Small airway inflammation in asthma.

Asthma was originally described as an inflammatory disease that predominantly involves the central airways. Pathological and physiological evidence reported during the past few years suggests that the inflammatory process extends beyond the central airways to the peripheral airways and the lung parenchyma. The small airways are capable of producing T-helper-2 cytokines, as well as chemokines, and they have recently been recognized as a predominant site of airflow obstruction in asthmatic persons. The inflammation at this distal site has been described as more severe than large airway inflammation. These findings are of great clinical significance, and highlight the need to consider the peripheral airways as a target in any therapeutic strategy for treatment of asthma.

Expression of IL-15 in inflammatory pulmonary diseases.

BACKGROUND: IL-15 is a T(H)1-related cytokine that shares many biologic activities with IL-2. Both cytokines bind a specific alpha subunit, and they share the same beta and gamma common receptor subunits for signal transduction. IL-15 has recently been shown to be upregulated in T cell-mediated inflammatory disorders, such as rheumatoid arthritis and inflammatory bowel diseases. However, the role and expression of IL-15 in inflammatory lung disease has not been investigated. OBJECTIVE: In the present study we have evaluated the expression of IL-15 mRNA and protein in bronchial biopsy specimens obtained from patients with sarcoidosis (n = 8), tuberculosis (n = 7), chronic bronchitis (n = 10), and bronchial asthma (n = 8) and compared its expression with that seen in normal control subjects (n = 11). METHODS: In situ hybridization and immunocytochemistry were used to detect the number of cells expressing IL-15 mRNA and protein, respectively, within sections of bronchial tissues from all subject groups. In addition, double immunocytochemistry was used to characterize the cellular source of IL-15. RESULTS: The number of IL-15(+) cells was significantly higher within tissue from patients with sarcoidosis, tuberculosis, and chronic bronchitis compared with that in asthmatic patients and normal control subjects. Similar results were obtained for IL-15 immunoreactivity by using immunohistochemistry. Furthermore, double immunostaining revealed that neutrophils and macrophages are the major source of IL-15. CONCLUSION: These results suggest that the expression of IL-15 may be associated with T(H)1-mediated chronic inflammatory diseases of the lung.

TH2 cytokine-associated transcription factors in atopic and nonatopic asthma: evidence for differential signal transducer and activator of transcription 6 expression.

BACKGROUND: The expression of IL-4 and IL-5 is increased in patients with atopic asthma compared with control subjects and correlates with indices of pulmonary function. In nonatopic asthma the expression of IL-4, unlike IL-5, fails to correlate with pulmonary function, and compared with their atopic counterparts, these patients have fewer cells expressing IL-4 receptor (IL-4R). As such, a deficiency in the IL-4 signaling pathway may be implicated in nonatopic asthma. The transcription factors GATA-3 and cMAF mediate IL-4 and IL-5 synthesis, whereas signal transducer and activator of transcription 6 (STAT-6) is critical for IL-4R signaling. OBJECTIVE: This study examines the expression profile of these transcription factors in asthma, according to atopic status. METHODS: With immunocytochemistry, the expression of GATA-3, cMAF, and STAT-6 protein was determined in sections of bronchial biopsy specimens from patients with atopic asthma (n = 7), patients with nonatopic asthma (n = 8), and control subjects (n = 8). RESULTS: Higher numbers of cells expressing GATA-3 and cMAF were observed in patients with atopic and those with nonatopic asthma than in control subjects and patients with tuberculosis (P <.001). There were also more STAT-6-immunoreactive cells in patients with atopic and those with nonatopic asthma than in control subjects (P <.0001, P <.05). Notably, however, fewer cells expressing STAT-6 protein were observed in nonatopic versus atopic asthma (P <.0001). CONCLUSIONS: These results demonstrate the upregulation of GATA-3 and cMAF in both variants of asthma and indicate that reduced IL-4R signaling, because of lower STAT-6 expression, may be a feature of nonatopic asthma.

Expression of IFN-gamma-inducible protein; monocyte chemotactic proteins 1, 3, and 4; and eotaxin in TH1- and TH2-mediated lung diseases.

BACKGROUND: Chemokines are involved in the influx of leukocytes into the airways in inflammatory lung diseases. The differential cell recruitment characteristic of T(H)1 versus T(H)2 immune responses may be associated with differential chemokine expression. OBJECTIVE: We investigated the expression of chemokines; monocyte chemotactic proteins (MCPs) 1, 3, and 4; eotaxin; and IFN-gamma-inducible protein 10 (IP-10) in both T(H)1- and T(H)2-mediated lung diseases. METHODS: By using immunocytochemistry and in situ hybridization, we examined the protein and mRNA expression, respectively, in bronchoalveolar lavage and biopsy samples in subjects with asthma, tuberculosis, sarcoidosis, and chronic bronchitis. RESULTS: Increased immunoreactivity and mRNA expression of IP-10 and of the MCPs was found in the bronchoalveolar lavage fluid and biopsy specimens of subjects with asthma and tuberculosis compared with that of control subjects (P <.005). IP-10, however, was particularly increased in subjects with sarcoidosis (P <.001). Eotaxin, on the other hand, was increased only in patients with asthma when compared with control subjects (P <.005). CONCLUSION: This study demonstrates that MCP-1, MCP-3, and MCP-4 expression is not specifically associated with lung diseases characterized by a particular cytokine profile. In contrast, IP-10 is mostly expressed in T(H)1-mediated diseases, and eotaxin expression seems to be specifically associated with lung diseases of a T(H)2 cytokine profile.

Inflammatory patterns of allergic and nonallergic rhinitis.

Rhinitis is a chronic condition of the nasal mucosa that affects a large segment of the population. The symptoms of rhinitis occur in a variety of sinonasal conditions, which may be broadly classified as allergic (seasonal or perennial) or nonallergic (infectious or a number of noninfectious etiologies) based on the presence or absence of atopy. The cytokine profile and inflammatory patterns underlying these two conditions vary because of certain differences in their pathophysiology as discussed in this review.

Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma.

BACKGROUND: We have recently demonstrated an increased number of glucocorticoid receptor-beta (GRbeta)-positive cells in steroid-insensitive subjects with severe asthma. Insensitivity to steroids may be a major contributing factor in fatal asthma; however, no such direct evidence has been report previously. OBJECTIVE: Our aims were to investigate the expression of GRbeta immunoreactivity, an endogenous inhibitor of steroid action previously associated with steroid insensitivity, within the airways of patients who died of slow-onset fatal asthma and to compare its expression in patients with emphysema and in nonasthmatic subjects who died of unrelated causes. Sections from airways, both large and small, were obtained from 7 patients who died of asthma, 6 who died from emphysema, and 8 who died from nonpulmonary diseases. Sections from lungs of 6 patients with mild asthma whose lungs were resected for carcinoma were also included as controls. METHODS: Tissue samples were processed for immunocytochemistry with a polyclonal antibody to GRbeta with use of the avidin-biotin technique and with monoclonal CD3, major basic protein, CD68, and elastase antibodies with the alkaline phosphatase-anti-alkaline phosphatase technique. Sequential immunocytochemistry was performed to phenotype the GRbeta immunoreactive cells. Tissue sections from both large (>2 mm) and small (<2 mm) airways were examined. RESULTS: There was a significantly greater number of GRbeta immunoreactive cells in fatal asthma compared with emphysema and controls (P <.001 and P <.05, respectively). There was no difference in the expression of GRbeta in emphysema compared with controls. GRbeta immunoreactivity was also significantly higher in fatal asthma compared with mild asthma. The expression of GRbeta in the small airways of patients with severe asthma did not differ significantly from that in the large airways. The majority of GRbeta-positive cells were T cells and to a lesser extent eosinophils, macrophages, and neutrophils. CONCLUSION: The results of this study support the association of GRbeta expression with fatal asthma and suggest that alternative anti-inflammatory agents need to be considered in the acute setting for patients who are not responding to steroid therapy.

Local synthesis of epsilon germline gene transcripts, IL-4, and IL-13 in allergic nasal mucosa after ex vivo allergen exposure.

BACKGROUND: The production of epsilon germline gene transcripts (Iepsilon(+)/Cepsilon(+) RNA) precedes class switch recombination to IgE and is induced by IL-4 and/or IL-13. Although Iepsilon and Cepsilon RNA(+) B cells have been identified within nasal tissue after in vivo allergen exposure, suggesting local germline transcription, whether these were resident or infiltrating B lymphocytes was not clear. OBJECTIVE: We sought to examine whether B cells resident to the nasal mucosa undergo epsilon germline transcription. METHODS: Nasal mucosal biopsy specimens were obtained from asymptomatic patients with seasonal allergic rhinitis and exposed to allergen ex vivo. Using immunocytochemistry, B lymphocytes were enumerated; with in situ hybridization, the number of cells expressing Iepsilon, Cepsilon, IL-4, and IL-13 messenger (m)RNA(+) cells was examined. RESULTS: Tissue cultured in medium containing specific allergen exhibited significantly more Iepsilon and Cepsilon RNA(+) cells compared with medium alone (P <.05). IL-4 and IL-13 mRNA synthesis also resulted from ex vivo allergen exposure; there were significantly more cells expressing transcripts for these cytokines within allergic nasal mucosal tissue cultured with allergen than medium alone (P <.05). Within allergen-stimulated tissue obtained from allergic patients, 30% of total B cells were Iepsilon RNA(+), and the majority of IL-4 and IL-13 mRNA(+) cells were T cells (68% and 44%, respectively) and mast cells (32% and 19%, respectively). CONCLUSION: These results demonstrate that the nasal mucosa is a site of epsilon germline gene transcription and suggest that local T cell and mast cell production of IL-4 and IL-13 may regulate this event.

Upregulation of the transcription factor GATA-3 in upper airway mucosa after in vivo and in vitro allergen challenge.

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.

Molecular pathology of allergic disease. II: Upper airway disease.

Allergic upper airway diseases such as allergic rhinitis and chronic sinusitis are an increasing problem. Although the pathogenesis remains elusive, an individual's genetic predisposition as well as exposure to the allergen are currently considered factors in their development. Clinical symptoms of sneezing, rhinorrhea, and congestion are primarily a consequence of granulocyte release of chemical mediators such as histamine, prostanoids, and leukotrienes as well as the infiltration of inflammatory cells. Observations subsequent to allergen provocation are comparable to natural exposure and as such much of our understanding of allergic responses is derived from this model. A prominence of CD4(+) T cells and eosinophils, synthesis and release of T(H)2 cytokines, and the coordinate expression of chemokines and adhesion molecules are all characteristic of the allergic response observed in rhinitis and sinusitis. Corticosteroids and immunotherapy target these inflammatory processes and have been observed to successfully reduce and shift the predominantly T(H)2 environment toward T(H)1 cytokine expression. As our understanding of the pathophysiologic features of allergic upper airway disease improves, as well as the relationship between their development and that of lower airway disease, new strategies of diagnosis and treatment will allow for more effective modulation of the allergic process and associated morbidity.

Evidence for local eosinophil differentiation within allergic nasal mucosa: inhibition with soluble IL-5 receptor.

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.

IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma.

BACKGROUND: Bronchial asthma is a chronic inflammatory disease associated with genetic components. Recently IL-9 has been reported as a candidate gene for asthma and to be associated with bronchial hyperresponsiveness and elevated levels of total serum IgE. OBJECTIVE: To investigate the contribution of IL-9 to the pathogenesis of asthma, we examined the expression of IL-9 and its receptor (IL-9R) in bronchial tissue from subjects with atopic asthma (n = 10), chronic bronchitis (n = 11), and sarcoidosis (n = 9) and from atopic (n = 7) and nonatopic (n = 10) healthy control subjects. METHODS: Bronchial biopsy specimens were examined for the presence of IL-9 and IL-9R protein and messenger RNA (mRNA) by immunocytochemistry and in situ hybridization, respectively. To phenotype the cells expressing IL-9 in asthmatic tissue, combined in situ hybridization and immunocytochemistry was also performed. RESULTS: There was a highly significant difference (P <.001) in the expression of IL-9 mRNA in asthmatic airways (20.6 +/- 4.0 cells/mm of basement membrane) compared with chronic bronchitis (5.6 +/- 4.4), sarcoidosis (2.5 +/- 1.8), atopic control subjects (7.7 +/- 2.2), and healthy control subjects (2.7 +/- 2.3). The number of IL-9 immunoreactive cells was also greater in asthmatic patients compared with the other groups (P <.05). Although the level of IL-9R mRNA expression did not differ in any of the groups (P >.05), IL-9R immunoreactivity was significantly higher in asthmatic compared with control subjects. Furthermore, IL-9 mRNA expression levels were also significantly correlated with FEV(1) (P <.05) and the airway responsiveness to methacholine producing a 20% fall in FEV(1) (P <. 01). The cells expressing IL-9 mRNA in asthmatic tissue were CD3(+) lymphocytes (68%), major basic protein(+) eosinophils (16%), and elastase(+) neutrophils (8%). CONCLUSION: The results of this study demonstrate the potential of IL-9 to be a marker for atopic asthma and furthermore suggest an important role for this cytokine in the pathophysiologic mechanisms of this disease.

In vivo expression of signal transducer and activator of transcription factor 6 (STAT6) in nasal mucosa from atopic allergic rhinitis: effect of topical corticosteroids.

BACKGROUND: The allergen-induced late nasal response is associated with a high local expression of interleukin (IL) -4, a TH2-type cytokine implicated in immunoglobulin (Ig) E production, tissue eosinophilia and other events considered to be relevant to allergic inflammation. Interaction of IL-4 with its receptor activates at least two distinct signalling pathways that culminate in the transcription of specific target genes. One pathway involves the activation of a transcription factor termed signal transducer and activator of transcription factor 6 (STAT6). OBJECTIVE: To investigate the expression of STAT6 in the allergen-induced late nasal response and to examine the effect of local steroid treatment on STAT6 expression. METHODS: Inferior turbinate biopsies were obtained from subjects with allergic rhinitis out of the allergen season. Subjects were then randomized into topical steroid- (n = 6) and placebo-treated (n = 6) groups in a double-blind fashion. After a 6-week treatment period, a second nasal biopsy was performed 24 h after local challenge with allergen. STAT6 immunoreactivity was examined in biopsy specimens by immunocytochemistry using a specific monoclonal antibody. Numbers of inflammatory cells (CD3+ T cells and MBP+ eosinophils) and IL-4 mRNA+ cells were investigated by immunocytochemistry and in situ hybridization, respectively. RESULTS: STAT6 immunoreactivity was detected in all biopsies studied and localized predominantly to inflammatory tissue of the nasal mucosa. After allergen challenge, expression of STAT6 was markedly increased in placebo-treated patients (P < 0.01). By confocal microscopy, STAT6 was localized to the cytoplasm and the nucleus of positively-staining cells. The allergen-induced increase in STAT6 immunoreactive cells was not observed in the steroid-treated patients. The change in STAT6 immunoreactivity after allergen challenge correlated significantly with the change in numbers IL-4 mRNA+ cells (r = 0.74, P = 0.006) and CD3+ T cells (r = 0.76, P = 0. 004), but not MBP+ eosinophils. CONCLUSION: This study provides the first evidence of increased STAT6 expression in vivo in human allergic inflammation. The results support a role for STAT6 and IL-4 in the pathogenesis of late nasal response and show that decreases in STAT6 expression parallel the reduction in IL-4 expression that occurs with topical steroid treatment.

Localization of IL-4 and IL-5 mRNA in Bronchial Biopsies.

Cytokines are important biochemical mediators essential in initiating and maintaining inflammatory reactions associated with allergic disease in man. Although cytokines can be secreted from a variety of different cell types, considerable attention has been focused on T-lymphocyte-derived cytokines, which have been clearly implicated in the modulation of the immune system. Bronchial asthma is associated with persistent infiltration of the airways with activated CD4(+)T-lymphocytes, as well as other inflammatory cells exhibiting a T-helper type-2 (Th2)-like cytokine profile (1-3).

Expression of interleukin (IL)-12 (p40) and IL-12 (beta 2) receptors in allergic rhinitis and chronic sinusitis.

BACKGROUND: Interleukin (IL)-12 is a relatively new and structurally distinct TH1-associated cytokine produced by B cells and macrophages, which may play a suppressive role in the development of allergic sinonasal mucosal responses. OBJECTIVE: We investigated the expression of IL-12 (inducible p40 subunit) and its receptor (IL-12R beta2 subunit) in tissue biopsies of naturally exposed patients with allergy-associated (ACS) and nonallergy-associated chronic sinusitis (NCS) and compared it with controls. We also examined IL-12 and IL-12R expression in biopsies from a ragweed allergen challenge model. In the allergen challenge model, the effect of pretreatment with topical corticosteroids on IL-12 and IL-12R expression was assessed. METHODS: To detect IL-12 and IL-12R mRNA, we employed the technique of in situ hybridization using digoxigenin-labelled riboprobes. RESULTS: In both ACS and NCS subjects there was decreased expression of IL-12 as compared with control (P < 0.05). IL-12R (beta2) expression was decreased in ACS subjects as compared with control (P < 0.05), however, there was no significant difference found between NCS subjects and control. In the allergen challenge subjects, there was a significant decrease in IL-12 expression following challenge (P < 0.05). This effect was abrogated by pretreatment of the subjects with topical corticosteroids. However, IL-12R (beta2) expression showed no change following allergen challenge while pretreatment with topical corticosteroids resulted in increased expression of the (beta2) receptor after allergen challenge (P < 0.05). CONCLUSION: Our data suggest that IL-12 plays a role in the in vivo suppression of the allergic inflammatory response and that the control of this suppression may be exerted largely via the IL-12 (beta2) receptor.

Monocyte chemotactic proteins in allergen-induced inflammation in the nasal mucosa: effect of topical corticosteroids.

BACKGROUND: Human allergen-induced rhinitis is associated with the recruitment and activation of inflammatory cells, particularly eosinophils and CD4(+) T cells, in the nasal mucosa. Chemokines are inflammatory mediators capable of attracting specific inflammatory cell populations. Monocyte chemotactic proteins (MCPs), a subfamily of CC chemokines, have been shown to induce chemotactic activity particularly in eosinophils, T cells, and monocytes under in vitro assay conditions. OBJECTIVE: To assess the contribution of MCPs in the recruitment of inflammatory cells in vivo, we investigated the allergen-induced late response in subjects with allergic rhinitis. METHODS: Patients were randomized to receive a 6-week treatment with either topical corticosteroid (n = 6) or a matched placebo (n = 6). Nasal inferior turbinate biopsy specimens were obtained from all subjects before and during allergen-induced late responses. By using immunocytochemistry, tissue sections were examined for the presence of MCP-1, MCP-3, and MCP-4 and for the phenotype of infiltrating cells within the nasal mucosa. In addition, double sequential immunocytochemistry was used to confirm the phenotype of MCP-immunoreactive positive cells. Furthermore, the effect of topical corticosteroids on the expression of MCPs and on the cellular infiltrate was also examined. RESULTS: MCP-1, MCP-3, and MCP-4 were expressed in all the baseline samples, with prominent staining observed within the nasal epithelium. Biopsy specimens taken after challenge exhibited significant upregulation in the expression of MCP-3 and MCP-4 (P <.001). On the other hand, this increase in response to allergen was reduced in patients pretreated with topical corticosteroids. Colocalization experiments revealed that the majority of MCP+ cells in the subepithelium were macrophages, followed by T cells and eosinophils. CONCLUSION: Our results demonstrate that allergen-induced rhinitis is associated with an increased expression of MCP-3 and MCP-4, which may be closely related to the influx of inflammatory cells and may thus contribute to the pathogenesis of allergic rhinitis.

Th-2 type cytokine receptors in allergic rhinitis and in response to topical steroids.

OBJECTIVES: Th-2 type cytokine production (Interleukin-4 [IL-4] and interleukin-5 [IL5]) has been demonstrated to play a significant role in the pathophysiology of allergic rhinitis (AR), and the treatment of AR with topical corticosteroids has been shown to reduce the expression of Th-2 type cytokines in vivo. However, the contribution and expression of Th-2 type cytokine receptors in AR and their response to corticosteroid treatment remain to be clarified. Objectives of the current study are 1. To examine the expression of the cytokine IL-4 and IL-5 receptors (IL-4R and IL-5R) in a nasal allergen challenge model and to contrast this with the expression of the receptor for the Th-1 type cytokine, interferon-gamma receptor (IFN-gammaR), and 2. to examine the effects of pretreatment with topical corticosteroid before allergen challenge on the expression of these same receptors. STUDY DESIGN: Randomized prospective study involving 14 ragweed-allergic subjects evenly divided between placebo and corticosteroid pretreatment. METHODS: Immunocytochemistry (alkaline phosphatase-antialkaline phosphatase labeling [APAAP] technique) was used to stain nasal biopsy specimens before and after allergen challenge. Antibodies used included anti-CD3, CD4, CD8, major basic protein (MBP), IL-4R, IL-5R, and IFN-gammaR. RESULTS: Following allergen challenge, we observed a significant increase in the Th-2 type cytokine receptors (IL-4R and IL-5R; P<.05), as well as a significant decrease in the expression of the Th-1 type cytokine receptor (IFN-gammaR; P<.05). Pretreatment with topical corticosteroids before nasal allergen challenge resulted in decreased expression of IL-4R (P<.05) and IL-5R (P<.05) and increased expression of IFN-gammaR (P<.05). Further, IL-4R and IL-5R expression correlated with eosinophil infiltration in the tissues. CONCLUSIONS: We have demonstrated that in AR, cytokine receptors for IL-4, IL-5, and IFN-gamma follow a similar pattern to their ligands. In addition, pretreatment with topical corticosteroids was shown to alter the cytokine receptor expression pattern from a Th-2 profile more toward a Th-1 profile.

Th-2 type cytokine receptors in allergic rhinitis and in response to topical steroids.

OBJECTIVES: Th-2 type cytokine production (interleukin-4 [IL-4] and interleukin-5 [IL-5]) has been demonstrated to play a significant role in the pathophysiology of allergic rhinitis (AR), and the treatment of AR with topical corticosteroids has been shown to reduce the expression of Th-2 type cytokines in vivo. However, the contribution and expression of Th-2 type cytokine receptors in AR and their response to corticosteroid treatment remain to be clarified. Objectives of the current study are 1. To examine the expression of the cytokine IL-4 and IL-5 receptors (IL-4R and IL-5R) in a nasal allergen challenge model and to contrast this with the expression of the receptor for the Th-1 type cytokine, interferon-gamma receptor (IFN-gammaR), and 2. to examine the effects of pretreatment with topical corticosteroid before allergen challenge on the expression of these same receptors. STUDY DESIGN: Randomized prospective study involving 14 ragweed-allergic subjects evenly divided between placebo and corticosteroid pretreatment. METHODS: Immunocytochemistry (alkaline phosphatase-antialkaline phosphatase labeling [APAAP] technique) was used to stain nasal biopsy specimens before and after allergen challenge. Antibodies used included anti-CD3, CD4, CD8, MBP, IL-4R, IL-5R, and IFN-gammaR. RESULTS: Following allergen challenge, we observed a significant increase in the Th-2 type cytokine receptors (IL-4R and IL-5R; P < .05), as well as a significant decrease in the expression of the Th-1 type cytokine receptor (IFN-gammaR; P < .05). Pretreatment with topical corticosteroids before nasal allergen challenge resulted in decreased expression of IL-4R (P < .05) and IL-5R (P < .05) and increased expression of IFN-gammaR (P <.05). Further, IL-4R and IL-5R expression correlated with eosinophil infiltration in the tissues. CONCLUSIONS: We have demonstrated that in AR, cytokine receptors for IL-4, IL-5, and IFN-gamma follow a similar pattern to their ligands. In addition, pretreatment with topical corticosteroids was shown to alter the cytokine receptor expression pattern from a Th-2 profile more toward a Th-1 profile.