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BACKGROUND: Esophageal histology is critical for diagnosis and surveillance of disease activity in eosinophilic esophagitis (EoE). A validated noninvasive biomarker has not been identified. We aimed to determine the utility of blood and urine eosinophil-associated proteins to diagnose EoE and predict esophageal eosinophilia. METHODS: Blood and urine were collected from children undergoing endoscopy with biopsy. Absolute eosinophil count (AEC), plasma eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein-1 (MBP-1), galectin-10 (CLC/GAL-10), Eotaxin-2 and Eotaxin-3, and urine osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) were determined. Differences were assessed between EoE and control, and with treatment response. The capacity to predict EoE diagnosis and esophageal eosinophil counts was assessed. RESULTS: Of 183 specimens were collected from 56 EoE patients and 15 non-EoE controls with symptoms of esophageal dysfunction; 33 EoE patients had paired pre-and post-treatment specimens. Plasma (CLC/GAL-10, ECP, EDN, Eotaxin-3, MBP-1) and urine (OPN) biomarkers were increased in EoE compared to control. A panel comprising CLC/GAL-10, Eotaxin-3, ECP, EDN, MBP-1, and AEC was superior to AEC alone in distinguishing EoE from control. AEC, CLC/GAL-10, ECP, and MBP-1 were significantly decreased in patients with esophageal eosinophil counts

Background: As a result of the all-year-round exposure to house dust mite (HDM), perennial rhinitis patients never have a clear symptom-free period. In this study, we investigated whether, despite these symptoms, we can still use nasal HDM provocations to study perennial allergic rhinitis and the effects of treatment. Methods: In a parallel-group study, after 1 week treatment with either fluticasone propionate aqueous nasal spray (FPANS) or placebo, 20 patients, allergic to HDM, registered symptoms (nasal obstruction, rhinorrhoea, sneezing, pruritus and eye symptoms) using three different scoring methods [Lebel, categorical and visual analogue scale (VAS)] and peak nasal inspiratory flow (PNIF) after HDM provocations. Provocations were performed with 1000 biological units/ml and 24 h later with 10 000 biological units/ml of HDM. Before and after the provocations, nasal mucosa biopsies were taken for immunohistochemical staining to determine the number of eosinophils. Results: House dust mite provocations resulted in an increase in symptoms and a decrease in PNIF. Even at high-dose provocation, the FPANS group registered significantly lower symptoms than the placebo group for nasal blockage, sneezing, eye symptoms, and PNIF in both early and late phases. FPANS also suppressed rhinorrhoea during the late phase and the influx of eosinophils in the lamina propria. Conclusion: Despite the high background of symptoms, allergic responses can be induced in this perennial rhinitis model. The VAS score seems most suited to detect these changes and the suppression of symptoms by 7 days of FPANS treatment. Epithelial eosinophilia at baseline was correlated positively with the severity of the reaction after the first provocation.

Background: Viral respiratory tract infections may cause both harmless common colds and severe asthma exacerbations; the differences in disease expression probably depend on the all_ergic status of the patient. To determine whether altered immunologic mechanisms underlie these differences, we investigated nasal inflammation during naturall_y acquired common cold. Methods: In a group of 16 patients (eight all_ergic), nasal brush samples were taken, and nasal symptoms were recorded during common cold, 2 weeks later (convalescence), and at baseline (>4 weeks without nasal symptoms). Nasal brush cells were stained immunohistochemicall_y for Langerhans cells, T cells, monocytes, neutrophils, B cells, macrophages, natural killer (NK) cells, mast cells, eosinophils, eotaxin, and RANTES. Results: Four rhinovirus, four coronavirus, three RSV, one Mycoplasma pneumoniae, and one influenza A/enterovirus double infection were confirmed. Increased numbers of T cells, monocytes, macrophages, NK cells, eosinophils, and RANTES- and eotaxin-positive cells, but not neutrophils, were observed during common cold in all_ergic and nonall_ergic patients, and increased numbers of mast cells in all_ergic patients. Compared to nonall_ergic patients, in all_ergic patients eosinophil influx persisted into convalescence. Conclusions: Prolonged nasal eosinophil influx was observed in all_ergic patients after common cold. What immunologic factors can induce prolonged eosinophil influx and whether this may increase the risk of subsequent all_ergen-induced hypersensitivity reactions must be studied further.

Topical corticosteroids have proved to be effective in the treatment of allergic rhinitis. The symptomatology of allergic rhinitis is considered to be the result of the accumulation and activation of inflammatory cells and cytokine release and hence the efficacy of corticosteroids is associated with their anti-inflammatory action. New advances in allergic inflammation now suggest that not only mast cells and eosinophils but also T-lymphocytes and antigen-presenting dendritic cells, play an important role in the inflammatory reaction. The effect of topical fluticasone propionate on cellular infiltration in the nasal mucosa is examined, with an emphasis on two studies performed in Rotterdam, The Netherlands. The cells influenced most by corticosteroid therapy were Langerhans' cells (antigen-presenting cells), which were almost completely eradicated, possibly resulting in diminished antigen presentation, and eosinophils. There was a reduction in the number of epithelial mast cells, but the number of T-lymphocytes only decreased following high doses of corticosteroid therapy or long-term treatment. However, T-lymphocyte function was influenced, as shown by the reduction in the T-helper2 (TH2)-related cytokines, interleukin (IL)-4 and IL-5. Topical corticosteroid therapy had no effect on the accumulation of macrophages. The reduction in antigen presentation, and the decrease in T-lymphocyte stimulation and cytokine production, may cause a reduced influx of eosinophils and other inflammatory cells, resulting in diminished symptomatology.

Mast cells in the nasal mucosa can be studied by means of monoclonal antibodies (mAb) against tryptase (T+MC) and chymase (C+MC). Fixation with acetone gives more positive cells than does fixation with Carnoy's fluid. In frozen biopsy specimens of allergic nasal mucosa fixed with acetone, the number of T+MC equals that of C+MC. When fixed with Carnoy's fluid, however, the number of T+MC is larger than the number of C+MC. The decrease in both T+MC and C+MC resulting from fixation with Carnoy's fluid is time-related and depends on the type of mAb used. Carnoy fixation time gives a decrease in the number of C+MC within 1 min, whereas the number of T+MC decreases only after 10 min. Within 1 min, the number of C+MC decreases to a level where continued fixation no longer gives further decreases in the number of cells. Two populations of mast cells can be distinguished here: one sensitive and the other insensitive to Carnoy's fluid. When double-staining is used, fixation with acetone gives three populations of mast cells: one positive for tryptase (T+C-MC), another positive for tryptase and chymase (T+C+MC), and a third one positive for chymase (T-C+MC). These three populations were found in lymph node, spleen, thymus, dermis, lung parenchyma, small intestinal submucosa, and nasal mucosa.

Mast cell degranulation, and the subsequent recruitment of infiltrating inflammatory cells, such as eosinophils, into the nasal mucosa has long been considered the most important model to explain allergic rhinitis. Several studies show a decrease in the number of eosinophils and possibly also mast cells during local corticosteroid treatment. Over the last decade, a new model to explain allergic inflammation has evolved. In this model, Langerhans' cells and T-cells play an important role. Langerhans' cells possess a high affinity receptor for IgE. In patients with allergic rhinitis, allergen provocation results in stimulation of T-cells by the IgE-positive Langerhans' cells. The T-cells produce a number of cytokines which stimulate IgE production as well as the inflammatory reaction. The number of T-cells is not usually influenced by corticosteroid treatment; however, the function of the T-cells, shown by the spectrum of cytokines produced, is clearly influenced. The cells that are most dramatically affected by local corticosteroid treatment are the Langerhans' cells, which completely disappear during treatment. This decrease suggests that there is a reduction in antigen presentation. The subsequent decrease in T-cell stimulation may result in a reduction of the reactions that are dependent on T-cell-derived mediators.

Background Sphingosine-1-phosphate (S1P) plays a crucial role in homeostasis of the immune system by regulating lymphocyte recirculation and inflammatory cell recruitment. The levels of S1P are tightly controlled through regulated production and controlled breakdown by sphingosine-lyase (SL). The S1P analogue FTY720 has been developed as an immunosuppressant in transplantation and tested as a treatment for various inflammatory diseases. FTY720 exploits S1P biology by acting as a S1P1 and S1P 3 agonist and by inhibiting S1P breakdown by SL. Objective Here, we investigate interfering S1P in allergic rhinitis (AR) and its way of action. Methods Allergic rhinitis was induced by sensitizing mice to ovalbumin (OVA) and challenging the nose with OVA allergen. At the time of allergen challenge, mice received topical intranasal treatment with FTY720. To address the relative contribution of SL inhibition in mediating its effects, some mice were treated with the SL inhibitor 2-acetyl-4-tetrahydroxybutyl (THI). Results FTY720 treatment resulted in significantly fewer eosinophils, mast cells and dendritic cells in the nasal mucosa of AR animals, compared with diluent treatment. Levels of IL-4, IL-5, IL-10 and IL-13 produced by lymph node cells fell significantly in FTY720-treated animals. Moreover, FTY720 proved potent enough to suppress inflammation in a model of persistent AR. In vitro and in vivo experiments indicate that FTY720 impaired Th2 differentiation and proliferation important in driving eosinophilia and induced apoptosis in mast cells. Conclusion Our results indicate that interfering with S1P metabolism is a powerful and feasible strategy to develop new topical agents that suppress AR.