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Background: Cow's milk protein allergy (CMPA) is the most common food allergy in early childhood. In most children CMPA resolves by age 5 or 6; however, if not treated correctly can provoke nutritional deficiency resulting in poor growth. Management consists of excluding cow's milk from the diet, with hypoallergenic formulas (or non-dairy alternatives) being introduced to meet nutritional requirements. Objectives: To compare the cost-effectiveness of hypoallergenic formulas in reducing allergic manifestations and promoting immune tolerance in infants with immunoglobulin E (IgE)-mediated symptoms of CMPA. Methods: A trial-based decision analytic cohort model was developed to simulate the occurrence of urticaria, eczema, asthma, rhinoconjunctivitis, or being symptom-free in infants with CMPA in the United Kingdom. Amino acid-based formula (AAF), extensively hydrolysed casein formula containing Lactobacillus rhamnosus Gorbach Goldin (EHCF+LGG), extensively hydrolysed whey formula (EHWF), and soy formula (SF) were compared using the National Health Service (NHS) perspective, 3-year time horizon and 3.5% discount rate for cost and health consequences. Hypoallergenic formulas comparative efficacy was sourced from a prospective cohort study. Resources required to manage allergic symptoms were sourced from published literature, validated by a UK clinician, and applied to UK cost resources. Results were reported as cost per additional child free from allergic manifestations at 3 years and cost per additional immune tolerant child at 3 years. Results: In the base case, infants receiving EHCF+LGG were associated with lower NHS resource use and improved CMPA tolerance. Over the 3-year treatment period, savings of £119, £476, and £1094 were achieved with EHCF+LGG compared to SF, EHWF and AAF, respectively. Infant formula accounted for the largest proportion of resource consumption averaging 44% for all comparators, with a minimum of 31% for SF and a maximum of 53% for AAF over 3 years. General practitioners' visits constituted the second highest cost component, approximately 17% of total costs across comparators. The results were robust to deterministic and probabilistic sensitivity analyses. Conclusions: Compared to AAF, SF, and EHWF hypoallergenic formulas, EHCF+LGG was the most cost-effective, associated with lower total costs and contributing to a higher proportion of children being symptom-free and developing immune tolerance 3-years after diagnosis.

Chronic urticaria is the presence of wheals and/or angioedema, with daily or intermittent symptoms lasting more than 6 weeks. Although rarely life threatening, it can be a cause of significant embarrassment and misery. In most cases, no underlying factor is identified. It is therefore important to have a structured approach to the assessment in order to exclude important diagnoses, minimise costly screening tests and ensure a correct diagnosis is made. This article aims to highlight the importance of a focused history, provides a clear scheme for establishing a diagnosis and recommends when to perform appropriate investigations. A short discussion regarding treatment options and prognosis is also provided., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Interleukin-9 (IL-9) has been implicated in the pathogenesis of allergic disorders. To examine the interaction between IL-9 and eosinophils, we evaluated mature peripheral blood eosinophils for their expression of the specific alpha-subunit of the IL-9 receptor (IL-9R-alpha). The expression of IL-9R-alpha by human eosinophils was detected at the messenger RNA (mRNA) and protein levels by reverse transcriptase-polymerase chain reaction (RT-PCR), flow cytometry, and immunocytochemical analysis, respectively. Functional analyses demonstrated that recombinant human (rh)IL-9 inhibited in vitro peripheral blood human eosinophil apoptosis in a concentration-dependent manner. We then examined the role of IL-9 in eosinophil differentiation using the human cord blood CD34(+) cells and human promyelocytic leukemia cells (HL-60). The addition of IL-9 to CD34(+) cells cultured in IL-3 and IL-5 enhanced eosinophil development, and IL-9 alone induced the expression of IL-5R-alpha. IL-9 also up-regulated the IL-5R-alpha chain cell surface expression during terminal eosinophil differentiation of the HL-60 cell line. Our findings suggest that IL-9 may potentiate in vivo eosinophil function by increasing their survival and IL-5-mediated differentiation and maturation. Taken together, these results suggest a mechanism by which IL-9 potentiates airway and tissue eosinophilia.

Interferon gamma is a T-helper cell (Th)-1-type cytokine that has been suggested to inhibit the development of an atopic Th2-type profile of cytokine expression. The aim of this study was to investigated the effect of exogenous rat interferon gamma on antigen-induced airway responses, and on Th1 and Th2-type cytokine messenger ribonucleic acid (mRNA) expression in the Brown Norway rat. Rats were actively sensitized to ovalbumin and 14 days later underwent an aerosolized ovalbumin challenge. Animals were intratracheally administered either interferon gamma (3,000 U) or control solvent 30 min prior to, and 2 and 4 h following, antigen challenge. Lung resistance was monitored over an 8-h time period. Using in situ hybridization and immunocytochemistry, the levels of Th1- (interleukin-12) and Th2-type (interleukin4 and -5) cytokine mRNA, and major basic protein expression in the bronchoalveolar lavage fluid of these rats 8 h after ovalbumin challenge were also determined. Administration of interferon gamma attenuated the development of the late-onset airways response in ovalbumin-sensitized antigen-challenged rats (p<0,05). The expression of interleukin-4 and -5 mRNA in the bronchoalveolar lavage fluid of interferon gamma treated rats was significantly attenuated compared to ovalbumin-challenged saline-treated controls (p<0.001). This was accompanied by a significant increase in the expression of interleukin-12 mRNA, and a reduction in eosinophil numbers. Intratracheal administration of interferon gamma modulates the allergic late-onset airways response in rats, and this is associated with a reduction in the expression of T-helper cell 2-type cytokines and an increase in interleukin-12 messenger ribonucleic acid expression within the airways. The present results support a role for interferon gamma in the pathophysiology of acute allergic airway responses, possibly by virtue of its ability to modulate T-helper cell 1- 2-type cytokine expression within the lungs.

Background: Allergic rhinitis is a complex upper airways disorder characterized by the infiltration of eosinophils and T(H2)-type T lymphocytes. GATA-3 is a novel transcription factor recently shown to regulate IL-5 and, possibly, IL-4 gene expression. We previously reported that GATA-3 is increased within the bronchial mucosa of allergic asthmatic subjects compared with control subjects., Objective: In the present study we set out to determine whether there is also an increased number of cells expressing GATA-3 messenger (m)RNA within the nasal mucosa of patients with allergic rhinitis., Methods: Inferior turbinate biopsy specimens were obtained from patients with allergic rhinitis and nonatopic control subjects before and after local allergen provocation in vivo. To assess the contribution of resident cells expressing GATA-3 mRNA, we also performed isolated explant studies in which nasal mucosal tissue from subjects with allergic rhinitis and nonatopic control subjects was cultured in allergen-treated medium. The presence of mRNA coding for GATA-3, IL-5, IL-4, IL-13, and GM-CSF was assessed by using in situ hybridization., Results: The number of GATA-3 mRNA(+) cells was increased after local allergen provocation in vivo (increase in GATA-3 mRNA(+) cells [mean +/- SEM]: subjects with allergic rhinitis, 11.3 +/- 8.7; control subjects, 1.2 +/- 4.1; P <.05) and in explanted nasal mucosa in vitro (subjects with allergic rhinitis, 10. 2 +/- 3.8; control subjects, 2.7 +/- 4.4; P <.05). The gene expression of GATA-3 was significantly correlated to the numbers of IL-5 (r = 0.87) and GM-CSF (r = 0.79) mRNA(+) cells but not with IL-4 or IL-13 mRNA(+) cells., Conclusion: In summary, the expression of the transcription factor GATA-3 was increased after allergen challenge, and this was evident in the absence of de novo inflammatory cell recruitment. GATA-3 may be a potential target in the treatment of allergic diseases, such as rhinitis.

Our understanding of the pathophysiology of asthma has undergone great advances in the past decade, particularly with the recognition of cytokines and the roles they may take in orchestrating the local immune response. With this information, it has been possible to target new therapeutic entities such as cytokine or chemokine receptors. Eosinophils and T lymphocytes have a special place in the inflammatory and structural alterations contributing to the asthmatic diathesis. It is possible that phenotype subsets of these cells exist and they hold the key to perpetuation of immunologic and physiologic abnormalities in asthma.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with tissue eosinophilia and the activation of T lymphocytes. The novel eosinophil chemoattractants, eotaxin and monocyte chemotactic protein (MCP)-4, are up-regulated at sites of allergic inflammation, yet their contribution to the pathophysiologic mechanisms of AD remains to be determined., Objective: We sought to investigate the expression of eotaxin and MCP-4 in acute and chronic lesions from patients with AD and to determine their relationship to the numbers of resident inflammatory cells., Methods: With use of in situ hybridization, the expression of eotaxin and MCP-4 messenger RNA (mRNA) in skin biopsy specimens from patients with acute and chronic AD skin lesions was compared with that of uninvolved skin from these patients and skin from healthy volunteers., Results: There was a constitutive expression of eotaxin and MCP-4 mRNA in skin biopsy specimens from healthy subjects. Positive signal for chemokine mRNA was observed both within the epidermis and inflammatory cells (macrophages, eosinophils, and T cells) of the subepidermis in AD skin lesions. Within the subepithelium acute and chronic skin lesions exhibited a significant increase in the numbers of eotaxin and MCP-4 mRNA-positive cells compared with uninvolved skin (P <.01), whereas the numbers of eotaxin and MCP-4 mRNA-positive cells were significantly higher in chronic AD compared with acute AD skin lesions (P <.005, P <.001, respectively). Correlations were observed between the expression of eotaxin and MCP-4 mRNA and the presence of eosinophils and macrophages, respectively, in AD lesions (r(2) = 0.84, r(2) = 0.94)., Conclusion: There is an increased expression of eotaxin and MCP-4 in acute and chronic lesions, suggesting that these chemotactic factors play a major role in the pathophysiologic mechanisms of AD.

To investigate the relationship between bronchial responsiveness and airway smooth-muscle (ASM) contractile properties, we studied inbred mice with known interstrain differences in airway responsiveness. Using oscillatory mechanics, we confirmed that A/J mice were hyperresponsive to methacholine (MCh) as compared with mice of the C3H/HeJ and C57BL/6J strains. Analysis of respiratory system resistance and elastance at different flow oscillation frequencies indicated that interstrain differences in responsiveness are present in both central and peripheral airways of these mice. We used video microscopy to measure the rate of contraction of explanted airways, and found that the airways of A/J mice contracted more rapidly than those of C3H/HeJ or C57BL/6J mice. In studies of a fourth strain (Balb/C) of mice, we found both bronchial hyperresponsiveness and increased ASM shortening velocity. The rank order of responsiveness among strains was the same as that for shortening velocity (A/J > Balb/C > C3H/HeJ > C57BL/6J). Furthermore, in each strain of mice, shortening velocity correlated with the achieved degree of airway narrowing and with a greater likelihood of airway closure in individual airways. In contrast, generation of isometric tension in trachealis, morphometric measurements of tracheal ASM, tracheal myosin content, and dose-response curves for MCh of explanted intraparenchymal bronchi failed to correspond to the in vivo phenotype of airway reactivity. These results indicate that bronchial responsiveness is related to ASM shortening velocity, and underscore the importance of smooth-muscle dynamics in understanding the mechanisms of bronchial responsiveness.

Background: IL-11 is a pleiotropic cytokine produced by a variety of stromal cells. Targeted overexpression of this cytokine in mice results in a remodeling of the airways and the development of airway hyperresponsiveness and airway obstruction., Objectives: Because these alterations mimic important pathologic and physiologic changes in the airways of some asthmatic patients, we investigated the expression of IL-11 messenger RNA (mRNA) within the airways of patients with mild to severe asthma and nonasthmatic control subjects., Methods: Fiberoptic bronchoscopy to obtain bronchial biopsy specimens was performed on patients with mild (n = 13), moderate (n = 10), and severe (n = 9) asthma and on nonasthmatic control subjects (n = 9)., Results: These patients differed in their extent of airway fibrosis with types I and III collagens being noted in greater quantities in the biopsy specimens from the severe and moderate asthmatics than in those from controls (P <.05). IL-11 mRNA expression was observed in the epithelial and subepithelial layers of asthmatic and nonasthmatic control subjects. The number of cells within the epithelium and subepithelium expressing IL-11 mRNA was greater in those with moderate and severe asthma compared with mild asthma and nonasthmatic subjects (P <.001). There were also greater numbers of IL-11 mRNA-positive cells within the subepithelium in severe compared with moderate asthma (P <.001). Immunostaining for IL-11 within the airway tissues confirmed translation of the mRNA into IL-11-immunoreactive protein in airway epithelial cells. Colocalization of IL-11 mRNA and immunoreactivity with resident inflammatory cells demonstrated that this cytokine was also expressed by major basic protein-positive eosinophils., Conclusion: These results suggest that IL-11 is involved in the chronic remodeling seen in asthmatic airways and is associated with increasing severity of the disease.

Eosinophil differentiation occurs within the bone marrow in response to eosinopoietic cytokines, particularly IL-5. Recently, however, eosinophil precursors (CD34/IL-5Ralpha+ cells) and IL-5 mRNA+ cells have been identified within the lungs of asthmatics, indicating that a population of eosinophils may differentiate in situ. In this report, we examined the presence of eosinophil precursors within allergic nasal mucosa and examined whether they undergo local differentiation following ex vivo stimulation. We cultured human nasal mucosa obtained from individuals with seasonal allergic rhinitis with either specific allergen, recombinant human IL-5 (rhIL-5), or allergen + soluble IL-5Ralpha (sIL-5Ralpha), shown to antagonize IL-5 function. Simultaneous immunocytochemistry and in situ hybridization demonstrated that there were fewer cells coexpressing CD34 immunoreactivity and IL-5Ralpha mRNA following culture with allergen or rhIL-5, compared with medium alone. Immunostaining revealed that the number of major basic protein (MBP) immunoreactive cells (eosinophils) was higher within tissue stimulated with allergen or rhIL-5, compared with unstimulated tissue. In situ hybridization detected an increase in IL-5 mRNA+ cells in sections from tissue cultured with allergen, compared with medium alone. These effects were not observed in tissue cultured with a combination of allergen and sIL-5Ralpha. Colocalization analysis indicated this expression to be mainly, but not exclusively, T cell (44%) and eosinophil (10%) derived. Our findings suggest that a subset of eosinophils may differentiate locally within allergic nasal mucosa, in what appears to be a highly IL-5-dependent fashion, and imply that this process might be regulated in vivo by endogenous production of sIL-5Ralpha.

Asthma is a complex disorder associated with eosinophil infiltration and the activation of T lymphocytes within the airways. Recent advances in the pathophysiologic mechanisms of asthma point to the importance of eosinophil-basophil progenitor cells and a family of transcription factors that underlie the development of T(H)2-type responses. Further research is needed to address the development of chronic inflammatory changes, the role of profibrotic cytokines, and especially their reliance on eosinophils in the lungs.

Cytokines have been implicated in the pathophysiology and development of pulmonary diseases such as tuberculosis and sarcoidosis. In particular, the numbers of cells expressing Th1-type cytokines such as IFN-gamma and IL-12 are increased within the lungs of patients with these granulomatous diseases. As a factor promoting the commitment of naive lymphocytes to a Th1-type profile of cytokine expression, IL-12 may be pivotal in the cascade of proinflammatory events within the airways. In this study, we examined the expression of the IL-12 receptor (IL-12R) mRNA in bronchoalveolar lavage (BAL) fluid from patients with active pulmonary tuberculosis (n = 6) and active pulmonary sarcoidosis (n = 6), and from allergic asthmatics (n = 6) and normal control subjects (n = 6). Bronchoscopy with BAL was undertaken, and cell cytospins were examined using the technique of in situ hybridization. There was a significant increase in the numbers of cells expressing mRNA for both beta(1) and beta(2) subunits of the IL-12R in active pulmonary sarcoidosis (p < 0.02, p < 0.01, respectively) and active pulmonary tuberculosis (p < 0.01, p < 0.005, respectively) compared with normal control subjects. In contrast, the allergic asthmatic patients exhibited a significant decrease in the number of IL-12R mRNA-positive cells (both beta(1) and beta(2) subunits (p < 0.01, p < 0.005, respectively), compared with the normal control subjects. These patients did, however, exhibit a significant increase in IL-4R mRNA, which was not evident in those with either tuberculosis or sarcoidosis when compared with normal subjects (p < 0.05). Colocalization studies demonstrated that CD8+ve cells are a principal site for the expression of IL-12R in tuberculosis. In sarcoidosis, IL-12R was expressed both on CD4+ve and CD8+ve cells. The increased expression of receptors for IL-12 in granulomatous diseases such as pulmonary tuberculosis and sarcoidosis provides evidence supporting the commitment of lymphocytes to a Th1-type cytokine profile in vivo.

Interleukin (IL)-18 is an interferon (IFN)-gamma-inducing cytokine suggested to be important in regulating inflammatory responses. This study investigated the pulmonary expression of IL-18 under conditions characterized by T-helper (Th)1 (lipopolysaccharide (LPS) treatment/sarcoidosis) and Th2 (ovalbumin (OVA) challenge/asthma) cytokine production. In situ hybridization and immunocytochemistry were used to determine the number of cells expressing IL-18, IFN-gamma, IL-5 and major basic protein (MBP) within lung tissue from Balb/c mice stimulated with LPS, OVA and in normal control mice. Bronchial biopsies from patients with sarcoidosis, asthma and control individuals were also examined. IL-18 was localized primarily to airway epithelium and mononuclear cells. Constitutive expression was observed within the lungs of control mice. Animals challenged with LPS exhibited more IL-18 messenger ribonucleic acid (mRNA)-positive and IFN-gamma immunoreactive cells, compared to control mice (p<0.01). OVA-challenged mice had fewer IL-18 mRNA positive and more IL-5 and MBP immunoreactive cells, compared to control mice (p<0.01). Similarly, constitutive expression of IL-18 protein was observed within the airway epithelium of control individuals, with more positive cells found within sarcoidosis tissue (p<0.01) and fewer within asthmatic tissue (p<0.01), compared to controls. These results demonstrate the expression of interleukin-18 within airway epithelium and the regulation of this cytokine under conditions of both T-helper1 and T-helper2 cytokine production.

Background: Although an eosinophilic infiltrate has been observed in the small airways of asthmatic individuals, the mechanisms responsible for cellular recruitment in the lung periphery remain to be clarified. Eotaxin and monocyte chemotactic protein (MCP)-4 are 2 eosinophil-associated chemokines shown to be upregulated at sites of allergic inflammation. However, their expression within the small airways of asthmatic individuals remains to be elucidated., Objective: We sought to determine the expression of eotaxin and MCP-4 in the peripheral airways and parenchyma of lungs of subjects with asthma and to assess their relationship to the numbers of resident eosinophils., Methods: We examined surgically resected lung tissue from 6 asthmatic and 10 nonasthmatic subjects for the presence of eotaxin and MCP-4 mRNA by in situ hybridization. Chemokine mRNA expression was examined with respect to the numbers of eosinophils within the airways, as detected by immunocytochemistry for major basic protein., Results: Numbers of chemokine mRNA-positive cells were significantly increased in the large and small airways of asthmatic subjects compared with nonasthmatic subjects. Although eotaxin and MCP-4 mRNA were widely expressed in the lungs of subjects with asthma, their expression was particularly evident within the bronchial epithelium and inflammatory cells. In the airways of the asthmatic individuals, the expression of eotaxin mRNA was significantly correlated to the numbers of eosinophils present., Conclusion: There is an increased expression of eotaxin and MCP-4 mRNA within the peripheral airways of lungs of asthmatic subjects, suggesting that these chemokines contribute to the small airways and peripheral lung inflammation in asthma.

Background: The local production of TH2 -type cytokines is thought to orchestrate the ongoing eosinophilic inflammation and contribute to the pathophysiologic features of allergic asthma. Previous studies investigating cytokine expression in asthmatic individuals have used invasive fiberoptic bronchoscopy techniques. To date, there have been no reports of cytokine mRNA expression in induced sputum as a means of quantifying local inflammatory events., Objectives: We examined whether IL-4, IL-5, and IFN-gamma mRNA expression could be detected in cells from induced sputum in subjects with mild asthma and normal control subjects. In addition, we compared the profile of inflammatory cells and cytokine mRNA in sputum and bronchial wash fluid., Methods: Cells positive for IL-4, IL-5, and IFN-gamma mRNA were determined by using in situ hybridization on cytospun aliquots of sputum induced by successive inhalations of hypertonic saline. Inflammatory cells were quantified by using immunologic cell surface markers and immunocytochemistry., Results: IL-4 and IL-5 mRNA were detected in the sputum of all asthmatic subjects, and the number of cells expressing these cytokines was significantly higher than that found in control subjects. Colocalization studies showed CD3-positive T cells were the major sources of IL-4 and IL-5 mRNA., Conclusions: This study demonstrates that induced sputum can be used to detect mRNA for TH2 -type cytokines in bronchial asthma and that the increase in IL-4 and IL-5 mRNA expression is similar to that seen with more invasive techniques. The qualitative differences in inflammatory cell numbers between sputum induction and bronchial wash are consistent with their sampling of different airway compartments.

Background: Recent studies have provided evidence for increased IL-4 expression in the airways of atopic and nonatopic asthmatic subjects. IL-4 is believed to perform important regulatory roles in asthma; however, the expression of the IL-4 receptor has not been investigated. In this study we examined the mRNA and protein expression of the specific alpha-subunit of the IL-4 receptor (alphaIL-4R) in bronchial biopsy specimens obtained from atopic and nonatopic asthmatic subjects., Methods: Asthmatic subjects and nonasthmatic control subjects were recruited, and lung function measurements were performed before bronchoscopy. Endobronchial biopsy specimens were examined for the presence of alphaIL-4R mRNA and immunoreactivity by using in situ hybridization and immunocytochemistry, respectively., Results: alphaIL-4R mRNA-positive and immunoreactive cells were detected in the epithelium and subepithelium in biopsy specimens from all subjects. Expression of alphaIL-4R mRNA and protein was significantly increased in the epithelium and subepithelium of biopsy specimens from atopic asthmatic subjects compared with atopic control subjects (P <.05 and P <.001, respectively). Epithelial alphaIL-4R mRNA expression and immunoreactivity did not differ significantly between nonatopic asthmatic subjects and nonatopic control subjects. Although the numbers of alphaIL-4R mRNA-positive cells were augmented in the submucosa of intrinsic asthmatic subjects compared with nonatopic control subjects (P <.05), alphaIL-4R immunoreactivity did not differ significantly between these groups. Increased alphaIL-4R immunoreactive signals were also detected in the endothelial cell layer in both atopic and intrinsic asthmatic subjects compared with atopic and nonatopic control subjects, respectively (P <.05). Combined in situ hybridization immunocytochemistry performed on biopsy sections from asthmatic and control subjects demonstrated alphaIL-4R mRNA expression in CD3-positive T cells and tryptasepositive mast cells, with T cells comprising the larger proportion of alphaIL-4R mRNA-positive cells. Numbers of alphaIL-4R mRNA-positive or immunoreactive cells did not correlate with CD3-positive cell numbers, numbers of IL-4 mRNA-positive cells, or indices of pulmonary function., Conclusion: These results demonstrate constitutive alphaIL-4R expression in normal airways and enhanced expression in airway tissue from asthmatic individuals.

Interleukin-5 (IL-5) is a potent eosinophilopoietic factor implicated in the chronic inflammatory cell accumulation accompanying bronchial asthma. However, its role in stimulating eosinophil differentiation within the bone marrow following allergen exposure remains to be elucidated. The aims of our study were to determine the expression of IL-5 within the bone marrow of sensitized and control mice after allergen exposure, and to investigate the cellular phenotype of IL-5-producing cells. Sensitized Balb/c mice were challenged with either ovalbumin (OVA) or sterile saline. After 6 h, the mice were exsanguinated and the bone marrow prepared for cytospins. Bone marrow-derived cells from OVA-sensitized mice exhibited an increase in IL-5 immunoreactivity and mRNA compared with those from nonsensitized control mice (p < 0. 05). After allergen challenge, there was a further increase in IL-5 expression (p < 0.05) within the bone marrow. Both sensitization and allergen challenge resulted in an increase in the number of cells expressing major basic protein (MBP) (p < 0.05). In nonsensitized mice, the IL-5 mRNA was expressed predominantly by CD34-positive (CD34+) progenitor cells. Following sensitization and allergen challenge, CD3-positive (CD3+) T lymphocytes were the major source of this cytokine. These results demonstrate the presence of IL-5 within the bone marrow of normal Balb/c mice. After sensitization and allergen challenge, the increase in IL-5-producing cells within the bone marrow is attributed by T lymphocytes.

Background: Nasal allergen provocation has demonstrated that allergen-induced rhinitis is associated with an increase in local IL-4 mRNA and IgE heavy chain (Cepsilon) and IgE heavy chain promoter (Iepsilon) RNA and that pretreatment with topical glucocorticosteroids inhibits the increase in these transcripts., Objective: This study was undertaken to determine whether observations made after acute allergen provocation can be extended to the case of chronic exposure experienced during the pollen season., Methods: Biopsy specimens were obtained from the inferior turbinate of 33 pollen-sensitive subjects with allergic rhinitis before and during pollen season. Patients were randomized in a double-blind fashion and treated with either topical steroids (200 microg fluticasone propionate twice daily; n = 16) or matched placebo nasal spray (n = 17) before the pollen season. Alkaline phosphatase anti-alkaline phosphatase immunocytochemistry was used to identify B cells (CD20+), and in situ hybridization was used to detect IL-4, Cepsilon, and Iepsilon RNA+ cells., Results: Baseline examination revealed IL-4 and Cepsilon RNA but virtually no Iepsilon RNA+ cells in the nasal mucosa. Analysis revealed a significant difference in the expression of Cepsilon and Iepsilon RNA+ cells (p < 0.001). Biopsy specimens taken after antigen exposure exhibited highly significant increases in placebo-treated (p < 0.001) but not steroid-treated patients. In both groups, the number of CD20+ cells was unchanged when preexposure and postexposure biopsy specimens were compared., Conclusions: These results show strong support for the hypothesis that IgE class switching occurs locally within the nasal mucosa of subjects with seasonal allergic rhinitis and that this response can be inhibited through strategies directed against local IgE production.