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The nasal cavity displays immune tolerance to commensal bacteria under homeostatic conditions, which is rapidly converted to a pro-inflammatory response upon infection. Yet, the factors that control this conversion are still largely unknown. Here, we provide evidence that Fc gamma receptor III (FcγRIII) stimulation breaks immune tolerance to bacteria in the human nasal cavity through activation of nasal epithelial cells, which are the first line of defense against invading microbes. While under steady-state conditions human nasal epithelial cells were completely non-responsive to Gram-negative bacteria P. aeruginosaor TLR4 ligand LPS, IgG opsonization of bacteria, as occurs upon infection, strongly induced production of pro-inflammatory agents such as IL-6 and IL-8. This breaking of tolerance to bacteria was completely dependent on FcγRIII, which amplified cytokine gene transcription through cross-talk with TLR4. In addition, we identified that epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps do not display LPS tolerance, thereby providing an explanation for the disturbed host defense responses of these patients. Taken together, these data are the first to identify FcγR expression on nasal epithelial cells, as well as to identify its important role in controlling the balance between tolerance and inflammation in the nasal cavity.

Rhinovirus and respiratory syncytial virus (RSV) are the most prevalent inducers of upper respiratory tract infections (URTI) in infants and may stimulate immune maturation. To estimate the amount of immune stimulation, nasal immune responses were examined during rhinovirus and RSV‐induced URTI in infants. Nasal brush samples were taken from infants (2–26 months; 57% atopic family) with rhinovirus‐induced URTI (N = 20), with RSV‐induced URTI (N = 7), and with rhinovirus‐induced rhinitis (N = 11), from children with asymptomatic rhinovirus infection (N = 7) and from eight non‐infected children. Numbers of nasal brush cells positive for Th1‐, Th2‐, regulatory and proinflammatory cytokines were measured by immunohistochemistry or by measuring protein levels using a cytometric bead array analysis. During rhinovirus and RSV‐induced URTI, fewer regulatory cytokine IL‐10 positive cells were found compared to non‐infected children. This fall was accompanied by an increase in levels of the Th1 cytokine TNFα. IL‐10 responses were inversely related to TNFα responses. No enhanced responses were observed for IFNγ, IL‐12 and IL‐18. Cytokine responses were comparable in children with rhinovirus‐induced URTI and in children with rhinitis, while responses in asymptomatic rhinovirus‐infected children were located between those for symptomatic and asymptomatic rhinovirus‐infected children. Cytokine responses did not depend on the age of the child or atopy in the family. In conclusion, reduced nasal IL‐10 responses during URTI in infants could facilitate the induction of a TNFα response. TNFα in turn could replace the immature production of IL‐12, IL‐18 and IFNγ during URTI to induce an effective clearance of the viral infection and which could stimulate the maturation of Th1 cytokine production in infancy. J. Med. Virol. 75:348–357, 2005. © 2004 Wiley‐Liss, Inc.

Respiratory syncytial virus (RSV) infections are a major cause of severe respiratory disease in infants. It has been shown that there is an increased frequency of childhood wheezing in ex‐bronchiolitic preteen children. This was postulated to be mediated by a vigorous virus‐specific Th2 response influencing the further development of the immune system. Little is known about the possible role of the immune response to clinically mild RSV infections in this respect. We have studied the RSV‐specific cellular immune response in infants with a laboratory‐confirmed RSV upper respiratory tract infection (URTI; n= 13, mean age 12 months, range 2–22 months) in comparison with infants with non‐RSV mediated URTI (n= 9, mean age 9.3 months, range 4–18 months) or infants with severe RSV bronchiolitis (n= 11, mean age 2.3 months, range 1–6 months). RSV‐specific cytokine‐producing cells were enumerated using the ELISPOT method in peripheral blood mononuclear cells and nasal brush T‐cells, collected during the acute and convalescent phase of the infection. Mixed Th1 (IFN‐γ) and Th2 (IL‐4 and IL‐13) responses were detected in all three groups. Frequencies of RSV‐specific T‐cells were lower in both URTI groups than in the RSV bronchiolitis group, and not significantly different between the RSV URTI and the non‐RSV URTI group. The absence of vigorous virus‐specific Th2 responses upon mild RSV infection does not support the hypothesis that these infections influence the development of the immune system and that they predispose for the development of atopic disease. J. Med. Virol. 70: 309–318, 2003. © 2003 Wiley‐Liss, Inc.

The nose is the airconditioner of the airways. Because normal breathing is through the nose, most airborne particles are filtered there; hence the nasal mucosa is the first line of defence against particles in the air. Pathogenic and non-pathogenic antigens continuously bombard the epithelium of the nasal airway. These antigens are mainly removed non-immunologically by the first defence layer of the mucosa, consisting of mucus, ciliated epithelial cells, glycoproteins/lysosymes. If the antigen passes this defence layer, specific and non-specific immunological defence mechanisms exist. The non-specific defence consists of phagocyting cells like neutrophils and macrophages and the complement activation. The specific defence mechanism (resulting in a specific immunological reaction in relation to a certain antigen) is formed by the antibodies, mainly secretory IgA and to a lesser extent IgG and immunocompetent cells in the nasal mucosa. Activation of the specific defence mechanisms may lead to inflammation which can be allergic. The intense co-operation of mechanical, aspecific and specific immunological defence results in a tightly controlled balance between a proper defence against pathogens and hypersensitivity. Failures in these defence mechanisms, or their co-operation, results in upper respiratory infection and/or allergy.

Background: Until now, it has not been possible to identify specific IgE locally in the airway mucosa. In this study we investigated the possibility of determining specific allergen binding locally in the nasal mucosa. Methods: Nasal mucosal biopsy specimens were taken from 11 patients with symptoms of an isolated grass pollen allergy, 10 patients with symptoms of perennial allergic rhinitis in response to house dust mite allergen, and 10 nonallergic control subjects. Sections of these biopsy specimens were stained by using commercially available biotinylated allergens (AlaSTAT, Diagnostic Products Corp.). Results: Staining with biotinylated grass pollen (GP1) demonstrated positive cells only in patients with grass pollen allergy. Biotinylated Dermatophagoides pteronyssinus (D1) only stained cells in patients with perennial allergy. Specific binding of allergen to cells of patients with allergy and the blocking experiments proved the method to be highly specific. Allergen-positive cells stained double with IgE, the high-affinity receptor for IgE (Fc@eRI), CD1, HLA-DR, tryptase, and chymase. Most allergen-positive cells proved to be mast cells. Conclusion: This immunohistochemical study shows the presence of specific IgE against grass pollen and house dust mite allergens locally on cells in the airway mucosa. (J Allergy Clin Immunol 1997;99:515-21.)

Topical corticosteroids are the therapy of choice for nonallergic, noninfectious perennial rhinitis (NANIPER). However, the efficacy of steroid therapy in NANIPER is controversial, as is its mode of action. To our surprise, of 300 patients initially diagnosed as having NANIPER, only 65 reached threshold nasal symptom scores. Patients were randomized into four different treatment regimens: placebo administered twice daily (BD) for 8 weeks, fluticasone propionate aqueous nasal spray (FPANS) (200 @mg) once daily (OD) and placebo OD for 8 weeks, FPANS (200 @mg) OD and placebo OD for 4 weeks followed by FPANS (200 @mg) BD for 4 weeks, and FPANS (200 @mg) BD for 8 weeks. A small decrease in nasal symptoms was found, which only reached significance for sneezing in the FPANS 200 @mg BD group. A significant dose-dependent decrease in immunocompetent cells was found in nasal biopsy specimens obtained before, after 4 weeks, and after 8 weeks of treatment. We conclude that FPANS did not significantly reduce nasal symptoms in this group of selected NANIPER patients, even though a significant effect on cells in the nasal mucosa was seen. (J Allergy Clin Immunol 1997;100:739-47.)

Background: Eosinophils are thought to play an important role in the symptomatology and pathophysiology of allergic rhinitis. Most quantitative studies on eosinophils in nasal mucosa have focused on the dynamics of eosinophils in the acute and late phases of the allergic reaction by using different cell sampling techniques. Little is known about the dynamics of eosinophils during a more prolonged period of allergen exposure and the activation of eosinophils induced by allergen challenge. Objective: The aim of this study was to investigate the dynamics and activation of the eosinophils in the nasal mucosa of patients with an isolated grass pollen allergy during an out-of-season 2-week allergen exposure, mimicking the natural grass pollen season. Methods: Seventeen patients with isolated grass pollen allergy and four control subjects were challenged daily with the allergen during a 2-week period in the winter. Nasal brush specimens were obtained before provocation and each day during the provocation period. Biopsy specimens were obtained once before, six times during, and once after the provocation period. Preparations made of nasal brush and nasal biopsy specimens were stained with the monoclonal antibody BMK 13 and Giemsa stain as paneosinophil markers and with the monoclonal antibody EG2 to identify activated eosinophils. Results: We found significant increases in the total number of eosinophils and the number of activated eosinophils in the epithelium and lamina propria. These increases were most explicit in the second week. BMK 13 was found to be a paneosinophil marker superior to Giemsa staining. Conslusion: Eosinophils are not only involved in the acute and late phases of the allergic reaction but are probably even more involved in the chronic phase.