linear acceleration causes utricular stimulation in the lower ear. In the ITD discrimination tests, the amplitudes of saw-tooth waves in the supine position with straight gaze were significantly different from those in the lateral decubitus position with downward or upward gaze. The saw-tooth waves in the lateral decubitus position with eye closed significantly shifted toward the upper ear compared to that in the supine position with eye closed. The saw-tooth waves in the lateral decubitus position with upward and with downward gaze shifted significantly toward the upper and lower ears, respectively, as compared to that in the supine position with straight gaze. We concluded that a sound image resulting from dichotic stimulation may be more dominantly influenced by the direction of eccentric gaze than by utricular stimulation that occurs due to gravitational linear acceleration.

Background: T cell immunoglobulin domain and mucin domain-containing molecule 3 (TIM-3), which is preferentially expressed on Th1 cells rather than Th2 cells, is considered to be a negative regulator of Th1 cell function. This suggests that TIM-3 indirectly enhances Th2-type immune responses by suppressing Th1 cell function. Methods: To investigate TIM-3's possible involvement in Th2-type acute and chronic airway inflammation, wild-type and TIM-3-deficient (TIM-3−/−) mice were sensitized and challenged with a house dust mite (HDM) extract. Airway inflammation and the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs) in the mice were determined by histological analysis and with a hemocytometer, respectively. Expression of mRNA in the lungs was determined by quantitative PCR, while the levels of cytokines in the BALFs and IgE in sera were determined by ELISA. Results: Despite constitutive expression of TIM-3 mRNA in the lungs, the number of eosinophils in bronchoalveolar lavage fluids (BALFs) and the score of pulmonary inflammation were comparable between wild-type and TIM-3−/− mice during both acute and chronic HDM-induced airway inflammation. On the other hand, the number of lymphocytes in the BALFs of TIM-3−/− mice was significantly increased compared with wild-type mice during HDM-induced chronic, but not acute, airway inflammation, while the levels of Th2 cytokines in the BALFs and HDM-specific IgG1 and IgG2a and total IgE in the sera were comparable in both groups. Conclusions: Our findings indicate that, in mice, TIM-3 is not essential for development of HDM-induced acute or chronic allergic airway inflammation, although it appears to be involved in reduced lymphocyte recruitment during HDM-induced chronic allergic airway inflammation.

Both interleukin (IL)-33 and IL-25 induce Th2 cytokine production by various cell types, suggesting that they contribute to development of allergic disorders. However, the precise roles of IL-33 and IL-25 in house dust mite (HDM)-induced allergic rhinitis (AR) remain unclear. Both IL-33 and IL-25 were produced mainly by nasal epithelial cells during HDM-induced AR. Eosinophil and goblet cell counts in the nose and IL-5 levels in lymph node cell culture supernatants were significantly decreased in IL-33-deficient, but not IL-25-deficient, mice compared with wild-type mice during HDM-induced AR, but the serum IgE and IgG1 levels did not differ. On the other hand, HDM-induced AR developed similarly in wild-type mice transferred with either IL-33-deficient BM cells or wild-type BM cells. IL-33, but not IL-25, produced by nasal epithelial cells was crucial for the development of murine HDM-induced AR. These observations suggest that IL-33 neutralization may be a potential approach for treatment of HDM-induced AR in humans.

Background Seasonal allergic rhinitis could predispose to the development of chronic bronchial inflammation. However, association between seasonal allergic rhinitis and airway function, especially exhaled nitric oxide [FENO], are not fully understood. Objectives The aim of this study was to evaluate the relationship among FENO and airway function and nasal symptoms in patients with seasonal allergic rhinitis without asthma. Methods We included 37 subjects [9 males and 28 females] in this study. Total serum IgE were investigated and specific IgE for 4 pollen allergens and 5 perennial antigens were determined by RAST. Sensitization to a specific allergen was defined as over RAST score 2. We compared 4 groups. Group A: 7 nonatopic subjects [no nasal symptoms and RIST, RAST negative, 1 males and 6 females, mean age: 33.2 24–52 years]. Group B: 10 atopic subjects with a sensitization to Japanese ceder without medication [6 males and 4 females, mean age: 44 20–58 years]. Group C: 10 atopic subjects with a sensitization to Japanese ceder who took oral anti-histamine medicine during pollen season [2 males and 8 females, mean age: 34.9 24–52 years]. Group D: 10 atopic subjects with a sensitization to Japanese ceder who receive intranasal corticosteroid treatment during pollen season [2 males and 8 females, mean age: 40.2 26–56 years]. Score of nasal symptoms, FENO, spirometry, total eosinophils, nasal eosinophils, were investigated before, during, and after pollen season. Results Regardless of having treatment or not, in comparison with the subjects without the allergy, FENO showed a statistically significant increase in all patients with a sensitization to Japanese after pollen season. In group D, v 50/v 25 was the tendency to adversely affect after the pollen season, and correlation between FeNO rate of the change and v 50/v25 rate of the change admitted. As for the other indexes, a statistically change were not showed in the comparison of each group. Conclusions These results suggest that FENO is a primarily marker of bronchial inflammation in patients with seasonal allergic rhinitis during pollen season and intranasal corticosteroid treatment may be effective for improvements in lower airway outcome.

Background Upper respiratory illness can adversely impact the lower airway. This study aimed to evaluate the relationship between clinical background and improvement in the lower airway after surgery for treatment of chronic rhinosinusitis. Methods A total of 22 patients with chronic rhinosinusitis surgically treated between January 2010 and February 2011 were included in the study. The presence or absence of asthma and peripheral blood eosinophils count were examined for all patients in addition to preoperative radioallergosorbent tests. Spirometry was conducted and fractional exhaled nitric oxide (NO) was measured at the preoperative, 1-month postoperative, and 3-month postoperative visits. Results The average level of NO in the exhaled air at the preoperative, 1-month postoperative, and 3-month postoperative visits was 51.5 ppb, 42.5 ppb, and 38.0 ppb, respectively. Although the average results of spirometry didn't show any improvement, forced expiratory volume in 1 second percentage improved in 2 of 4 cases with obstructive ventilatory disturbance. There were 10 improved cases, which were defined as those showing more than 1.2-fold difference in the ratio of preoperative NO level to the 3-month postoperative one. The remaining 12 cases, including 4 of 6 cases with asthma, 5 of 7cases with eosinophilia, and 4 of 4 cases with animal dander allergy were unimproved cases. Conclusions Chronic rhinosinusitis can cause latent lower respiratory disease. Endoscopic sinus surgery can improve the status of the lower airway. However, the effectiveness of surgery is significantly less in cases of animal dander allergy.