| 1. |
- Månsson, Anne, et al.
(författare)
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TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis.
- 2010
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Ingår i: International archives of allergy and immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 151:2, s. 118-28
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIM: Viral respiratory infections are increasingly implicated in allergic exacerbations. Virus-induced activation of eosinophils through Toll-like receptors (TLRs) could be involved. The present study was designed to examine TLR3 expression in eosinophils from bone marrow (BM) and peripheral blood (PB) during symptomatic allergic rhinitis, and to evaluate the functional responsiveness of TLR3 in purified eosinophils. METHODS: BM and PB samples were obtained from healthy volunteers and patients with seasonal allergic rhinitis outside and during the pollen season. Eosinophils were analyzed for TLR3 expression by flow cytometry. Polyinosinic:polycytidylic acid [poly(I:C)], an agonist for TLR3, was used to assess its functional role in purified eosinophils and the intracellular signaling pathways involved. RESULTS: TLR3 expression was demonstrated in BM and PB eosinophils. It was higher in BM-derived than in circulating cells and it was downregulated in both compartments during symptomatic allergic rhinitis. TLR3 expression was also downregulated in the presence of interleukin (IL)-4 and IL- 5. Stimulation with poly(I:C) increased the percentage of CD11b+ cells and enhanced the secretion of IL-8, effects mediated via the p38 mitogen-activated protein kinases and nuclear factor-kappaB signaling pathways. Moreover, pretreatment with IL-5 augmented the poly(I:C)-induced IL-8 release. CONCLUSIONS: Eosinophils activated via TLR3 might be more able to home and recruit leukocytes to sites of inflammation. The decreased TLR3 expression during symptomatic allergic rhinitis and in the presence of Th2 cytokines indicates a role in allergic airway inflammation. Thus, eosinophils might function as a link between viral infections and exacerbations of allergic disease.
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| 2. |
- Chavali, Sreenivas, et al.
(författare)
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MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases
- 2013
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Ingår i: Rna-a Publication of the Rna Society. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 19:11, s. 1552-1562
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.
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| 3. |
- Chavali, Sreenivas, et al.
(författare)
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Network properties of human disease genes with pleiotropic effects
- 2010
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Ingår i: BMC Systems Biology. - 1752-0509. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The phenotypic consequence of a human disease gene is largely affected by the topological position of its protein product in the molecular interaction network. Here, we investigated the differences in properties of specific human disease genes that are associated with one phenotype and shared genes with pleiotropic effects in the context of molecular interaction networks. We find that the shared genes have an intermediate centrality between essential and specific genes. Shared genes causing phenotypically divergent diseases (phenodiv genes) are more central to those causing phenotypically similar diseases (phenosim genes). Shared genes had higher number of disease gene interactors compared to specific genes, implying a higher likelihood of finding a novel disease gene in the network neighborhood of shared genes. Specific genes are more co-expressed with their interactors than shared genes. Relatively restricted tissue co-expression with interactors appears to be a function of shared genes leading to pleiotropy. We demonstrate essential and phenodiv genes with comparable connectivities (degrees) are intra-modular and inter-modular hubs with the former highly co-expressed with their interactors contrary to the phenodiv genes. Essential genes are predominantly nuclear proteins with transcriptional regulator activities while phenodiv genes are cytoplasmic proteins involved in signal transduction. Our results demonstrate that the ability of a disease gene to influence the cellular network determines its role in manifesting different and divergent diseases.
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| 4. |
- Clancy, Trevor, et al.
(författare)
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Immunological network signatures of cancer progression and survival.
- 2011
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Ingår i: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. METHODS: To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. RESULTS: The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. CONCLUSIONS: The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides.
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| 5. |
- Pedicini, Marco, et al.
(författare)
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Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation.
- 2010
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Ingår i: PLoS computational biology. - : Public Library of Science (PLoS). - 1553-7358 .- 1553-734X. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.
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| 6. |
- Schoenrock, A., et al.
(författare)
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Efficient prediction of human protein-protein interactions at a global scale
- 2014
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Ingår i: Bmc Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Our knowledge of global protein-protein interaction (PPI) networks in complex organisms such as humans is hindered by technical limitations of current methods. Results: On the basis of short co-occurring polypeptide regions, we developed a tool called MP-PIPE capable of predicting a global human PPI network within 3 months. With a recall of 23% at a precision of 82.1%, we predicted 172,132 putative PPIs. We demonstrate the usefulness of these predictions through a range of experiments. Conclusions: The speed and accuracy associated with MP-PIPE can make this a potential tool to study individual human PPI networks (from genomic sequences alone) for personalized medicine.
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| 7. |
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| 8. |
- Wang, Hui, et al.
(författare)
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Identification of novel biomarkers in seasonal allergic rhinitis by combining proteomic, multivariate and pathway analysis
- 2011
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Ingår i: Plos ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Abstract BACKGROUND: Glucocorticoids (GCs) play a key role in the treatment of seasonal allergic rhinitis (SAR). However, some patients show a low response to GC treatment. We hypothesized that proteins that correlated to discrimination between symptomatic high and low responders (HR and LR) to GC treatment might be regulated by GCs and therefore suitable as biomarkers for GC treatment. METHODOLOGY/PRINCIPAL FINDINGS: We identified 953 nasal fluid proteins in symptomatic HR and LR with a LC MS/MS based-quantitative proteomics analysis and performed multivariate analysis to identify a combination of proteins that best separated symptomatic HR and LR. Pathway analysis showed that those proteins were most enriched in the acute phase response pathway. We prioritized candidate biomarkers for GC treatment based on the multivariate and pathway analysis. Next, we tested if those candidate biomarkers differed before and after GC treatment in nasal fluids from 40 patients with SAR using ELISA. Several proteins including ORM (P<0.0001), APOH (P<0.0001), FGA (P<0.01), CTSD (P<0.05) and SERPINB3 (P<0.05) differed significantly before and after GC treatment. Particularly, ORM (P<0.01), FGA (P<0.05) and APOH (P<0.01) that belonged to the acute phase response pathway decreased significantly in HR but not LR before and after GC treatment. CONCLUSIONS/SIGNIFICANCE: We identified several novel biomarkers for GC treatment response in SAR with combined proteomics, multivariate and pathway analysis. The analytical principles may be generally applicable to identify biomarkers in clinical studies of complex diseases.
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| 9. |
- Åberg, Nils, 1943, et al.
(författare)
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A nasally applied cellulose powder in seasonal allergic rhinitis (SAR) in children and adolescents; reduction of symptoms and relation to pollen load.
- 2011
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Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley. - 1399-3038 .- 0905-6157. ; 22:6, s. 594-599
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Tidskriftsartikel (refereegranskat)abstract
- Åberg N, Dahl Å, Benson M. A nasally applied cellulose powder in seasonal allergic rhinitis (SAR) in children and adolescents; reduction of symptoms and relation to pollen load. Pediatr Allergy Immunol 2011: Doi: 10.1111/j.1399-3038.2011.01182.x. ABSTRACT: Background: A nasally applied cellulose powder is increasingly used in many countries as a remedy for allergic rhinitis. The absence of side effects makes the treatment particularly attractive in children. The efficacy in pollen allergic children, however, is not studied, nor is the relation to various pollen exposures. Methods: During the birch pollen season in 2009, a double blind, placebo-controlled study was conducted in 53 subjects, aged 8-18yr, with allergic rhinitis attributed to birch pollen. All children were on daily oral antihistamine. Reminders and reporting of symptom scores were made by SMS on mobile phones. Pollen was collected in a volumetric trap from which figures of pollen concentrations from 1979 to 2009 were available. Results: There was a significant reduction in total symptom scores from the nose (Placebo 7.29, Active 6.07, p=0.033) and specifically for running nose (Placebo 2.56, Active 2.03, p=0.017). All symptoms from the nose, eyes and lower airways were lower in the active group but reached significance only as earlier. The best effect was seen after days with low or moderate pollen counts (≤100/m(3) ), the predominating pollen load over 31yr in the area. No clinically significant adverse effects were seen. Conclusions: The product reduces symptoms of SAR in children and adolescents. Original data on pollen concentrations over 31yr are presented with levels mainly in the low range favouring the observed efficacy profile. SMS communication on mobile phone for reminders and recording symptom scores was an excellent logistics tool.
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