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- Bergin, Ann-Marie, 1975
(author)
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Functional genetics of the interleukin-4 receptors in allergic asthma
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Asthma is a complex disorder, with both genetic and environmental factors contributing to disease development. Our aim was to analyse possible associations between genetic variations of immunologically important genes and the susceptibility to and severity of allergic asthma in adults. For this purpose we used the candidate gene approach in a well-defined subgroup of allergic asthma. We investigated polymorphisms in the various genes, CD14, CLEC4E, DNAJA2, HARS, IL4R, IL10, TBX21, TGFB1, TNF and CIITA, by dynamic allele-specific hybridization (DASH), TaqMan allelic discrimination, LightCycler allelic discrimination or restriction endonuclease mapping. We found that polymorphisms in the IL4R gene associated with susceptibility to the disease and that soluble and membrane bound IL-4R forms were differently expressed in allergic asthma patients compared to non-asthmatic controls. To validate the impact of IL4R polymorphisms on the expression of the IL-4R splice forms, we used the minigene assay, a method frequently applied to investigate alternative splicing. The results demonstrated significant differences in the expression of the soluble form as an effect of four genetic variations flanking the alternative exon 8 of the IL4R gene. Polymorphisms in the specific regulator of MHC class II expression, the class II transactivator, CIITA gene, had previously been associated with inflammatory diseases and expression of both CIITA and HLA-DRA. We investigated CIITA and HLA-DRA together with the soluble and membrane bound IL-4R expression, in cultured peripheral blood mononuclear cells from allergic patients and non-allergic controls, as candidates for pathways responsive to IL-4 and IFN-gamma stimulation. Adult allergic patients showed increasing response to IL-4 stimulation and non-responsiveness towards IFN-gamma induction, which was manifested by an altered CIITA and IL-4R expression. The results also demonstrated a possible functional link between the CIITA and IL-4 pathways in the human immune system.In conclusion, variations in the IL4R gene associate with susceptibility to allergic asthma in Swedish Caucasians. Furthermore soluble IL-4R can be seen as a marker for allergic asthma, but even though genetic variations in the IL4R gene have a direct effect on expression levels of the two different splice forms, they do not explain the differences in IL4R levels seen between asthmatic and non-asthmatic individuals. Furthermore, allergic individuals show a CIITA independent upregulation of HLA-DRA, possibly through the IL-4 pathway.
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- Calander, Ann-Marie, 1957, et al.
(author)
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Matrix metalloproteinase-9 (gelatinase B) deficiency leads to increased severity of Staphylococcus aureus-triggered septic arthritis.
- 2006
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In: Microbes and infection / Institut Pasteur. - : Elsevier BV. - 1286-4579. ; 8:6, s. 1434-9
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Journal article (peer-reviewed)abstract
- Matrix metalloproteinases constitute a family of structurally related endopeptidases that are crucial for the normal turnover of the extracellular matrix. Elevated levels of MMP-9 have been demonstrated in synovial fluids of rheumatoid arthritis patients, and a correlation with the severity of the disease has been described. The aim of this study was to explore the impact of MMP-9 expression on joint inflammation and destruction in a model of bacterially induced septic arthritis. MMP-9 knock-out mice and C57Bl6 congenic controls were inoculated intravenously or intra-articularly with Staphylococcus aureus. Arthritis was evaluated clinically and by means of histology. Zymographic analyses were performed to study ex vivo induction of MMP-9 following exposure to S. aureus. The MMP-9 knock-out mice displayed a significantly higher frequency and severity, but not destructivity, of arthritis than did the wild-type mice. The knock-out mice also proved to harbour an increased number of bacteria locally in joints and systemically in kidneys, possibly by impaired extravasation and recruitment of leukocytes and a deficient early defence against infection. Our findings indicate that deficiency in MMP-9 increases the degree of joint inflammation due to decreased bacterial clearance.
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- Hesselmar, Bill, 1955, et al.
(author)
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Interleukin-4 receptor polymorphisms in asthma and allergy: relation to different disease phenotypes.
- 2010
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In: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 99:3, s. 399-403
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Journal article (peer-reviewed)abstract
- Aim: Inheritance and genetic factors are supposed to influence susceptibility to asthma and allergy. We tested if single nucleotide polymorphisms (SNPs) in the IL4R gene were associated with susceptibility to such diseases, or if they were related to the phenotypic presentation of asthma and allergic rhinoconjunctivitis (ARC). Methods: Three hundred and nine 12- to 13-year-old children were included. Six SNPs in the IL4R were analysed in response to current allergic disease, and to presentation of specific asthma and ARC phenotypes. Questionnaires were used to determine allergic disease status, and skin prick tests to evaluate sensitization to common airborne allergens. Results: Less eczema was seen in individuals with the AA-genotype of rs2057768, and less ARC among those with the AA-genotype of rs2107356, especially ARC associated with sensitization to pollen. The AA-genotype of rs2057768 and the TT genotype of rs3024632 were associated with a specific asthma phenotype. Conclusion: Variations within the IL4R gene are associated with allergic diseases in children, preferably with eczema and disease phenotypes of ARC and asthma.
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- Holmén, Nathalie, 1979, et al.
(author)
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Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity.
- 2006
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In: Inflammatory bowel diseases. - 1078-0998. ; 12:6, s. 447-56
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Journal article (peer-reviewed)abstract
- BACKGROUND: Factors determining the extension and degree of inflammation in the colonic mucosa of patients with ulcerative colitis (UC) are largely unknown, but CD4+CD25high regulatory T cells (Tregs) have been implicated to play an important role in suppressing inflammation. Therefore, the aims of this study were to determine whether colonic Tregs have suppressive effects on colonic effector T cells in UC and to analyze the association between segmental colonic Treg distribution and disease activity. MATERIALS AND METHODS: The suppressive activity of colonic CD4+CD25high Tregs from patients with active UC was determined in coculture assays measuring proliferation and cytokine production. The frequency of Tregs and the expression of the Treg marker FOXP3 were analyzed with flow cytometry and RT-PCR in isolated cells and the whole mucosa from patients with active and inactive disease, as well as healthy mucosa. RESULTS: Colonic CD4+CD25high T cells from patients with UC suppressed the proliferation and cytokine secretion of colonic effector CD4+ T cells. Healthy controls but not patients with UC had lower Treg frequencies in the sigmoid than in the ascending colon. Patients with UC with active disease had increased frequency of colonic Tregs. The frequency of Tregs was positively correlated with colonic disease activity and serum C-reactive protein. CONCLUSIONS: Colonic CD4+CD25high Tregs are able to suppress colonic effector T cell activity in vitro, and the Treg frequency in the inflamed intestine increases with disease activity in patients with active UC. This suggests that Tregs may be outnumbered by other inflammatory cells or that their suppressive activity may be influenced by the in vivo environment.
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