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  • 1.
    Adner, Mikael
    et al.
    Malmö University Hospital, Sweden.
    Rose, Andrew C
    Johnson and Johnson Pharmaceutical Research and Development, La Jolla, California, USA.
    Zhang, Yaping
    Malmö University Hospital, Sweden.
    Swärd, Karl
    Lund University, Sweden.
    Benson, Mikael
    Malmö University Hospital, Sweden.
    Uddman, Rolf
    Malmö University Hospital, Sweden.
    Shankley, Nigel P
    Johnson and Johnson Pharmaceutical Research and Development, La Jolla, California, USA.
    Cardell, Lars-Olaf
    Malmö University Hospital, Sweden.
    An assay to evaluate the long-term effects of inflammatory mediators on murine airway smooth muscle: evidence that TNFalpha up-regulates 5-HT(2A)-mediated contraction2002In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 137, no 7, p. 971-982Article in journal (Refereed)
    Abstract [en]

    1. Asthma research is arguably limited by an absence of appropriate animal models to study the pharmacology of inflammatory mediators that affect airway hyperresponsiveness and remodelling. Here we assessed an assay based on mouse tracheal segments cultured for 1-32 days, and investigated contractile responses mediated by muscarinic and 5-hydroxytryptamine (5-HT) receptors following long-term exposure to tumour necrosis factor-alpha (TNFalpha). 2. Following culture, in the absence of TNFalpha, maximum contractile responses to KCl and carbachol were similar, with an increase in response up to day two and a decrease to a stable level after 8 days. Maximal relaxations to isoprenaline were not affected by the culture procedure. The potency of KCl and isoprenaline increased throughout the study. DNA microarray data revealed that global gene expression changes were greater when tissues were introduced to culture than when they were maintained in culture. The morphology of smooth muscle cells was maintained throughout the culture period. 3. 5-HT induced a weak contraction in both fresh and cultured (up to 8 days) segments. Culture with TNFalpha produced a time- and concentration-dependent increase in the maximal contraction to 5-HT, evidently mediated by 5-HT(2A) receptors, whereas, the potency for carbachol was reduced. 4. In conclusion, the phenotype of airway smooth muscle remained largely intact during the culture period, even though minor changes were obtained during the first days of culture. The time-dependent effect of TNFalpha indicates the importance of studying the long-term effect of cytokines on the smooth muscle cells in relation to airway hyperresponsiveness and remodelling.

  • 2.
    Auffray, Charles
    et al.
    European Institute Syst Biol and Med, France; University of Lyon, France.
    Balling, Rudi
    University of Luxembourg, Luxembourg.
    Barroso, Ines
    Wellcome Trust Sanger Institute, England.
    Bencze, Laszlo
    Semmelweis University, Hungary.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Bergeron, Jay
    Pfizer Inc, MA 02139 USA.
    Bernal-Delgado, Enrique
    IACS IIS Aragon, Spain.
    Blomberg, Niklas
    EL IXIR, England.
    Bock, Christoph
    Austrian Academic Science, Austria; Medical University of Vienna, Austria; Max Planck Institute Informat, Germany.
    Conesa, Ana
    Principe Felipe Research Centre, Spain; University of Florida, FL 32610 USA.
    Del Signore, Susanna
    Bluecompan Ltd, England.
    Delogne, Christophe
    KPMG Luxembourg, Luxembourg.
    Devilee, Peter
    Leiden University, Netherlands.
    Di Meglio, Alberto
    European Org Nucl Research CERN, Switzerland.
    Eijkemans, Marinus
    University of Utrecht, Netherlands.
    Flicek, Paul
    European Bioinformat Institute EMBL EBI, England.
    Graf, Norbert
    University of Saarland, Germany.
    Grimm, Vera
    Forschungszentrum Julich, Germany.
    Guchelaar, Henk-Jan
    Leiden University, Netherlands.
    Guo, Yi-Ke
    University of London Imperial Coll Science Technology and Med, England.
    Glynne Gut, Ivo
    BIST, Spain.
    Hanbury, Allan
    TU Wien, Austria.
    Hanif, Shahid
    Assoc British Pharmaceut Ind, England.
    Hilgers, Ralf-Dieter
    University of Klinikum Aachen, Germany.
    Honrado, Angel
    SYNAPSE Research Management Partners, Spain.
    Rod Hose, D.
    University of Sheffield, England.
    Houwing-Duistermaat, Jeanine
    University of Leeds, England.
    Hubbard, Tim
    Kings Coll London, England; Genom England, England.
    Helen Janacek, Sophie
    European Bioinformat Institute EMBL EBI, England.
    Karanikas, Haralampos
    University of Athens, Greece.
    Kievits, Tim
    Vitr Healthcare Holding BV, Netherlands.
    Kohler, Manfred
    Fraunhofer Institute Molecular Biol and Appl Ecol ScreeningPor, Germany.
    Kremer, Andreas
    ITTM SA, Luxembourg.
    Lanfear, Jerry
    Pfizer Ltd, England.
    Lengauer, Thomas
    Max Planck Institute for Informatics, Saarbrucken, Germany.
    Maes, Edith
    Health Econ and Outcomes Research, Belgium.
    Meert, Theo
    Janssen Pharmaceut NV, Belgium.
    Mueller, Werner
    University of Manchester, England.
    Nickel, Dorthe
    Institute Curie, France.
    Oledzki, Peter
    Linguamat Ltd, England.
    Pedersen, Bertrand
    PwC Luxembourg, Luxembourg.
    Petkovic, Milan
    Philips, Netherlands.
    Pliakos, Konstantinos
    KU Leuven Kulak, Belgium.
    Rattray, Magnus
    University of Manchester, England.
    Redon i Mas, Josep
    University of Valencia, Spain.
    Schneider, Reinhard
    University of Luxembourg, Luxembourg.
    Sengstag, Thierry
    SIB, Switzerland; University of Basel, Switzerland.
    Serra-Picamal, Xavier
    Agency Health Qual and Assessment Catalonia AQuAS, Spain.
    Spek, Wouter
    EuroBioForum Fdn, Netherlands.
    Vaas, Lea A. I.
    Fraunhofer Institute Molecular Biol and Appl Ecol ScreeningPor, Germany.
    van Batenburg, Okker
    EuroBioForum Fdn, Netherlands.
    Vandelaer, Marc
    Integrated BioBank Luxembourg, Luxembourg.
    Varnai, Peter
    Technopolis Grp, England.
    Villoslada, Pablo
    Hospital Clin Barcelona, Spain.
    Antonio Vizcaino, Juan
    European Bioinformat Institute EMBL EBI, England.
    Peter Mary Wubbe, John
    European Platform Patients Org Science and Ind Epposi, Belgium.
    Zanetti, Gianluigi
    CRS4, Italy; BBMRI ERIC, Austria.
    Making sense of big data in health research: Towards an EU action plan2016In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 8, no 71Article in journal (Refereed)
    Abstract [en]

    Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health arid healthcare for all Europearis.

  • 3.
    Barrenäs, Fredrik
    et al.
    The Unit for Clinical Systems Biology, Department of Pediatrics, The Queen Silvia Children’s Hospital, Göteborg, Sweden.
    Andersson, Bengt
    The Department of Microbiology and Immunology, Göteborg University, Sweden.
    Cardell, Lars Olaf
    Laboratory for Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Malmö, Sweden.
    Langston, Michael
    Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA.
    Mobini, Reza
    The Unit for Clinical Systems Biology, Department of Pediatrics, The Queen Silvia Children’s Hospital, Göteborg, Sweden.
    Perkins, Andy
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, TN, USA.
    Soini, Juhani
    Centre for Biotechnology, University of Turku and Åbo Academy University, Finland.
    Ståhl, Arne
    The Allergy Laboratory, Göteborg University, Sweden.
    Benson, Mikael
    The Unit for Clinical Systems Biology, Department of Pediatrics, The Queen Silvia Children’s Hospital, Sweden.
    Gender differences in inflammatory proteins and pathways in seasonal allergic rhinitis2008In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 42, no 3, p. 325-329Article in journal (Refereed)
    Abstract [en]

    In model organisms, thousands of genes differ in expression between females and males. It is not known if differences on a similar scale are found in humans nor how this relates to disease. However, in allergic disease gender differences in the levels of both inflammatory cells and proteins have been shown. In this study, we found lower nasal fluid allergen-specific IgE in women than men with seasonal allergic rhinitis (SAR). This led to genome-wide analyses of gene expression in allergen-challenged CD4(+) cells from patients with SAR before and after treatment with cortisone. Before treatment, 975 genes differed in expression between women and men: 337 were higher in women. After treatment only 428 genes and one pathway differed in expression. The genes that differed in expression between women and men were over-represented in 10 pathways. Five of the pathways regulated chemotaxis. All five were less active in women. One of the pathways was induced by the eosinophilic chemokine CCL4. Analysis of nasal fluid CCL4 protein confirmed lower levels in women with seasonal allergic rhinitis, before and during the pollen season. By contrast, nasal fluid CCL3 levels did not differ between the genders. In summary, this study shows gender differences in specific inflammatory pathways and proteins in patients with seasonal allergic rhinitis. Further studies are warranted to examine if such differences have diagnostic and therapeutic implications in allergic diseases.

  • 4.
    Barrenäs, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bruhn, Sören
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, University of Gothenburg, Gothenburg, Sweden.
    Langston, Michael A
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, USA.
    Nestor, Colm
    Östergötlands Läns Landsting.
    Rogers, Gary
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, USA .
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Disease-Associated MRNA Expression Differences in Genes with Low DNA Methylation2012Manuscript (preprint) (Other academic)
    Abstract [en]

    Although the importance of DNA methylation for mRNA expression has been shown for individualgenes in several complex diseases, such a relation has been difficult to show on a genome-wide scale.Here, we used microarrays to examine the relationship between DNA methylation and mRNAexpression in CD4+ T cells from patients with seasonal allergic rhinitis (SAR) and healthy controls.SAR is an optimal disease model because the disease process can be studied by comparing allergenchallengedCD4+ T cells obtained from patients and controls, and mimicked in Th2 polarised T cellsfrom healthy controls. The cells from patients can be analyzed to study relations between methylationand mRNA expression, while the Th2 cells can be used for functional studies. We found that DNAmethylation, but not mRNA expression clearly separated patients from controls. Similar to studies ofother complex diseases, we found no general relation between DNA methylation and mRNAexpression. However, when we took into account the absence or presence of CpG islands in thepromoters of disease associated genes an association was found: low methylation genes without CpGislands had significantly higher expression levels of disease-associated genes. This association wasconfirmed for genes whose expression levels were regulated by a transcription factor of knownrelevance for allergy, IRF4, using combined ChIP-chip and siRNA mediated silencing of IRF4expression. In summary, disease-associated increases of mRNA expression were found in lowmethylation genes without CpG islands in CD4+ T cells from patients with SAR. Further studies arewarranted to examine if a similar association is found in other complex diseases.

  • 5.
    Barrenäs, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Chavali, Sreenivas
    MRC-Laboratory of Molecular Biology, University of Cambridge, Hills Road, Cambridge, CB2 0QH, UK.
    Alves, Alexessander Couto
    Department of Genomics of Common Disease, School of Public Health, Imperial College, UK.
    Coin, Lachlan
    Department of Genomics of Common Disease, School of Public Health, Imperial College, UK.
    Jarvelin, Marjo-Riitta
    Department of Genomics of Common Disease, School of Public Health, Imperial College, UK.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, University of Gothenburg, Gothenburg, Sweden.
    Langston, Michael A
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, USA .
    Ramasamy, Adaikalavan
    Department of Genomics of Common Disease, School of Public Health, Imperial College, London, UK .
    Rogers, Gary
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, USA .
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Highly interconnected genes in disease-specific networks are enriched for disease-associated polymorphisms2012In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 6, p. R46-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Complex diseases are associated with altered interactions between thousands of genes. We developed a novel method to identify and prioritize disease genes, which was generally applicable to complex diseases.

    RESULTS: We identified modules of highly interconnected genes in disease-specific networks derived from integrating gene-expression and protein interaction data. We examined if those modules were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. First, we analyzed publicly available gene expression microarray and genome-wide association study (GWAS) data from 13, highly diverse, complex diseases. In each disease, highly interconnected genes formed modules, which were significantly enriched for genes harboring disease-associated SNPs. To test if such modules could be used to find novel genes for functional studies, we repeated the analyses using our own gene expression microarray and GWAS data from seasonal allergic rhinitis. We identified a novel gene, FGF2, whose relevance was supported by functional studies using combined small interfering RNA-mediated knock-down and gene expression microarrays. The modules in the 13 complex diseases analyzed here tended to overlap and were enriched for pathways related to oncological, metabolic and inflammatory diseases. This suggested that this union of the modules would be associated with a general increase in susceptibility for complex diseases. Indeed, we found that this union was enriched with GWAS genes for 145 other complex diseases.

    CONCLUSIONS: Modules of highly interconnected complex disease genes were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies.

  • 6.
    Barrenäs, Fredrik
    et al.
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Chavali, Sreenivas
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Holme, Petter
    Department of Physics, Umeå University, Umeå, Sweden; Department of Energy Science, Sungkyunkwan University, Suwon, Korea.
    Mobini, Reza
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Benson, Mikael
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Network properties of complex human disease genes identified through genome-wide association studies2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 11, p. e8090-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias.

    PRINCIPAL FINDINGS: We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process.

    CONCLUSIONS: This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.

  • 7.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Clinical implications of omics and systems medicine: focus on predictive and individualized treatment2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 3, p. 229-240Article, review/survey (Refereed)
    Abstract [en]

    Many patients with common diseases do not respond to treatment. This is a key challenge to modern health care, which causes both suffering and enormous costs. One important reason for the lack of treatment response is that common diseases are associated with altered interactions between thousands of genes, in combinations that differ between subgroups of patients who do or do not respond to a given treatment. Such subgroups, or even distinct disease entities, have been described recently in asthma, diabetes, autoimmune diseases and cancer. High-throughput techniques (omics) allow identification and characterization of such subgroups or entities. This may have important clinical implications, such as identification of diagnostic markers for individualized medicine, as well as new therapeutic targets for patients who do not respond to existing drugs. For example, whole-genome sequencing may be applied to more accurately guide treatment of neurodevelopmental diseases, or to identify drugs specifically targeting mutated genes in cancer. A study published in 2015 showed that 28% of hepatocellular carcinomas contained mutated genes that potentially could be targeted by drugs already approved by the US Food and Drug Administration. A translational study, which is described in detail, showed how combined omics, computational, functional and clinical studies could identify and validate a novel diagnostic and therapeutic candidate gene in allergy. Another important clinical implication is the identification of potential diagnostic markers and therapeutic targets for predictive and preventative medicine. By combining computational and experimental methods, early disease regulators may be identified and potentially used to predict and treat disease before it becomes symptomatic. Systems medicine is an emerging discipline, which may contribute to such developments through combining omics with computational, functional and clinical studies. The aims of this review are to provide a brief introduction to systems medicine and discuss how it may contribute to the clinical implementation of individualized treatment, using clinically relevant examples.

  • 8.
    Benson, Mikael
    Sahlgrenska University Hospital, Göteborg.
    Cytokiner och deras lösliga receptorer vid allergisk rinit2001In: Incitament, ISSN 1103-503x, Vol. 10, no 3, p. 211-217Article in journal (Other academic)
  • 9.
    Benson, Mikael
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Pathophysiological effects of glucocorticoids on nasal polyps: an update2005In: Current Opinion in Allergy and Clinical Immunology, ISSN 1528-4050, E-ISSN 1473-6322, Vol. 5, no 1, p. 31-35Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: The exact mechanisms by which glucocorticoids exert their beneficial effects on nasal polyps are not clearly defined. Nasal polyps, asthma and allergic rhinitis share common features such as mucosal infiltration with eosinophils and mast cells as well as local IgE production. The present review is an update on the pathophysiological mechanisms of glucocorticoids on nasal polyps described during the last 2 years.

    RECENT FINDINGS: The reduction of leukocyte numbers in nasal polyps following glucocorticoid treatment depends on several mechanisms, for example altered balance between the two isoforms of the human glucocorticoid receptors, GRalpha and GRbeta. Another explanation may be inhibition of CD4+ T by CD8+ T cells. Increased expression of the antiinflammatory cytokine transforming growth factor beta may contribute to this. A DNA microarray study which examined the expression of some 22 000 genes showed increased expression of several antiinflammatory genes in nasal polyps after treatment with glucocorticoids. The antiinflammatory gene that increased most was uteroglobin (also known as Clara cell protein 16) which is abundantly expressed in airway secretions and thought to have an important role in regulating inflammation.

    SUMMARY: Glucocorticoids affect both pro and antiinflammatory pathways in nasal polyps. Upregulation of antiinflammatory genes such as transforming growth factor beta and uteroglobin may play an important role. Elucidation of these mechanisms may help us to understand not only the effects of glucocorticoids on nasal polyps, but also on related disorders such as allergic rhinitis and asthma.

  • 10.
    Benson, Mikael
    et al.
    Malmö General Hospital, Sweden.
    Adner, M
    Malmö General Hospital, Sweden.
    Cardell, L O
    Malmö General Hospital, Sweden.
    Cytokines and cytokine receptors in allergic rhinitis: how do they relate to the Th2 hypothesis in allergy?2001In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 31, no 3, p. 361-367Article in journal (Refereed)
  • 11.
    Benson, Mikael
    et al.
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Adrian, Katrin
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Falkenberg, Cecilia
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Larsson, Anna-Karin
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Rosberg, Sten
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Wennergren, Göran
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Wåhlander, Håkan
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Kjellmer, Ingemar
    Sahlgrenska Universitetssjukhuset/Östra, Göteborg.
    Åberg, Björn
    NUsjukhuset, Trollhättan.
    Interaktivt träningsprogram för studenter i Göteborg. Utbildning i pediatrik på internet: [An interactive training program for students in Gothenburg. Education in pediatrics on the Internet]1997In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 94, no 51-52, p. 4928-4930Article in journal (Refereed)
    Abstract [sv]

    Utbildning via Internet erbjuds medicine studerande före tjänstgöring på barnakuten vid Sahlgrenska Universitetssjukhuset/ Östra. Programmet tar upp vanliga och viktiga problem på en barnmedicinsk akutmottagning samt visar hur dessa kan lösas.

  • 12.
    Benson, Mikael
    et al.
    Central Hospital, Helsingborg, Sweden.
    Blennow, G
    University Hospital, Lund, Sweden.
    Rosén, I
    University Hospital, Lund, Sweden.
    Intrathecal immunoglobulin production and minor motor seizures1987In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 76, no 1, p. 147-150Article in journal (Refereed)
    Abstract [en]

    Five infants with idiopathic infantile minor motor seizures had an elevated immunoglobulin G (IgG) index ((cerebrospinal fluid IgG/serum IgG):(cerebrospinal fluid albumin/serum albumin)). The infants had prolonged prodromal symptoms, and bad prognosis. It is suggested that immunological mechanisms may contribute to the pathophysiology in certain cases of infantile spasms.

  • 13.
    Benson, Mikael
    et al.
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Breitling, Rainer
    Groningen Bioinformatics Centre, University of Groningen, The Netherlands.
    Network theory to understand microarray studies of complex diseases2006In: Current molecular medicine, ISSN 1566-5240, E-ISSN 1875-5666, Vol. 6, no 6, p. 695-701Article in journal (Refereed)
    Abstract [en]

    Complex diseases, such as allergy, diabetes and obesity depend on altered interactions between multiple genes, rather than changes in a single causal gene. DNA microarray studies of a complex disease often implicate hundreds of genes in the pathogenesis. This indicates that many different mechanisms and pathways are involved. How can we understand such complexity? How can hypotheses be formulated and tested? One approach is to organize the data in network models and to analyze these in a top-down manner. Globally, networks in nature are often characterized by a small number of highly connected nodes, while the majority of nodes have few connections. The highly connected nodes serve as hubs that affect many other nodes. Such hubs have key roles in the network. In yeast cells, for example, deletion of highly connected proteins is associated with increased lethality, compared to deletion of less connected proteins. This suggests the biological relevance of networks. Moving down in the network structure, there may be sub-networks or modules with specific functions. These modules may be further dissected to analyze individual nodes. In the context of DNA microarray studies of complex diseases, gene-interaction networks may contain modules of co-regulated or interacting genes that have distinct biological functions. Such modules may be linked to specific gene polymorphisms, transcription factors, cellular functions and disease mechanisms. Genes that are reliably active only in the context of their modules can be considered markers for the activity of the modules and may thus be promising candidates for biomarkers or therapeutic targets. This review aims to give an introduction to network theory and how it can be applied to microarray studies of complex diseases.

  • 14.
    Benson, Mikael
    et al.
    Drottning Silvias barn- och ungdomssjukhus, Göteborg.
    Cardell, Lars Olaf
    Universitetssjukhuset MAS, Malmö.
    Hohmann, Stefan
    Göteborgs universitet.
    Jirstrand, Mats
    Fraunhofer-Chalmers centrum för industrimatematik, Göteborg.
    Langston, Michael
    University of Tennessee/ Oak Ridge National Laboratory, USA.
    Mobini, Reza
    Drottning Silvias barnsjukhus, Göteborg.
    Nerman, Olle
    Chalmers, Göteborg.
    Systembiologin kan förändra sjukvården radikalt. Ger underlag för individualiserad prediktion, prevention och behandling: [Systems biology can radically change health care. Basis for individualized prediction, prevention and treatment]2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 42, p. 3037-3041Article in journal (Refereed)
    Abstract [sv]

    Vanliga sjukdomar som allergi, diabetes och cancer är komplexa, dvs de beror på obalans mellan ett stort antal gener och miljöfaktorer, snarare än på enskilda »felande« gener. Det finns teknik för att samtidigt analysera mRNA- och proteinuttryck för alla människans gener. Detta har resulterat i väldiga datamängder, som kan bidra till att öka förståelsen av komplexa sjukdomar. Problemet är att strukturera och tolka informationen.

    Systembiologi syftar till att konstruera ett teoretiskt ramverk för att beskriva hur molekylära signalvägar och nätverk, snarare än enskilda molekyler, orsakar sjukdom. Detta har börjat ge kliniska resultat, tex individualiserad medicinering vid behandling av cancer.

    Inom de närmsta decennierna förutspås systembiologisk forskning få klinisk betydelse, inte bara för att individualisera behandling, utan även för att förutsäga eller förebygga sjukdomar. Läkemedelsindustrin gör också stora systembiologiska satsningar för att utveckla nya mediciner.

    Det är därför angeläget att svenska kliniker, forskare och beslutsfattare snarast tar ställning till hur klinisk systembiologisk forskning ska bedrivas i Sverige.

    I denna artikel ges en introduktion till nya tekniker för att samtidigt studera människans alla gener. Dessutom beskrivs systembiologiska principer för att tolka resultaten och vilka kliniska konsekvenser detta kan få.

  • 15.
    Benson, Mikael
    et al.
    Malmö University Hospital, Sweden.
    Carlsson, Björn
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carlsson, Lena M S
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mostad, Petter
    Chalmers Technical University, Gothenburg, Sweden.
    Svensson, Per-Arne
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Cardell, Lars-Olaf
    Malmö University Hospital, Sweden.
    DNA microarray analysis of transforming growth factor-beta and related transcripts in nasal biopsies from patients with allergic rhinitis2002In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 18, no 1, p. 20-25Article in journal (Refereed)
    Abstract [en]

    Decreased activity of anti-inflammatory cytokines like transforming growth factor (TGF)-beta may contribute to allergic inflammation. In vivo effects of TGF-beta-effects are difficult to infer from local concentrations, since TGF-beta-effects depend on a complex system of regulatory proteins and receptors. Instead the effects of TGF-beta might be inferred by examining TGF-beta-inducible transcripts. In this study DNA microarrays were used to examine local expression of TGF-beta, TGF-beta-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-beta, were higher in patients than in controls. DNA microarray analysis of nasal mucosa showed expression of transcripts encoding TGF-beta, TGF-beta-regulatory proteins and -receptors at variable levels in patients and controls. By comparison, analysis of 28 TGF-beta-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-beta and a complex system of regulatory genes and receptors are expressed in the nasal mucosa. Low expression of TGF-beta-inducible transcripts may indicate decreased TGF-beta activity in allergic rhinitis. DNA microarray analysis may be a way to study cytokine effects in vivo.

  • 16.
    Benson, Mikael
    et al.
    Malmö University Hospital and Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Carlsson, Björn
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carlsson, Lena M S
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wennergren, Göran
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Cardell, Lars Olaf
    Malmö University Hospital, Sweden.
    Increased expression of Vascular Endothelial Growth Factor-A in seasonal allergic rhinitis2002In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 20, no 6, p. 268-273Article in journal (Refereed)
    Abstract [en]

    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.

  • 17.
    Benson, Mikael
    et al.
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Carlsson, L.
    Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Gothenburg, Sweden.
    Guillot, G.
    INRA-MIA, Paris, France; Gothenburg Stochastic Centre, Chalmers University of Technology, Gothenburg, Sweden.
    Jernås, M.
    Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Gothenburg, Sweden.
    Langston, M. A.
    Department of Computer Science, University of Tennessee, Knoxville, TN, USA.
    Rudemo, M.
    Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Andersson, B.
    Department of Clinical Immunology, Sahlgrenska Academy, Gothenburg, Sweden.
    A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis2006In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 7, no 6, p. 514-521Article in journal (Refereed)
    Abstract [en]

    We performed a network-based analysis of DNA microarray data from allergen-challenged CD4(+) T cells from patients with seasonal allergic rhinitis. Differentially expressed genes were organized into a functionally annotated network using the Ingenuity Knowledge Database, which is based on manual review of more than 200,000 publications. The main function of this network is the regulation of lymphocyte apoptosis, a role associated with several genes of the tuber necrosis factor superfamily. The expression of TNFRSF4, one of the genes in this family, was found to be 48 times higher in allergen-challenged cells than in diluent-challenged cells. TNFRSF4 is known to inhibit apoptosis and to enhance Th2 proliferation. Examination of a different material of allergen-stimulated peripheral blood mononuclear cells showed a higher number of interleukin-4(+) type 2 CD4(+) T (Th2) cells in patients than in controls (P<0.01), as well as a higher number of non-apoptotic Th2 cells in patients (P<0.01). The number of Th2 cells expressing TNFRSF4, TNFSF7 and TNFRSF1B was also significantly higher in patients. Treatment with anti-TNFSF4 resulted in a significantly decreased number of Th2 cells (P<0.05). A logical inference from all this is that the proliferation of allergen-challenged Th2 cells is associated with a decreased apoptosis of Th2 cells and an increase in TNFRSF4 signalling.

  • 18.
    Benson, Mikael
    et al.
    Malmö University Hospital, Sweden.
    Carlsson, Lena
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Adner, Mikael
    Malmö University Hospital, Sweden.
    Jernås, Margareta
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rudemo, Mats
    Chalmers University of Technology, Gothenburg, Sweden.
    Sjögren, Anders
    Chalmers University of Technology, Gothenburg, Sweden.
    Svensson, Per Arne
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Uddman, Rolf
    Malmö University Hospital, Sweden.
    Cardell, Lars Olaf
    Malmö University Hospital, Sweden.
    Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps2004In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 113, no 6, p. 1137-1143Article in journal (Refereed)
    Abstract [en]

    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.

  • 19.
    Benson, Mikael
    et al.
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Fransson, M.
    Laboratory for Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Malmö, Sweden.
    Martinsson, T.
    Department of Clinical Genetics, Gothenburg, Sweden.
    Naluai, Å.T.
    Department of Clinical Genetics, Gothenburg, Sweden.
    Uddman, R.
    Laboratory for Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Malmö, Sweden.
    Cardell, L. O.
    Laboratory for Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Malmö, Sweden.
    Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis2007In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 62, no 2, p. 178-183Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Decreased levels of the anti-inflammatory Clara Cell Protein 16 (CC16) are found in intermittent allergic rhinitis (IAR) and asthma. In asthma this decrease has been associated with hyperreactivity and the A38G single nucleotide polymorphism (SNP). The aim of this study was to examine if IAR is associated with signs and symptoms of rhinitis and the A38G SNP.

    METHODS: Nasal fluid CC16 was analyzed in 20 patients with IAR before allergen challenge and 1 and 6 h after challenge, and from 28 healthy controls. The A38G SNP was analyzed in 80 patients with IAR and 106 controls. Nasal biopsies were obtained from three subjects in each group for immunohistochemical analysis of CC16.

    RESULTS: In the allergen-challenged patients symptoms and rhinoscopic signs of rhinitis increased after 1 h and normalized after 6 h. In contrast, nasal fluid CC16 decreased 1 h after allergen challenge and returned to baseline after 6 h. Nasal fluid CC16 levels did not differ from controls before and 6 h after challenge. Immunohistochemical investigation showed intense CC16 staining in the nasal epithelium of both patients before season and healthy controls, but weak staining in symptomatic patients during season. No significant association between the A38G SNP and IAR was found.

    CONCLUSION: There was an inverse relation between nasal fluid CC16 levels and symptoms and signs of rhinitis in allergen-challenged patients with IAR. However, there was no association between IAR and the A38G SNP.

  • 20.
    Benson, Mikael
    et al.
    Malmö University Hospital, Sweden and Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Jansson, L.
    Astra Zeneca R&D Lund, Sweden.
    Adner, M.
    Malmö University Hospital, Sweden.
    Luts, A.
    Astra Zeneca R&D Lund, Sweden.
    Uddman, R.
    Malmö University Hospital, Sweden.
    Cardell, L.O.
    Malmö University Hospital, Sweden.
    Gene profiling reveals decreased expression of uteroglobin and other anti-inflammatory genes in nasal fluid cells from patients with intermittent allergic rhinitis2005In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 35, no 4, p. 473-478Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Intermittent allergic rhinitis (IAR) results from interactions between a large number of pro- and anti-inflammatory mediators. Little is known about anti-inflammatory mediators in IAR. DNA microarrays allow simultaneous analysis of the whole transcriptome in a sample.

    OBJECTIVE:

    To identify anti-inflammatory transcripts in nasal fluid cells from patients with IAR during season and from healthy controls.

    METHODS:

    Nasal lavage fluids were obtained from 15 patients with symptomatic birch/and or grass pollen-induced IAR and 28 healthy controls. RNA was extracted from the nasal fluid cells and pooled into one patient- and one control pool. These were analysed with DNA microarrays containing more than 44,927 genes and variants.

    RESULTS:

    Seventeen thousand three hundred and fifty three genes were expressed in the controls and 17 928 in the patients. One thousand five hundred and seventy nine of the genes had higher expression in patients than in controls, and 1570 had lower expression in patients. Out of 189 up-regulated inflammatory genes, 187 were pro-inflammatory and two were anti-inflammatory. These genes regulated key steps of inflammation, ranging from influx of leukocytes to immunoglobulin production. By comparison, out of 49 down-regulated inflammatory genes, 36 were pro-inflammatory and 13 were anti-inflammatory. The anti-inflammatory gene that decreased most in expression in the patients was uteroglobin (also known as Clara Cell protein 16, CC16). The nasal fluid concentrations of uteroglobin protein were significantly lower in patients than in controls, 5.43+/-1.53 and 12.93+/-2.53 ng/mL, respectively (P<0.05).

    CONCLUSION:

    IAR is associated with decreased expression of uteroglobin and other anti-inflammatory genes.

  • 21.
    Benson, Mikael
    et al.
    East Hospital, Göteborg, Sweden.
    Jodal, Ulf
    Göteborg University, Sweden.
    Agace, William
    Lund University, Sweden.
    Hellström, Mikael
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Mårild, Staffan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rosberg, Sten
    Göteborg University, Sweden.
    Sjöström, Michael
    Umeå University, Sweden.
    Wettergren, Björn
    Jönsson, Susanne
    Svanborg, Catharina
    Lund University, Sweden.
    Interleukin (IL)-6 and IL-8 in children with febrile urinary tract infection and asymptomatic bacteriuria1996In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 174, no 5, p. 1080-1084Article in journal (Refereed)
    Abstract [en]

    Urine and serum interleukin (IL)-6 and IL-8 responses were higher in children with febrile urinary tract infection (n = 61) than in those with asymptomatic bacteriuria (n = 39). By univariate analysis, cytokine levels were related to age, sex, reflux, renal scarring, urine leukocytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and bacterial properties (P fimbriae but not hemolysin). Multivariate modeling showed that urine IL-6 responses were higher in girls than boys, increased with age, and were positively associated with CRP, ESR, serum IL-6, and urine leukocyte counts. The urine IL-8 response was not influenced by age, but it was influenced by P fimbriae and was associated with ESR, CRP, urine leukocytes, and female sex. The results show that cytokine responses to urinary tract infection vary with the severity of infection and that cytokine activation is influenced by a variety of host and bacterial variables.

  • 22.
    Benson, Mikael
    et al.
    Göteborg University, Sweden.
    Jodal, Ulf
    Göteborg University, Sweden.
    Andreasson, A
    Karlsson, Åke
    Rydberg, Johan
    Svanborg, Catharina
    Interleukin 6 response to urinary tract infection in childhood1994In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 13, no 7, p. 612-616Article in journal (Refereed)
    Abstract [en]

    This study analyzed the interleukin 6 (IL-6) response in 114 children with suspected urinary tract infection (UTI). Urine and serum samples were obtained at the time of enrollment. There were 90 children with UTI, 41 with and 49 without a temperature > or = 38.5 degrees C. The remaining 24 children did not have bacteriuria; 11 were febrile and 13 were not. The urinary IL-6 concentrations were higher in the children with UTI (mean, 129 units/ml) than in the children without bacteriuria (mean, 7 units/ml, P < 0.01). In contrast the serum IL-6 did not differ between children with or without UTI or between children with or without a temperature > or = 38.5 degrees C. The urinary IL-6 response was higher in children who were infected with P fimbriated Escherichia coli than in other children with UTI (P < 0.05). There was a correlation of urinary IL-6 with the degree of proteinuria, hematuria and urinary leukocyte counts (P < 0.001, P < 0.05, P < 0.05, respectively) but not with serum IL-6, CRP or temperature, and of serum IL-6 to C-reactive protein (P = 0.053) and renal concentrating capacity (P < 0.05). The results demonstrate that infections of the urinary tract activate an IL-6 response in children and that the magnitude of the IL-6 response is influenced by the properties of the infecting strain.

  • 23.
    Benson, Mikael
    et al.
    East Hospital, Gothenburg.
    Kjellmer, I.
    East Hospital, Gothenburg.
    Rosberg, S.
    East Hospital, Gothenburg.
    Billig, H.
    Gothenburg University, Gothenburg.
    Can paediatricians benefit from the Internet?1997In: Archives of Disease in Childhood, ISSN 0003-9888, E-ISSN 1468-2044, Vol. 77, no 2, p. 179-182Article in journal (Refereed)
    Abstract [en]

    It is likely that many paediatricians will find the Internet useful. The main benefits are probably the ease and speed of communication and immediate access to a few databases such as MEDLINE. It is also practical to integrate the import, processing, storage, and export of data into one's own computer. It is also possible that the Internet in all its forms will become an integrated part of our daily paediatric practice as a result of the increased usage of the Internet by patients, parents, and paediatricians.

  • 24.
    Benson, Mikael
    et al.
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Langston, Michael A.
    Department of Computer Science, University of Tennessee, Knoxville, USA.
    Adner, Mikael
    Laboratory for Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Andersson, Bengt
    Department of Clinical Immunology, Sahlgrenska Academy, Gothenburg, Sweden.
    Torinssson-Naluai, Åsa
    Department of Clinical Genetics and Göteborg Genomics, Sahlgrenska Academy, Gothenburg, Sweden.
    Cardell, Lars Olaf
    Laboratory for Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    A network-based analysis of the late-phase reaction of the skin2006In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 118, no 1, p. 220-225Article in journal (Refereed)
    Abstract [en]

    Background

    The late-phase reaction (LPR) of the skin is an in vivo model of allergic inflammation.

    Objective

    We sought to identify disease-associated pathways in the LPR using a network-based analysis.

    Methods

    The LPR was examined by means of DNA microarray analysis of skin biopsy specimens from 10 patients with allergic rhinitis and 10 healthy control subjects. The results were further analyzed in 2 different materials consisting of nasal fluids and allergen-challenged CD4+ T cells from patients with allergic rhinitis.

    Results

    The DNA microarray analysis revealed several genes of known relevance to allergy. The eosinophil marker Charcot-Leyden crystal protein (CLC) that encodes Charcot-Leyden crystal protein differed most in expression. A network-based analysis showed upregulation of IL-4– and CCL4-dependent pathways and downregulation of a TGF-β–induced pathway. CCL4 is expressed by CD4+ T cells and chemotactic for eosinophils. We hypothesized that allergen induces release of CCL4 from TH2 cells and that this contributes to influx of eosinophils. Further analysis showed increase of CCL4 protein in nasal fluids from allergic patients during the season. Allergen challenge of PBMCs resulted in proliferation of TH2 cells and increased production of CCL4 in CD4+ T cells from allergic patients. An analysis of the DNA microarray data revealed a significant correlation between CCL4 and the eosinophil marker CLC.

    Conclusion

    A network-based analysis of the LPR showed increased activity of IL-4– and CCL4- dependent pathways and downregulation of the TGF-β–induced pathway. Allergen-induced release of CCL4 from TH2 cells might contribute to influx of eosinophils during the LPR.

    Clinical implications

    Involvement of multiple interacting pathways indicates that it might be difficult to identify one single mediator as a biomarker or drug target in allergic inflammation.

  • 25.
    Benson, Mikael
    et al.
    Unit for Clinical Systems Biology, Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Mobini, R.
    Unit for Clinical Systems Biology, Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Barrenäs, F.
    Unit for Clinical Systems Biology, Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Halldén, C.
    Department of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden.
    Naluai, Å.T.
    Department of Clinical Genetics, Sahlgrenska Academy, Gothenburg, Sweden.
    Säll, T.
    Department of Cell and Organism Biology, Lund University, Lund, Sweden.
    Cardell, L.O.
    Division of ENT diseases Huddinge, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
    A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis2009In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 64, no 9, p. 1286-1291Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway.

    OBJECTIVE: To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR.

    METHODS: CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls.

    RESULTS: Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls.

    CONCLUSION: Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.

  • 26.
    Benson, Mikael
    et al.
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Olsson, M
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Rudemo, M
    Chalmers University of Technology, Gothenburg, Sweden.
    Wennergren, G
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Cardell, L O
    Malmö University Hospital, Sweden.
    Pros and cons of microarray technology in allergy research2004In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 34, no 7, p. 1001-1006Article in journal (Refereed)
  • 27.
    Benson, Mikael
    et al.
    Malmö University Hospital, Sweden .
    Reinholdt, J
    Royal Dental College, Aarhus, Denmark.
    Cardell, L O
    Malmö University Hospital, Sweden.
    Allergen-reactive antibodies are found in nasal fluids from patients with birch pollen-induced intermittent allergic rhinitis, but not in healthy controls2003In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 58, no 5, p. 386-392Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increased levels of allergen-reactive immunoglobulins (Igs) have been reported in nasal fluids from patients with intermittent allergic rhinitis (IAR) sensitive to ragweed and grass. The aims of this study were to make a detailed characterization of nasal fluid Igs in birch pollen-induced IAR.

    METHODS: Nasal fluids were obtained from 23 patients with birch pollen-induced IAR during and after the birch pollen season, and from 20 healthy controls. Nasal fluid total and Bet v 1-reactive (IgA), IgE and IgG as well as albumin were analyzed by immunoassays. The integrity of IgA and IgG, and the molecular form of IgA were assessed by Western blotting and column fractionation, respectively.

    RESULTS: Nasal fluid total IgE and IgG, but not IgA, were higher in patients compared with controls. Western blotting indicated no significant degradation of IgA (including S-IgA) and IgG. Most of the IgA, including Bet v 1-reactive antibodies, was of the secretory form and of the IgA1 subclass. Bet v 1-reactive IgA and IgG were present in all patients, but was mostly nondetectable in controls. No significant differences in the levels of Bet v 1-reactive IgA and IgG were found in patients during the birch pollen season compared with off season. Both Bet v 1 and Bet v 2-reactive IgE were nondetectable in most samples.

    CONCLUSIONS: Nasal fluid Bet v 1-reactive IgA and IgG were found in all patients with birch pollen-induced IAR, but not in controls. However, no significant differences were found between patients during and after the birch pollen season.

  • 28.
    Benson, Mikael
    et al.
    Pediatric Allergy Research Group, Queen Silvia Children's Hospital, Göteborg, Sweden.
    Steenhoff Hov, D. A.
    PubGene, Oslo, Norway.
    Clancy, T.
    PubGene, Oslo, Norway.
    Hovig, E.
    Norwegian Radium Hospital, Oslo, Norway.
    Rudemo, M.
    Chalmers University of Technology, Göteborg, Sweden.
    Cardell, L. O.
    Malmö University Hospital, Sweden.
    Connectivity can be used to identify key genes in DNA microarray data: a study based on gene expression in nasal polyps before and after treatment with glucocorticoids.2007In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 127, no 10, p. 1074-1079Article in journal (Refereed)
    Abstract [en]

    CONCLUSIONS: The presented analysis of nasal polyposis using connectivity based on the PubGene literature co-citation network demonstrates that this tool can be used to identify key genes in DNA microarray studies of human polygenic diseases.

    OBJECTIVES: DNA microarray studies of complex diseases may reveal differential expression of hundreds of genes. According to network theory and studies of yeast cells, genes that are connected with several other genes appear to have key regulatory roles. This study aimed to examine if this principle can be translated to DNA microarray studies of human disease, using nasal polyposis as a base for the analysis.

    MATERIALS AND METHODS: The connectivity of differentially expressed genes from a previously described microarray study of nasal polyposis before and after treatment with glucocorticoids was determined. This was done using the literature co-citation network PubGene.

    RESULTS: In all, 166 genes were differentially expressed; 39 of these were previously defined as inflammatory and considered important for nasal polyposis. The connectivity of all differentially expressed genes was analysed using the PubGene literature co-citation network. Seventy-four of the 166 genes were connected to other genes. By contrast, the average number of connected genes among 100 sets of 166 randomly chosen genes was 31.5. A small number of the differentially expressed genes were highly connected, while most genes had few or no connections. This indicated a scale-free network. The most connected gene was interleukin-8, an inflammatory gene of known importance for nasal polyposis. Twenty-eight of the 74 connected genes were inflammatory (38%), compared with 11 of the 92 unconnected genes (12%), p < 0.0001. Since most evidence suggests that nasal polyps are inflammatory in their nature, this supports the hypothesis that connected genes have more disease relevance than unconnected genes.

  • 29.
    Benson, Mikael
    et al.
    Sahlgrenska University Hospital, Göteborg.
    Strannegård, Inga-Lisa
    Sahlgrenska University Hospital, Göteborg.
    Strannegård, Örjan
    Sahlgrenska University Hospital, Göteborg.
    Wennergren, Göran
    Sahlgrenska University Hospital, Göteborg.
    Topical steroid treatment of allergic rhinitis decreases nasal fluid TH2 cytokines, eosinophils, eosinophil cationic protein, and IgE but has no significant effect on IFN-gamma, IL-1beta, TNF-alpha, or neutrophils2000In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 106, no 2, p. 307-312Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Topical treatment with glucocorticoids (GCs) is known to decrease eosinophils but not neutrophils in patients with allergic rhinitis.

    OBJECTIVE: We sought to examine whether the differential effects of GC treatment on eosinophils and neutrophils are mirrored by differential effects on T(H)1/T(H)2 cytokines and the neutrophil-associated cytokines IL-1beta and TNF-alpha.

    METHODS: Differential counts of eosinophils and neutrophils in nasal fluids from 60 children with seasonal allergic rhinitis treated with a topical GC were examined after staining with May-Grünwald-Giemsa stain. Nasal fluid levels of IFN-gamma, IL-4, IL-6, IL-10, IL-1beta, and TNF-alpha were examined with ELISA, and IgE and eosinophil cationic protein (ECP) levels were examined with RIA.

    RESULTS: After GC treatment, there was a statistically significant decrease of the T(H)2 cytokines IL-4, IL-6, and IL-10, as well as ECP and IgE. By contrast, there were no significant changes of the levels of IFN-gamma, IL-1beta, TNF-alpha, or neutrophils. In the GC-treated patients IL-1beta and TNF-alpha levels correlated with neutrophils and ECP, and IL-1beta correlated with eosinophils. Furthermore, ECP correlated with both eosinophils and neutrophils. Neither IL-1beta nor TNF-alpha correlated with IgE. Patients with high neutrophil counts after GC treatment were found to have significantly higher eosinophil counts and ECP than patients with low counts.

    CONCLUSIONS: The beneficial effects of topical treatment with GC in patients with allergic rhinitis could be attributed to downregulation of T(H)2 cytokines, with an ensuing decrease of eosinophils, ECP, and IgE. It is possible that neutrophils could counteract the beneficial effects of GCs by releasing the proinflammatory cytokines IL-1beta and TNF-alpha.

  • 30.
    Benson, Mikael
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Strannegård, Inga-Lisa
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Wennergren, Göran
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Strannegård, Örjan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Cytokines in nasal fluids from school children with seasonal allergic rhinitis1997In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 8, no 3, p. 143-149Article in journal (Refereed)
    Abstract [en]

    Allergic rhinitis is a particularly good model for studies of cytokine production in vivo. In this study the occurrence of the cytokines IL-4, IL-5, IL-10 and IFN-gamma as well as the soluble receptor for IL-4 in nasal lavage fluids were assayed in 38 school children, with seasonal allergic rhinitis, and 19 healthy age-matched, non-atopic controls, using highly sensitive enzyme immunoassays. IL-4 levels in patients with seasonal allergic rhinitis were markedly increased in comparison with those in non-atopic controls or in atopic patients before the start of the pollen season. In controls, but not in the atopic patients, levels of IFN-gamma and IL-5 were significantly higher in specimens obtained during the pollen season than in those obtained outside the season. The IL-4/IFN-gamma ratios were significantly higher in atopic than in non-atopic subjects and further increased in atopic patients during the season. In addition to IL-4, elevated levels of IL-10 were observed in association with seasonal rhinitis. Following treatment with a topical steroid (budesonide) there was a statistically significant increase of the levels of soluble IL-4 receptor. These findings indicate that nonatopic and atopic individuals react to pollen exposure with distinct cytokine patterns in agreement with the Th1/Th2 concept. Topical steroids may possibly decrease inflammation by increasing the formation of soluble IL-4 receptor.

  • 31.
    Benson, Mikael
    et al.
    Sahlgrenska University Hospital, Göteborg.
    Strannegård, Inga-Lisa
    Sahlgrenska University Hospital, Göteborg.
    Wennergren, Göran
    Sahlgrenska University Hospital, Göteborg.
    Strannegård, Örjan
    Sahlgrenska University Hospital, Göteborg.
    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 rhinitis2000In: Allergy and Asthma Proceedings, ISSN 1088-5412, E-ISSN 1539-6304, Vol. 21, no 2, p. 89-95Article in journal (Refereed)
    Abstract [en]

    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.

  • 32.
    Benson, Mikael
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Strannegård, Inga-Lisa
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Wennergren, Göran
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Strannegård, Örjan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Interleukin-5 and interleukin-8 in relation to eosinophils and neutrophils in nasal fluids from school children with seasonal allergic rhinitis1999In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 10, no 3, p. 178-185Article in journal (Refereed)
    Abstract [en]

    The objectives of this study were to measure interleukins 5 and 8 (IL-5 and IL-8) in relation to eosinophils and neutrophils, in nasal lavage fluids from 60 school children with allergic rhinitis, and to determine the influence of treatment with a topical steroid (budesonide) on the levels of the two cytokines. Highly sensitive enzyme immunoassays were used to analyze IL-5 and IL-8. IL-5 levels and relative eosinophil counts in nasal lavage fluid increased significantly in patients with allergic rhinitis during the pollen season, compared with values obtained before the start of the season, and decreased significantly after treatment with budesonide. By contrast, no significant changes in IL-8 or neutrophils were found during the pollen season, nor did they decrease following treatment. In the untreated patients, IL-5 levels correlated significantly with eosinophil counts but not with neutrophil counts, whereas IL-8 levels correlated with neutrophil counts but not with eosinophil counts. After budesonide treatment, the correlation between IL-8 and neutrophils remained, and a correlation between IL-8 and eosinophils emerged. These findings support the concepts that IL-5 has a key role in regulating eosinophils and that IL-8 is important for the regulation of neutrophils. Whereas IL-5 and relative eosinophil counts are profoundly affected by topical steroid treatment, IL-8 and neutrophils are not demonstrably affected by such treatment. It is possible that neutrophils, through the release of IL-8, could be chemotactic for eosinophils in steroid-treated patients.

  • 33.
    Benson, Mikael
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Strannegård, Inga-Lisa
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Wennergren, Göran
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Strannegård, Örjan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Low levels of interferon-gamma in nasal fluid accompany raised levels of T-helper 2 cytokines in children with ongoing allergic rhinitis2000In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 11, no 1, p. 20-28Article in journal (Refereed)
    Abstract [en]

    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.

  • 34.
    Benson, Mikael
    et al.
    Malmö University Hospital, Sweden.
    Svensson, P A
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carlsson, B
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jernås, M
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Reinholdt, J
    Aarhus University Hospital, Denmark.
    Cardell, L O
    Malmö University Hospital, Sweden.
    Carlsson, L
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    DNA microarrays to study gene expression in allergic airways2002In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 32, no 2, p. 301-308Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: 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.

    OBJECTIVE: To study gene expression in nasal mucosal biopsies from patients with allergic rhinitis using DNA micro-arrays.

    METHODS: Nasal biopsies were obtained from 14 patients with symptomatic birch pollen-induced allergic rhinitis and five healthy controls. RNA was extracted from the biopsies and pooled into one patient pool and one control pool. These were analysed in duplicate with DNA micro-arrays containing more than 12 000 known genes.

    RESULTS: Approximately half of the genes were expressed in the patient and control samples. Guided by the current literature we chose 32 genes of possible relevance to allergic airway inflammation and investigated their relative expression. Among these, transcripts encoding immunoglobulins and their receptors were most abundant. The expression of cytokines and growth factors was low, whereas their corresponding receptors and cell surface markers displayed higher expression levels. IgA had the highest expression of all 12 626 genes. RT-PCR showed that IgA1 was the predominant subclass. This was confirmed by the protein level in nasal fluids. Allergen-specific IgA was significantly higher in patients than in controls and correlated significantly with eosinophil granulae proteins.

    CONCLUSION: DNA micro-array analysis can be used to identify genes of possible relevance to allergic airway inflammation. In this study, the expression profile in the nasal mucosa was quantitatively dominated by immunoglobulins, particularly IgA. Protein analyses in nasal fluids indicated a role for allergen-specific IgA in eosinophil degranulation.

  • 35.
    Benson, Mikael
    et al.
    Malmö University Hospital, Sweden.
    Uddman, Rolf
    Malmö University Hospital, Sweden.
    Cardell, Lars Olaf
    Malmö University Hospital, Sweden.
    Epithelial cells in nasal fluids from patients with allergic rhinitis: how do they relate to epidermal growth factor, eosinophils and eosinophil cationic protein?2002In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 122, no 2, p. 202-205Article in journal (Refereed)
    Abstract [en]

    The nasal epithelium protects the underlying tissue from damage. Epithelial cell growth is controlled by epidermal growth factor (EGF) and is possibly affected by toxic proteins, e.g. eosinophil cationic protein (ECP). The aims of this study were to examine nasal fluid epithelial cell counts and their relations to EGF, eosinophils and ECP in 23 patients with seasonal allergic rhinitis and 20 healthy controls. Nasal fluid epithelial cell counts were lower in patients than in controls. EGF levels did not differ between patients and controls, and correlated with epithelial cell counts in controls but not in patients. Eosinophils and ECP were higher in patients than in controls, but did not correlate with epithelial cell counts. The role of growth factors, such as EGF, in regulating epithelial cells merits further study.

  • 36.
    Benson, Mikael
    et al.
    Malmö University Hospital and Queen Silvia Children’s Hospital, Gothenburg, Sweden .
    Wennergren, Göran
    Queen Silvia Children’s Hospital, Gothenburg, Sweden .
    Fransson, Mattias
    Malmö University Hospital,Sweden.
    Cardell, Lars Olaf
    Malmö University Hospital, Sweden.
    Altered levels of the soluble IL-1, IL-4 and TNF receptors, as well as the IL-1 receptor antagonist, in intermittent allergic rhinitis2004In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 134, no 3, p. 227-232Article in journal (Refereed)
    Abstract [en]

    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.

  • 37.
    Bogefors, J.
    et al.
    Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Rydberg, C.
    Division of ENT diseases, CLINTEC, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Uddman, R.
    Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Fransson, M.
    Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Månsson, A.
    Division of ENT diseases, CLINTEC, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Benson, Mikael
    Unit for Clinical Systems Biology, Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Adner, M.
    National Institute of Environmental medicine, Karolinska Institutet, Stockholm, Sweden.
    Cardell, Lars Olaf
    Division of ENT diseases, CLINTEC, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Nod1, Nod2 and Nalp3 receptors, new potential targets in treatment of allergic rhinitis?2010In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 65, no 10, p. 1222-1226Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recently, a new set of pattern-recognition receptors, the nucleotide-binding oligomerization domain (Nod)-like receptors (NLRs), have emerged. Their activation, either by allergens or microbes, triggers an inflammatory response. The knowledge about NLRs in human airways is limited.

    AIM OF THE STUDY: To investigate presence of NLRs in the human nose of healthy individuals and patients with intermittent allergic rhinitis outside and during pollen season.

    METHODS: The expression of Nod1, Nod2, and Nalp3 in nasal biopsies was determined with real-time RT-PCR and immunohistochemistry. Cultured primary human nasal epithelial cells (HNECs) were analyzed using real-time RT-PCR and flow cytometry to further verify the presence of NLRs in the epithelium.

    RESULTS: Immunohistochemical analysis revealed presence of Nod1, Nod2, and Nalp3 in the nasal epithelium. This was corroborated in cultured HNECs. Patients suffering from symptomatic allergic rhinitis exhibited lower Nod1 and Nalp3 mRNA levels than both controls and patients during pollen season. Nod2 expression was found in all specimens tested, but no differences were seen between the three groups.

    CONCLUSION: Nod1, Nod2, and Nalp3 receptors were found to be present in the human nose. The expression of Nod1 and Nalp3 were down-regulated during pollen season among patients with allergic rhinitis. This opens up for new insights and novel therapeutic strategies in inflammatory airway disease.

  • 38.
    Bousquet, J.
    et al.
    University Hospital Montpellier, France MACVIA LR, France ARIA, France European Academic Allergy and Clin Immunol, France European Innovat Partnership Act and Health Ageing, France European Innovat Partnership Act and Health Ageing, France University of Montpellier I, France .
    Addis, A.
    European Innovat Partnership Act and Health Ageing, France European Innovat Partnership Act and Health Ageing, Italy .
    Adcock, I.
    University of London Imperial Coll Science Technology and Med, England Royal Brompton and Harefield NIHR Biomed Research Unit, England .
    Agache, I.
    ARIA, France Romanian Alliance Chron Resp Disease, Romania Transylvania University, Romania .
    Agusti, A.
    University of Barcelona, Spain CIBER Enfermedades Resp, Spain .
    Alonso, A.
    Hospital Clin Barcelona, Spain .
    Annesi-Maesano, I.
    ARIA, France .
    M. Anto, J.
    University of Pompeu Fabra, Spain .
    Bachert, C.
    ARIA, France Ghent University Hospital, Belgium Ghent University Hospital, Belgium .
    E. Baena-Cagnani, C.
    ARIA, France Catholic University, Argentina .
    Bai, C.
    Chinese Medical Assoc, Peoples R China .
    Baigenzhin, A.
    EuroAsian Resp Soc, Kazakhstan .
    Barbara, C.
    European Innovat Partnership Act and Health Ageing, France Portuguese National Programme Resp Disease, Portugal .
    Barnes, P.J.
    University of London Imperial Coll Science Technology and Med, England Royal Brompton and Harefield NIHR Biomed Research Unit, England .
    Bateman, E.D.
    ARIA, France University of Cape Town, South Africa .
    Beck, L.
    Health Innovat Centre Southern Denmark, Denmark .
    Bedbrook, A.
    MACVIA LR, France ARIA, France .
    Bel, E.H.
    University of Amsterdam, Netherlands .
    Benezet, O.
    MACVIA LR, France .
    Bennoor, K.S.
    ARIA, France Bangladesh Lung Fdn, Bangladesh National Institute Disease Chest and Hospital, Bangladesh .
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Bernabeu-Wittel, M.
    European Innovat Partnership Act and Hlthy Ageing, Spain Andalusian Healthcare Serv, Spain .
    Bewick, M.
    NHS England, England .
    Bindslev-Jensen, C.
    ARIA, France Odense University Hospital, Denmark Odense University Hospital, Denmark .
    Blain, H.
    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France .
    Blasi, F.
    University of Milan, Italy .
    Bonini, M.
    ARIA, France University of Roma La Sapienza, Italy .
    Bonini, S.
    ARIA, France University of Naples 2, Italy Italian National Research Council, Italy .
    Boulet, L.P.
    ARIA, France University of Laval, Canada .
    Bourdin, A.
    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France INSERM, France .
    Bourret, R.
    University Hospital Montpellier, France MACVIA LR, France .
    Bousquet, P.J.
    ARIA, France .
    Brightling, C.E.
    Glenfield Hospital, England .
    Briggs, A.
    University of Glasgow, Scotland .
    Brozek, J.
    ARIA, France McMaster University, Canada McMaster University, Canada .
    Buh, R.
    Mainz University Hospital, Germany .
    Bush, A.
    ARIA, France University of London Imperial Coll Science Technology and Med, England University of London Imperial Coll Science Technology and Med, England .
    Caimmi, D.
    University Hospital Montpellier, France MACVIA LR, France .
    Calderon, M.
    University of Costa Rica, Costa Rica University of London Imperial Coll Science Technology and Med, England .
    Calverley, P.
    University of Liverpool, England Aintree University Hospital NHS Fdn Trust, England .
    Camargos, P.A.
    ARIA, France University of Federal Minas Gerais, Brazil .
    Camuzat, T.
    MACVIA LR, France .
    Canonica, G.W.
    ARIA, France University of Genoa, Italy .
    Carlsen, K.H.
    ARIA, France University of Oslo, Norway Oslo University Hospital, Norway .
    Casale, T.B.
    ARIA, France .
    Cazzola, M.
    University of Roma Tor Vergata, Italy .
    Cepeda Sarabia, A.M.
    ARIA, France University of Simon Bolivar, Colombia Soc Latinoamer Allergia Asma and Immunol, Italy .
    Cesario, A.
    IRCCS San Raffaele Pisana, Italy .
    Chen, Y.Z.
    Peking and Centre Asthma Research and Educ, Peoples R China .
    Chkhartishvili, E.
    Grigol Robakidze University, Rep of Georgia .
    Chavannes, N.
    ARIA, France Int Primary Care Resp Grp, Netherlands Leiden University, Netherlands .
    Chiron, R.
    University Hospital Montpellier, France MACVIA LR, France .
    Chuchalin, A.
    ARIA, France WHO, Russia Pulmonol Research Institute, Russia Russian Resp Soc, Russia .
    Chung, K.F.
    University of London Imperial Coll Science Technology and Med, England Royal Brompton and Harefield NIHR Biomed Research Unit, England .
    Cox, L.
    ARIA, France Nova SE University, FL USA .
    Crooks, G.
    NHS Scotland, Scotland .
    G. Crooks, M.
    Hull York Medical Sch, England .
    A. Cruz, A.
    ARIA, France WHO, Russia University of Federal Bahia, Brazil CNPq, Brazil .
    Custovic, A.
    ARIA, France European Academic Allergy and Clin Immunol, France University of Manchester, England .
    Dahl, R.
    ARIA, France Odense University Hospital, Denmark Odense University Hospital, Denmark .
    E. Dahlen, S.
    Karolinska Institute, Sweden .
    De Blay, F.
    ARIA, France Soc Francaise Allergol, France Strasbourg University, France .
    Dedeu, T.
    European Regional and Health Author, Belgium .
    Deleanu, D.
    ARIA, France University of Medical and Pharm Iuliu Hatieganu, Romania .
    Demoly, P.
    University Hospital Montpellier, France MACVIA LR, France ARIA, France European Academic Allergy and Clin Immunol, France European Innovat Partnership Act and Health Ageing, France University of Montpellier I, France .
    Devillier, P.
    ARIA, France University of Versailles St Quentin, France .
    Didier, A.
    Soc Pneumol Langue Francaise, France University of Toulouse, France .
    T. Dinh-Xuan, A.
    Paris Descartes University, France .
    Djukanovic, R.
    University of Southampton, England NIHR, England .
    Dokic, D.
    ARIA, France University of Ss Cyril and Methodius, Macedonia .
    Douagui, H.
    ARIA, France Centre Hospital University of Beni Messous, Algeria .
    Dubakiene, R.
    ARIA, France Lithuanian Soc Allergol and Clin Immunol, Lithuania Vilnius State University, Lithuania .
    Eglin, S.
    University of Liverpool, England .
    Elliot, F.
    NHS Scotland, Scotland .
    Emuzyte, R.
    ARIA, France Lithuanian Soc Allergol and Clin Immunol, Lithuania Vilnius State University, Lithuania .
    Fabbri, L.
    University of Modena and Reggio Emilia, Italy .
    Fink Wagner, A.
    Global Allergy and Asthma Patient Platform, Austria .
    Fletcher, M.
    WHO, Russia Educ Heatlh, England .
    Fokkens, W.J.
    ARIA, France University of Amsterdam, Netherlands European Rhinol Soc, Portugal .
    Fonseca, J.
    ARIA, France Portuguese National Programme Resp Disease, Portugal Porto Age Up Consortium, Portugal University of Porto, Portugal University of Porto, Portugal Institute and Hospital CUF Porto, Portugal .
    Franco, A.
    University of Nice Sophia Antipolis, France .
    Frith, P.
    Repatriat Gen Hospital, Australia .
    Furber, A.
    Wakefield Council, England .
    Gaga, M.
    Athens Chest Hospital, Greece Athens Chest Hospital, Greece .
    Garces, J.
    European Innovat Partnership Act and Health Ageing, Spain University of Valencia, Spain .
    Garcia-Aymerich, J.
    University of Pompeu Fabra, Spain .
    Gamkrelidze, A.
    ARIA, France National Centre Disease Control and Public Health Georgia, Rep of Georgia .
    Gonzales-Diaz, S.
    ARIA, France Soc Latinoamer Allergia Asma and Immunol, Italy .
    Gouzi, F.
    University Hospital Montpellier, France INSERM, France .
    A. Guzman, M.
    ARIA, France University of Chile, Chile .
    Haahtela, T.
    ARIA, France Helsinki University Hospital, Finland .
    Harrison, D.
    Public Health Blackburn Darwen, England .
    Hayot, M.
    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France .
    G. Heaney, L.
    Queens University of Belfast, North Ireland .
    Heinrich, J.
    MeDALL, Mechanisms of the Development of Allergy.
    Hellings, P. W.
    ARIA, France European Academic Allergy and Clin Immunol, France University Hospital Leuven, Belgium .
    Hooper, J.
    Public Health Kirklees, England .
    Humbert, M.
    Soc Pneumol Langue Francaise, France .
    Hyland, M.
    University of Plymouth, England .
    Iaccarino, G.
    University of Salerno, Italy IRCCS Multimed, Italy .
    Jakovenko, D.
    MACVIA LR, France .
    R. Jardim, J.
    University of Federal Sao Paulo, Brazil .
    Jeandel, C.
    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France .
    Jenkins, C.
    George Institute Global Heatlh, Australia University of Sydney, Australia .
    L. Johnston, S.
    ARIA, France University of London Imperial Coll Science Technology and Med, England .
    Jonquet, O.
    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France .
    Joos, G.
    Ghent University Hospital, Belgium .
    S. Jung, K.
    Hallym University, South Korea .
    Kalayci, O.
    ARIA, France European Academic Allergy and Clin Immunol, France Hacettepe University, Turkey .
    Karunanithi, S.
    Director of Public Health, Lancashire, UK.
    Keil, T.
    Charite, Germany University of Wurzburg, Germany .
    Khaltaev, N.
    ARIA, France WHO, Russia .
    Kolek, V.
    Czech Alliance Against Chron Resp Disease, Poland .
    L. Kowalski, M.
    Medical University of Lodz, Poland .
    Kull, I.
    Karolinska Institute, Sweden .
    Kuna, P.
    ARIA, France European Innovat Partnership Act and Health Ageing, France WHO, Russia Medical University of Lodz, Poland .
    Kvedariene, V.
    ARIA, France European Academic Allergy and Clin Immunol, France Lithuanian Soc Allergol and Clin Immunol, Lithuania Vilnius State University, Lithuania .
    T. Le, L.
    ARIA, France WHO, Russia University of Medical and Pharm, Vietnam .
    C. Lodrup Carlsen, K.
    ARIA, France University of Oslo, Norway Oslo University Hospital, Norway .
    Louis, R.
    University of Liege, Belgium .
    MacNee, W.
    University of Edinburgh, Scotland .
    Mair, A.
    Scottish Govt, Scotland .
    Majer, I.
    University of Bratislava, Slovakia .
    Manning, P.
    Bon Secours Hospital, Ireland .
    de Manuel Keenoy, E.
    European Innovat Partnership Act and Health Ageing, France Kronikgune, Spain .
    R. Masjedi, M.
    Shahid Beheshti University of Medical Science, Iran .
    Meten, E.
    ARIA, France Karolinska Institute, Sweden .
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    European Innovat Partnership Act and Health Ageing, France Portuguese National Programme Resp Disease, Portugal .
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    Royal Brompton Hospital, England .
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    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France .
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    University Hospital Montpellier, France MACVIA LR, France European Innovat Partnership Act and Health Ageing, France University of Montpellier I, France .
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    Geneva School Med, Switzerland University Hospital Geneva, Switzerland .
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    University Hospital Pulm Disease, Croatia .
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    ARIA, France Institute Pneumol Marius Nasta, Romania .
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    University of Belgrade, Serbia COPD Serbia, Serbia .
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    Bordeaux University, France .
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    Paris Descartes University, France Paris Municipal, France .
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    European Innovat Partnership Act and Hlthy Ageing, Spain .
    Morais-Almeida, M.
    Hospital CUF Descobertas, Portugal .
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    NHS England, England .
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    Hop Polyclin Dakar IHS, Senegal .
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    ARIA, France Mustapha Hospital, Algeria .
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    ARIA, France Hospital Hospital Bros Buda, Hungary .
    Neou, A.
    Charite, Germany .
    Nicod, L.
    CHUV Lausanne, Switzerland .
    OHehir, R.
    ARIA, France Alfred Hospital, Australia Monash University, Australia .
    Ohta, K.
    ARIA, France Tokyo National Hospital, Japan Teikyo University, Japan .
    Paggiaro, P.
    University Hospital Pisa, Italy .
    Palkonen, S.
    ARIA, France .
    Palmer, S.
    University of York, England .
    Papadopoulos, N. G.
    ARIA, France European Academic Allergy and Clin Immunol, France University of Manchester, England University of Athens, Greece .
    Papi, A.
    University of Ferrara, Italy .
    Passalacqua, G.
    ARIA, France University of Genoa, Italy .
    Pavord, I.
    University of Oxford, England .
    Pigearias, B.
    SPLF, Espace francophone de Pneumologie.
    Plavec, D.
    University of JJ Strossmayer, Croatia .
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    University of Groningen, Netherlands .
    Price, D.
    ARIA, France Int Primary Care Resp Grp, Netherlands University of Aberdeen, Scotland .
    Rabe, K. F.
    University of Kiel, Germany .
    Radier Pontal, F.
    MACVIA LR, France .
    Redon, J.
    European Innovat Partnership Act and Health Ageing, France University of Valencia, Spain .
    Rennard, S.
    University of Nebraska Medical Centre, NE USA .
    Roberts, J.
    Salford Royal NHS Fdn Trust, England .
    Robine, J. M.
    MACVIA LR, France INSERM, France .
    Roca, J.
    University of Barcelona, Spain CIBER Enfermedades Resp, Spain .
    Roche, N.
    University of Paris 05, France Soc Pneumol Langue Francaise, France .
    Rodenas, F.
    European Innovat Partnership Act and Health Ageing, Spain University of Valencia, Spain .
    Roggeri, A.
    Arcispedale S Maria Nuova Hospital, Italy .
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    Assoc Asthme and Allergies, France .
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    ARIA, France European Innovat Partnership Act and Health Ageing, France Portuguese National Programme Resp Disease, Portugal WHO, Russia .
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    ARIA, France Int Primary Care Resp Grp, Netherlands Woodbrook Medical Centre, England University of Edinburgh, Scotland .
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    European Innovat Partnership Act and Health Ageing, France Medical University of Lodz, Poland Medical University of Warsaw, Poland .
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    Centre Medical Docente La Trinidad, Venezuela .
    Schunemann, H. J.
    McMaster University, Canada McMaster University, Canada .
    Sheikh, A.
    University of Edinburgh, Scotland Harvard University, MA 02115 USA .
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    Queens University of Belfast, North Ireland Royal Belfast Hospital Sick Children, North Ireland .
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    University Hospital Heraklion, Greece .
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    Catholic University of Louvain, Belgium .
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    University of Paris 06, France INSERM, France Grp Hospital Pitie Salpetriere Charles Foix, France Fonds Dotat Rech Sante Resp Fdn Souffle, France .
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    National Advisory Group, Respiratory Managed Clinical Networks in Scotland.
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    Health Institute Technology Transfer, Spain .
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    ARIA, France WHO, Russia EuroAsian Resp Soc, Kyrgyzstan National Centre Cardiol and Internal Med, Kyrgyzstan .
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    University of Sao Paulo, Brazil .
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    University of Amsterdam, Netherlands .
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    University of Oslo, Norway .
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    Regional Medical Manager (North), NHS England, UK.
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    Observatoire wallon de la santé, Direction générale opérationnelle Pouvoirs locaux, action sociale et Santé, Service public de Wallonie, Belgium .
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    WHO, Russia .
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    Coimbra University Hospital, Portugal .
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    University of Salerno, Italy .
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    ARIA, France Medical University of Vienna, Austria .
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    University of Barcelona, Spain CIBER Enfermedades Resp, Spain .
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    ARIA, France Lithuanian Soc Allergol and Clin Immunol, Lithuania Vilnius State University, Lithuania .
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    University of Turku, Finland .
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    CHU Lyon, France CHU Lyon, France University of Lyon 1, France .
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    ARIA, France INSERM, France .
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    FILHA, Finnish Lung Association.
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    University of Manchester, England Odense University Hospital, Denmark .
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    Arcispedale S Maria Nuova IRCCS, Italy .
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    CNR, Italy CNR, Italy Clin Physiol IFC, Italy .
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    University Hospital Montpellier, France MACVIA LR, France University of Montpellier I, France .
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    University of Marburg, Germany .
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    Sotiria Hospital, Greece .
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    Cumbria County Council, PA USA .
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    Charite, Germany .
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    Soc Francaise Allergol, France CHRU, France .
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    University of Plymouth, England .
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    ARIA, France Karolinska Institute, Sweden .
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    University of N Carolina, NC USA .
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    North England EU Health Partnership, Belgium .
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    ARIA, France Olmsted Medical Centre, MN USA University of Minnesota, MN USA .
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    ARIA, France .
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    Integrated care pathways for airway diseases (AIRWAYS-ICPs)2014In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 44, no 2, p. 304-323Article in journal (Refereed)
    Abstract [en]

    The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYS-ICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

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    Hietzing Hospital, Austria.
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    Medical University of Sofia, Bulgaria.
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    European Innovat Partnership Act and Health Ageing Re, France.
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    University of Groningen, Netherlands.
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    University of Cape Town, South Africa.
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    University of Aberdeen, Scotland; Research Real Life, England.
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    LungenClin Grosshansdorf, Germany; University of Kiel, Germany.
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    Medical University of Warsaw, Poland.
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    Maison Profess Liberales, France.
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    SLAAI, Mexico.
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    Hospital University of Coimbra, Portugal.
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    Assoc Asthme and Allergie, France.
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    Helsinki University Hospital, Finland.
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    Institute Invest Sanitaria Palma IdisPa, Spain.
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    Complesso Integrato Columbus, Italy.
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    University of Federal Parana, Brazil.
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    University of Misouri, MI USA.
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    CHU Rangueil Larrey, France.
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    Oslo University Hospital, Norway; University of Oslo, Norway.
    Smit, H. A.
    University of Utrecht, Netherlands.
    Sole, D.
    University of Federal Sao Paulo, Brazil.
    Sooronbaev, T.
    Euroasian Resp Soc, Kyrgyzstan.
    Spranger, O.
    Global Allergy and Asthma Platform GAAPP, Austria.
    Stelmach, R.
    University of Sao Paulo, Brazil.
    Strandberg, T.
    European Union Geriatr Medical Soc, Austria.
    Sunyer, J.
    Centre Research Environm Epidemiol, Spain; Hospital del Mar, Spain; CIBER Epidemiol and Salud Publ, Spain; University of Pompeu Fabra, Spain.
    Thijs, C.
    Maastricht University, Netherlands.
    Todo-Bom, A.
    University of Coimbra, Portugal.
    Triggiani, M.
    University of Salerno, Italy.
    Valenta, R.
    Medical University of Vienna, Austria.
    Valero, A. L.
    IDIBAPS, Spain.
    van Hage, M.
    Karolinska Institute, Sweden.
    Vandenplas, O.
    Catholic University of Louvain, Belgium.
    Vezzani, G.
    Research Hospital, Italy; Regional Agency Health and Social Care, Italy.
    Vichyanond, P.
    Mahidol University, Thailand.
    Viegi, G.
    CNR, Italy.
    Wagenmann, M.
    University of Klinikum Dusseldorf, Germany.
    Walker, S.
    Asthma UK, England.
    Wang, D. Y.
    National University of Singapore, Singapore.
    Wahn, U.
    Aura Andalucia, Jaen, Spain.
    Williams, D. M.
    University of N Carolina, NC USA.
    Wright, J.
    Bradford Royal Infirm, England.
    Yawn, B. P.
    Olmsted Medical Centre, MN USA.
    Yiallouros, P. K.
    Cyprus University of Technology, Cyprus; Hospital Archbishop Makarios III, Cyprus.
    Yusuf, O. M.
    Allergy and Asthma Institute, Pakistan.
    Zar, H. J.
    University of Cape Town, South Africa.
    Zernotti, M. E.
    University of Catolica Cordoba, Argentina.
    Zhang, L.
    Capital Medical University, Peoples R China.
    Zhong, N.
    Guangzhou Medical University, Peoples R China.
    Zidarn, M.
    University of Clin Resp and Allerg Disease, Slovenia.
    Chatzi, L,
    Mercier, J.
    University of Montpellier, France.
    Dedeu, T,
    Hyland, ME,
    Majer, I,
    Manning, P,
    Paggiaro, P,
    Rosado-Pinto, J,
    Rodenas, F,
    MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): the new generation guideline implementation2015In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 70, no 11, p. 1372-1392Article in journal (Refereed)
    Abstract [en]

    Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.

  • 40.
    Bruhn, Sören
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Barrenäs, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Mobini, R.
    Östergötlands Läns Landsting.
    Andersson, B. A.
    Sahlgrenska University Hospital.
    Chavali, S.
    MRC Lab Molecular Biol, Cambridge, UK.
    Egan, B. S.
    Genepathway, Inc., San Diego, CA, USA.
    Hovig, E.
    Norwegian Radium Hospital.
    Sandve, G. K.
    University of Oslo.
    Langston, M. A.
    University of Tennessee, Knoxville, TN, USA.
    Rogers, G.
    University of Tennessee, Knoxville, TN, USA.
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis2012In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 67, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Background: The transcription factor (TF) IRF4 is involved in the regulation of Th1, Th2, Th9, and Th17 cells, and animal studies have indicated an important role in allergy. However, IRF4 and its target genes have not been examined in human allergy. Methods: IRF4 and its target genes were examined in allergen-challenged CD4+ cells from patients with IAR, using combined gene expression microarrays and chromatin immunoprecipitation chips (ChIP-chips), computational target prediction, and RNAi knockdowns. Results: IRF4 increased in allergen-challenged CD4+ cells from patients with IAR, and functional studies supported its role in Th2 cell activation. IRF4 ChIP-chip showed that IRF4 regulated a large number of genes relevant to Th cell differentiation. However, neither Th1 nor Th2 cytokines were the direct targets of IRF4. To examine whether IRF4 induced Th2 cytokines via one or more downstream TFs, we combined gene expression microarrays, ChIP-chips, and computational target prediction and found a putative intermediary TF, namely ETS1 in allergen-challenged CD4+ cells from allergic patients. ETS1 increased significantly in allergen-challenged CD4+ cells from patients compared to controls. Gene expression microarrays before and after ETS1 RNAi knockdown showed that ETS1 induced Th2 cytokines as well as disease-related pathways. Conclusions: Increased expression of IRF4 in allergen-challenged CD4+ cells from patients with intermittent allergic rhinitis leads to activation of a complex transcriptional program, including Th2 cytokines.

  • 41.
    Bruhn, Sören
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Fang, Yu
    Guiyang Medical Coll, Peoples R China University of Gothenburg, Sweden .
    Barrenäs, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Konstantinell, Aelita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Kronke, Andrea
    Cenix BioScience GmbH, Germany .
    Sonnichsen, Birte
    Cenix BioScience GmbH, Germany .
    Bresnick, Anne
    Albert Einstein Coll Med, NY 10461 USA .
    Dulyaninova, Natalya
    Albert Einstein Coll Med, NY 10461 USA .
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Zhao, Yelin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Klingelhofer, Jorg
    University of Copenhagen, Denmark .
    Ambartsumian, Noona
    University of Copenhagen, Denmark .
    Beck, Mette K.
    Technical University of Denmark, Denmark .
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Bona, Elsa
    Boras Hospital, Sweden .
    Xiang, Zou
    University of Gothenburg, Sweden .
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy2014In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 6, no 218Article in journal (Refereed)
    Abstract [en]

    The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

  • 42.
    Bruhn, Sören
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Katzenellenbogen, Mark
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Krönke, Andrea
    Cenix BioScience GmbH, Dresden, Germany.
    Sönnichsen, Birte
    Cenix BioScience GmbH, Dresden, Germany.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Combining gene expression microarray- and cluster analysis with sequence-based predictions to identify regulators of IL-13 in allergy2012In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 60, no 3, p. 736-740Article in journal (Refereed)
    Abstract [en]

    The Th2 cytokine IL-13 plays a key role in allergy, by regulating IgE, airway hyper secretion, eosinophils and mast cells. In this study, we aimed to identify novel transcription factors (TFs) that potentially regulated IL-13. We analyzed Th2 polarized naïve T cells from four different blood donors with gene expression microarrays to find clusters of genes that were correlated or anti-correlated with IL13. These clusters were further filtered, by selecting genes that were functionally related. In these clusters, we identified three transcription factors (TFs) that were predicted to regulate the expression of IL13, namely CEBPB, E2F6 and AHR. siRNA mediated knockdowns of these TFs in naïve polarized T cells showed significant increases of IL13, following knockdown of CEBPB and E2F6, but not AHR. This suggested an inhibitory role of CEBPB and E2F6 in the regulation of IL13 and allergy. This was supported by analysis of E2F6, but not CEBPB, in allergen-challenged CD4+ T cells from six allergic patients and six healthy controls, which showed decreased expression of E2F6 in patients. In summary, our findings indicate an inhibitory role of E2F6 in the regulation of IL-13 and allergy. The analytical approach may be generally applicable to elucidate the complex regulatory patterns in Th2 cell polarization and allergy.

  • 43.
    Chavali, Sreenivas
    et al.
    The Unit for Clinical Systems Biology, University of Gothenburg, Sweden.
    Barrenäs, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kanduri, Kartiek
    The Unit for Clinical Systems Biology, University of Gothenburg, Sweden.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Network properties of human disease genes with pleiotropic effects2010In: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 4, no 78Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The ability of a gene to cause a disease is known to be associated with the topological position of its protein product in the molecular interaction network. Pleiotropy, in human genetic diseases, refers to the ability of different mutations within the same gene to cause different pathological effects. Here, we hypothesized that the ability of human disease genes to cause pleiotropic effects would be associated with their network properties.

    RESULTS: Shared genes, with pleiotropic effects, were more central than specific genes that were associated with one disease, in the protein interaction network. Furthermore, shared genes associated with phenotypically divergent diseases (phenodiv genes) were more central than those associated with phenotypically similar diseases. Shared genes had a higher number of disease gene interactors compared to specific genes, implying higher likelihood of finding a novel disease gene in their network neighborhood. Shared genes had a relatively restricted tissue co-expression with interactors, contrary to specific genes. This could be a function of shared genes leading to pleiotropy. Essential and phenodiv genes had comparable connectivities and hence we investigated for differences in network attributes conferring lethality and pleiotropy, respectively. Essential and phenodiv genes were found to be intra-modular and inter-modular hubs with the former being highly co-expressed with their interactors contrary to the latter. Essential genes were predominantly nuclear proteins with transcriptional regulation activities while phenodiv genes were cytoplasmic proteins involved in signal transduction.

    CONCLUSION: The properties of a disease gene in molecular interaction network determine its role in manifesting different and divergent diseases.

  • 44.
    Chavali, Sreenivas
    et al.
    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
    Bruhn, Sören
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Tiemann, Katrin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sætrom, Pål
    Norwegian University of Science and Technology, Trondheim, Norway.
    Barrenäs, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Saito, Takaya
    Norwegian University of Science and Technology, Trondheim, Norway.
    Kanduri, Kartiek
    University of Gothenburg, Sweden .
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases2013In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 19, no 11, p. 1552-1562Article in journal (Refereed)
    Abstract [en]

    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.

  • 45.
    Clancy, Trevor
    et al.
    The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    Pedicini, Marco
    Institute for Computing Applications, National Research Council, Rome, Italy.
    Castiglione, Filippo
    Institute for Computing Applications, National Research Council, Rome, Italy.
    Santoni, Daniele
    Institute for Computing Applications, National Research Council, Rome, Italy.
    Nygaard, Vegard
    The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    Lavelle, Timothy J
    The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    Benson, Mikael
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Hovig, Eivind
    The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
    Immunological network signatures of cancer progression and survival2011In: BMC medical genomics, ISSN 1755-8794, Vol. 4, p. 28-Article in journal (Refereed)
    Abstract [en]

    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.

  • 46.
    Clermont, Gilles
    et al.
    University of Pittsburgh School of Medicine, PA , USA.
    Auffray, Charles
    CNRS Institute of Biological Sciences, Villejuif Cedex, France.
    Moreau, Yves
    K.U. Leuven, ESAT/SCD, Leuven-Heverlee, Belgium.
    Rocke, David M
    University of California, Davis, USA.
    Dalevi, Daniel
    Chalmers and Göteborg University, Sweden.
    Dubhashi, Devdatt
    Chalmers and Göteborg University, Sweden.
    Marshall, Dana R
    Meharry Medical College, Nashville, TN , USA.
    Raasch, Peter
    University of Rostock, Germany.
    Dehne, Frank
    Carleton University, Ottawa, Ontario, Canada.
    Provero, Paolo
    University of Torino, Italy .
    Tegner, Jesper
    Karolinska Universitetssjukhuset, Solna, Stockholm, Sweden.
    Aronow, Bruce J
    University of Cincinnati, OH, USA.
    Langston, Michael A
    University of Tennessee, Knoxville, USA.
    Benson, Mikael
    The Unit for Clinical Systems Biology, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Bridging the gap between systems biology and medicine2009In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 1, no 9Article in journal (Refereed)
    Abstract [en]

    Systems biology has matured considerably as a discipline over the last decade, yet some of the key challenges separating current research efforts in systems biology and clinically useful results are only now becoming apparent. As these gaps are better defined, the new discipline of systems medicine is emerging as a translational extension of systems biology. How is systems medicine defined? What are relevant ontologies for systems medicine? What are the key theoretic and methodologic challenges facing computational disease modeling? How are inaccurate and incomplete data, and uncertain biologic knowledge best synthesized in useful computational models? Does network analysis provide clinically useful insight? We discuss the outstanding difficulties in translating a rapidly growing body of data into knowledge usable at the bedside. Although core-specific challenges are best met by specialized groups, it appears fundamental that such efforts should be guided by a roadmap for systems medicine drafted by a coalition of scientists from the clinical, experimental, computational, and theoretic domains.

  • 47.
    Couto Alves, Alexessander
    et al.
    University of London Imperial Coll Science Technology and Med, England .
    Bruhn, Sören
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ramasamy, Adaikalavan
    University of London Imperial Coll Science Technology and Med, England .
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Holloway, John W.
    University of Southampton, England .
    Hartikainen, Anna-Liisa
    University of Oulu, Finland .
    Jarvelin, Marjo-Riitta
    University of London Imperial Coll Science Technology and Med, England .
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Balding, David J.
    University of London Imperial Coll Science Technology and Med, England .
    Coin, Lachlan J M.
    University of London Imperial Coll Science Technology and Med, England .
    Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed)
    Abstract [en]

    Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

  • 48.
    De Beule, Joachim
    et al.
    Vrije Universiteit Brussel, Belgium.
    Hovig, Eivind
    The Norwegian Radium Hospital Montebello, Oslo, Norway .
    Benson, Mikael
    Queen Silvia Children’s Hospital Gothenburg, Sweden .
    Introducing Dynamics into the Field of Biosemiotics A Formal Account with Examples from Language and Immunology2011In: Biosemiotics, ISSN 1875-1342, E-ISSN 1875-1350, Vol. 4, no 1, p. 5-24Article in journal (Refereed)
    Abstract [en]

    Coding plays a universal and pervasive role in biological organization, in forms such as genetic coding (DNA to protein translation), RNA processing, gene regulation, protein modification, cell signalling, immune responses, epigenetic development and natural language. Nevertheless, the ways and means by which organic codes are formed and used are still poorly understood. A formal model is presented in this paper to investigate the emergence of conventional codes among code users. The relationship between the formation and the usage of codes is discussed, and a biological mechanism involving coding is identified in the context of the immune system.

  • 49.
    Edström, Måns
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Gustafsson, Mika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Huddinge University Hospital.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Regulatory T cells in Multiple Sclerosis – Indications of impaired function of suppressive capacity and a role for chemokines2014Manuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND Regulatory T cells (Treg) are critical for immune regulation and homeostasis. In multiple sclerosis (MS), the function of these cells has been shown to be impaired, although the underlying mechanism has yet to be shown. In the current study, we aimed to characterize and assess the phenotypical, functional and transcriptional characteristics of memory and naïve Treg in MS patients and controls.

    MATERIAL AND METHODS 27 patients with relapsing-remitting disease were included, along with 29 healthy controls. Flow cytometry was used for detailed phenotyping of Treg subpopulations CD4+CD45RA+/- and CD4dimCD25++ and their expression of FOXP3, CD39 and HELIOS. CFSE (proliferation marker) and CD69 (activation marker) were used to investigate the functional capacity of Treg. A microarray was employed for genome-wide transcriptional characterization of isolated Treg.

    RESULTS CD4+CD45RA–CD25++ activated Treg displayed a higher expression of FOXP3 and CD39 than resting CD4+CD45RA+CD25+ Treg, while no significant phenotypical differences were observed in Treg subpopulations between patients and controls. However, a lower anti-proliferative capacity was observed in activated Treg of MS patients compared with those of controls (p<0.05), while suppression of activation was similar to controls. Gene set enrichment analysis (GSEA) of microarray data revealed enrichment for the GO gene set ‘chemokine receptor binding’ in MS Treg.

    CONCLUSION Although numerical phenotypical assessment of resting and activated Tregs did not reveal any significant difference between patients and controls, functional co-culturing experiments showed an impaired function in activated Treg of MS patients. Furthermore, GSEA revealed immune-related gene sets overexpressed in Treg of MS patients, possibly containing clues to the functional impairment. In particular over-activity in chemokine signalling in Treg would be of interest for further investigation.

  • 50.
    Fransson, Mattias
    et al.
    Laboratory of Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Benson, Mikael
    Department of Pediatrics, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Erjefält, Jonas S
    Department of Experimental Medical Science, Lund University Hospital, Lund University, Sweden.
    Jansson, Lennart
    AstraZeneca R&D, Lund, Sweden.
    Uddman, Rolf
    Laboratory of Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Björnsson, Sven
    Department of Clinical Chemistry, Malmö University Hospital, Lund University, Malmö, Sweden.
    Cardell, Lars-Olaf
    Laboratory of Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Adner, Mikael
    Laboratory of Clinical and Experimental Allergy Research, Department of Oto-Rhino-Laryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Expression of Toll-like receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis2007In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 8, no 17Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Allergic rhinitis is an inflammatory disease of the upper airway mucosa that also affects leukocytes in bone marrow and peripheral blood. Toll-like receptor 9 (TLR9) is a receptor for unmethylated CpG dinucleotides found in bacterial and viral DNA. The present study was designed to examine the expression of TLR9 in the nasal mucosa and in leukocytes derived from different cellular compartments during symptomatic allergic rhinitis.

    METHODS: The study was based on 32 patients with seasonal allergic rhinitis and 18 healthy subjects, serving as controls. Nasal biopsies were obtained before and after allergen challenge. Bone marrow, peripheral blood and nasal lavage fluid were sampled outside and during pollen season. The expression of TLR9 in tissues and cells was analyzed using immunohistochemistry and flow cytometry, respectively.

    RESULTS: TLR9 was found in several cell types in the nasal mucosa and in different leukocyte subpopulations derived from bone marrow, peripheral blood and nasal lavage fluid. The leukocyte expression was generally higher in bone marrow than in peripheral blood, and not affected by symptomatic allergic rhinitis.

    CONCLUSION: The widespread expression of TLR9 in the nasal mucosa along with its rich representation in leukocytes in different compartments, demonstrate the possibility for cells involved in allergic airway inflammation to directly interact with bacterial and viral DNA.

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