| 1. |
- Benson, Mikael, 1954, et al.
(författare)
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Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps.
- 2004
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 113:6, s. 1137-43
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes. OBJECTIVE: We sought to identify GC-regulated anti-inflammatory genes in nasal polyps. METHODS: Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects. RESULTS: Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps. CONCLUSION: Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.
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| 2. |
- Benson, Mikael, 1954, et al.
(författare)
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Altered levels of the soluble IL-1, IL-4 and TNF receptors, as well as the IL-1 receptor antagonist, in intermittent allergic rhinitis
- 2004
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Ingår i: Int Arch Allergy Immunol. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 134:3, s. 227-32
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The effects of cytokines are modulated by soluble cytokine receptors (SCR) and receptor antagonists. Therefore, allergic disease may depend on altered proportions between cytokines, their SCR and receptor antagonists, rather than absolute changes in cytokine levels. Little is known about SCR in intermittent allergic rhinitis (IAR). OBJECTIVE: To examine the concentrations of SCR, i.e. sIL-1R2, sIL-4R, sIL-6R and sTNFR1, as well as the interleukin-1 receptor antagonist (IL-1Ra) in nasal fluids from allergen-challenged patients with IAR and healthy controls. METHODS: 30 patients with birch- or grass-pollen-induced IAR and 30 healthy controls were studied. In the patients nasal fluids were obtained before as well as 1 and 6 h after allergen provocation. RESULTS: Both symptom scores and rhinoscopic signs of rhinitis increased in the patients after allergen challenge. Comparisons between patients and controls showed that sIL-4R was lower in patients before and 1 and 6 h after provocation. IL-1Ra was lower before and 1 h after provocation. In addition, lower concentrations of sTNFR1 were found in patients after 1 h, while sIL-1R2 concentrations were higher after 1 h. Comparisons of patients before and after challenge showed that IL-1Ra and sTNFR1 decreased after 1 h, while sIL-1R2 increased. No significant differences were found compared to 6 h. sIL-6R did not significantly differ between the study groups. CONCLUSIONS: After allergen challenge, significant changes in the nasal fluid levels of IL-1Ra, sIL-1R2 and sTNFR1 were found. By contrast, sIL-4R remained at lower levels than in controls both before and after challenge. Since sIL-4R modulates IgE synthesis, this may play a role in the pathogenesis of IAR.
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| 3. |
- Benson, Mikael, 1954
(författare)
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Cytokines and their soluble receptors in nasal fluids from school children with allergic rhinitis
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergic inflammation is associated with a shift in the balance between cytokines produced by two T helper subsets (Th1 and Th2) towards a preponderance of Th2 cells. Interleukin (IL)-4 is produced by Th2 cells and interferon-g (IFN-g) by Th1 cells. The ratio IL-4/IFN-g is often used as a marker of the balance between the cytokines. The effects of cytokines are modulated by soluble cytokine receptors (SCR). Aims: The general aim of the study was to find how Th1 and Th2 cytokines and their SCR regulate inflammatory cells and their products. For this nasal lavage fluid from school children with allergic rhinitis was examined as a local and in vivo model of allergic inflammation. A specific aim was to study the effects of topical treatment with glucocorticoids (GC) on Th1/Th2 cytokines, inflammatory cells and their products.Methods: Nasal fluids were obtained and handled in standardized ways: differential counts of inflammatory cells were measured by light microscopy, cytokine concentrations were assayed by ELISA; and eosinophil cationic protein (ECP) and IgE were determined by radioimmunoassay. Air pollen counts were determined daily by the Department of Botany in Göteborg.Material: Nasal lavage fluids from school children with allergic rhinitis and healthy controls were obtained before and during the pollen season, and from the allergic patients after treatment with a topical glucocorticoid. The study was performed during two consecutive pollen seasons, 1996 and 1997.Results: The nasal fluids were examined in a step-wise fashion, starting with Th1/Th2 cytokines. In the first study IL-4/IFN-g ratios were higher, and IFN-g levels lower in allergic patients during the pollen season compared to patients before season and compared to healthy controls. In the patients both IL-4/IFN-g ratios and IL-4 increased during the pollen season. In the second, larger, study these findings were repeated and in addition the Th2 cytokines IL-4, IL-5, and IL-10 - but not the Th1 cytokine IFN-g - were found to be higher in patients during than before the pollen season. Eosinophil counts and the levels of IgE and ECP in nasal fluid increased concurrently with development of clinical symptoms of rhinitis.In both studies IL-4 and IL-5 correlated with eosinophils, but not neutrophils, in the untreated patients with allergic rhinitis. Conversely, the neutrophil-associated chemokine IL-8 correlated with neutrophils, but not with eosinophils. In the second study the correlations between Th2 cytokines and IgE and ECP were analysed; IL-4, IL-5, IL-6 as well as IL-10 correlated with IgE and ECP.The soluble IL-4 receptor (IL-4sR), but neither IL-6sR, IL-1sR2, TNFsR1 nor TNFsR2 were found to increase in the patients during the pollen season. IL-4sR correlated with IgE and eosinophils. By contrast, none of the other soluble cytokine receptors correlated with IgE. Treatment with a topical glucocorticoid decreased the levels of IgE, ECP, and the Th2 cytokines IL-4, IL-5, IL-6, IL-10, but not IFN-g, nor the neutrophil associated cytokines IL-1b and TNF-a. In the treated patients IL-1b and TNF-a correlated with neutrophils and ECP, and IL-1b with eosinophils. Treated patients with high neutrophil counts had higher eosinophils and ECP, but not IgE, than patients with low counts.Conclusions: The results are compatible with the hypothesis that allergic rhinitis is causally related to a shift in the balance between Th1 and Th2 cytokines towards a Th2 predominance, possibly because of deficient IFN-g production. Correlation studies suggested that increase of the Th2 cytokines results in increased ECP, IgE and eosinophil counts. Theoretically the effects of the cytokines may be either inhibited or enhanced by SCR. Our findings of positive correlations between various SCR and either eosinophils, neutrophils, ECP or IgE might be explained by the existence of enhancing effects. Treatment with a topical steroid resulted in decrease of symptoms, eosinophils, ECP and IgE, but not of neutrophils. The treatment appeared to have a differential effect on cytokines, suppressing Th2 cytokines without any significant effect on the Th1 cytokine IFN-g. These effects of steroid treatment should be expected to be highly beneficial in view of the presumed, great importance of the Th1 and Th2 cytokine balance in the pathogenesis of allergic reactions.
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| 4. |
- Benson, Mikael, 1954, et al.
(författare)
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DNA microarray analysis of chromosomal susceptibility regions to identify candidate genes for allergic disease: A pilot study
- 2004
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 124:7, s. 813-819
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Tidskriftsartikel (refereegranskat)abstract
- Objective-To examine whether DNA microarray analysis of chromosomal susceptibility regions for allergy can help to identify candidate genes. Material and Methods-Nasal biopsies were obtained from 23 patients with allergic rhinitis and 12 healthy controls. RNA was extracted from the biopsies and pooled into three patient and three control pools. These were then analysed in duplicate with DNA microarrays containing 12626 genes. Candidate genes were further examined in nasal biopsies (real-time polymerase chain reaction) and blood samples (single nucleotide polymorphisms) from other patients with allergic rhinitis and from controls. Results-A total of 37 differentially expressed genes were identified according to criteria involving both the size and consistency of the gene expression levels. The chromosomal location of these genes was compared with the chromosomal susceptibility regions for allergic disease. Using a statistical method, five genes were identified in these regions, including serine protease inhibitor, Kazal type, 5 (SPINK5) and HLA-DRB2. The relevance of these genes was examined in other patients with allergic rhinitis and in controls; none of the genes were differentially expressed in nasal biopsies. Moreover, no association between allergic rhinitis and SPINK5 polymorphisms was found, at either the genotype or haplotype level. Conclusions-DNA microarray analysis of chromosomal susceptibility regions did not lead to identification of candidate genes that could be validated in a new material. However, because gene polymorphisms may cause differential gene expression, further studies, including validation data, are needed to examine this approach.
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| 5. |
- Benson, Mikael, 1954, et al.
(författare)
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DNA microarray analysis of transforming growth factor-β and related transcripts in nasal biopsies from patients with allergic rhinitis
- 2002
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Ingår i: Cytokine. ; 18:1, s. 20-25
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Tidskriftsartikel (refereegranskat)abstract
- Decreased activity of anti-inflammatory cytokines like transforming growth factor (TGF)-β may contribute to allergic inflammation. In vivo effects of TGF-β-effects are difficult to infer from local concentrations, since TGF-β-effects depend on a complex system of regulatory proteins and receptors. Instead the effects of TGF-β might be inferred by examining TGF-β-inducible transcripts. In this study DNA microarrays were used to examine local expression of TGF-β, TGF-β-regulatory and -inducible transcripts in nasal biopsies from patients with symptomatic allergic rhinitis and healthy controls. In addition, nasal fluids were analysed with cytological and immunological methods. Nasal fluid eosinophils, albumin, eosinophil granulae proteins and IgE, but not TGF-β, were higher in patients than in controls. DNA microarray analysis of nasal mucosa showed expression of transcripts encoding TGF-β, TGF-β-regulatory proteins and -receptors at variable levels in patients and controls. By comparison, analysis of 28 TGF-β-inducible transcripts indicated that 23 of these had lower measurement values in patients than in controls, while one was higher, and the remaining four were absent in both patients and controls. In summary, TGF-β and a complex system of regulatory genes and receptors are expressed in the nasal mucosa. Low expression of TGF-β-inducible transcripts may indicate decreased TGF-β activity in allergic rhinitis. DNA microarray analysis may be a way to study cytokine effects in vivo.
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| 6. |
- Benson, Mikael, 1954, et al.
(författare)
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DNA microarrays to study gene expression in allergic airways.
- 2002
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Ingår i: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. - : Wiley. - 0954-7894 .- 1365-2222. ; 32:2, s. 301-8
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Tidskriftsartikel (refereegranskat)abstract
- Allergic rhinitis results from interactions between a large number of cells and mediators in different compartments of the body. DNA microarrays allow simultaneous measurement of expression of thousands of genes in the same tissue sample.
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| 7. |
- Benson, Mikael, 1954, et al.
(författare)
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Increase of the soluble IL-4 receptor (IL-4sR) and positive correlation between IL-4sR and IgE in nasal fluids from school children with allergic rhinitis.
- 2000
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Ingår i: Allergy and asthma proceedings. - : OceanSide Publications. - 1088-5412 .- 1539-6304. ; 21:2, s. 89-95
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Tidskriftsartikel (refereegranskat)abstract
- Soluble cytokine receptors (SCR) can either act as inhibitors, by competitively inhibiting cytokines from binding to their membrane-bound receptors, or as enhancers, by serving as cytokine carriers. We have previously found that the levels of the Th2 cytokines interleukin (IL)-4, IL-5, IL-6, and IL-10 were positively correlated to eosinophils and IgE in nasal fluids from 60 children with seasonal allergic rhinitis. In this study, nasal fluids were reexamined to analyze IL-4sR, IL-6sR, IL-1 beta, TNF-alpha, IL-1sR2, TNF-sR1, and TNFsR2 in relation to eosinophils, neutrophils, ECP, and IgE. In allergic patients IL-4sR increased significantly during the pollen season, and weak, but positive correlations with IgE and eosinophils were found (r = 0.45, P < 0.001 and r = 0.4, P < 0.001 respectively). By contrast, none of the other SCR showed increases or correlations with IgE. However, positive correlations between IL1 beta, TNF-alpha, IL-6sR, IL-1sR2, TNF-sR1, TNF-sR2, and either neutrophils or ECP were found. Also, in healthy controls, these cytokines and their receptors were positively correlated to neutrophils or ECP. Thus, increased levels of the soluble IL-4 receptor, as well as IgE, were specifically associated with allergic rhinitis, whereas all other SCR correlated with either inflammatory cells or their products, in both allergic and healthy subjects. These results may suggest that SCR in vivo act as cytokine enhancers, rather than inhibitors.
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| 8. |
- Benson, Mikael, 1954, et al.
(författare)
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Increased expression of Vascular Endothelial Growth Factor-A in seasonal allergic rhinitis.
- 2002
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 20:6, s. 268-73
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Tidskriftsartikel (refereegranskat)abstract
- Increased vascular dilatation and permeability characterize allergic rhinitis. In this study oligonucleotide microarrays (Affymetrix HuGe95A) were used to identify differentially expressed vasoactive genes in nasal biopsies from 23 patients with symptomatic seasonal allergic rhinitis (SAR) and 12 healthy controls. RNA was extracted from the biopsies and pooled in three patient and three control pools. Out of 12,626 analysed transcripts, 39 were higher and 81 lower in the patients. Of these transcripts two have vasoactive effects: Vascular Endothelial Growth Factor-A (VEGF-A) and the Beta-1-Adrenergic Receptor. Both were higher in patients than in controls. The mean +/- SEM expression levels in arbitrary units of VEGF-A were 130 +/- 123 in the patients and 59 +/- 53 in the controls. The fold ratio in expression levels between patients/controls was 2.2. The corresponding values for the beta-1-adrenergic receptor were 129 +/- 123 in the patients and 40 +/- 31 in the controls. The fold ratio between patient/controls was 3.2. The role of VEGF-A was assessed by determining VEGF-A concentrations in nasal fluids from another 30 patients with SAR before and after allergen provocation. VEGF-A increased from 124.3 +/- 30.2 to 163.2 +/- 37.8 pg/ml after challenge, P < 0.05. In summary, oligonucleotide microarray analysis of nasal biopsies and protein analyses of nasal fluids indicate that VEGF-A may be an important mediator in SAR.
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| 9. |
- Benson, Mikael, 1954, et al.
(författare)
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Low levels of interferon-gamma in nasal fluid accompany raised levels of T-helper 2 cytokines in children with ongoing allergic rhinitis.
- 2000
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Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley-Blackwell. - 0905-6157 .- 1399-3038. ; 11:1, s. 20-8
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Tidskriftsartikel (refereegranskat)abstract
- The T-helper 2 (Th2) cytokines interleukin-(IL-) 4, IL-5, IL-6, IL-10 and the Th1 cytokine IFN-gamma and their associations with eosinophil, eosinophil cationic protein (ECP) and immunoglobulin (Ig) E were studied in nasal lavage fluid from 60 school children with allergic seasonal rhinitis and 36 nonatopic healthy controls, before and during the pollen season. Eosinophil differential counts and IgE increased significantly in the patients during the pollen season. The eosinophil differential counts, ECP and IgE were all significantly higher during the season than in specimens simultaneously obtained from the nonatopic controls. Before season, the levels of ECP and IgE, but not eosinophils, were significantly higher in the patients than in the controls. During the season the nasal lavage fluid levels of IFN-gamma were significantly lower and the IL-4/IFN-gamma quotients significantly higher in the allergic than in the control children. In the allergic children, but not in the controls, the nasal fluid levels of the Th2 cytokines IL-4, IL-5 and IL-10 increased during the season, and together with IL-6, were correlated with the differential counts of eosinophils, and with the levels of ECP and IgE. These findings are compatible with the hypothesis that a deficient release of the Th1 cytokine IFN-gamma plays an important role in the pathogenesis of allergic inflammation. Regardless of whether the defective IFN-gamma secretion is primary or a consequence of suppression by other cytokines, it will in the atopic subjects enhance the release of Th2 cytokines, which in turn will facilitate the development of allergic inflammation.
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| 10. |
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