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  • 51.
    Fransson, Mattias
    et al.
    Malmö University Hospital, Sweden.
    Benson, Mikael
    Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wennergren, Göran
    Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Cardell, Lars-Olaf
    Malmö University Hospital, Sweden.
    A role for neutrophils in intermittent allergic rhinitis2004Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 124, nr 5, s. 616-620Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: In patients with intermittent allergic rhinitis, allergen challenge may induce both early- and late-phase responses. The aim of this study was to examine the correlation between inflammatory cells in the nasal lavage fluid and clinical parameters following pollen challenge.

    MATERIAL AND METHODS: Nasal lavage fluids were obtained from 29 patients with intermittent allergic rhinitis before and 1 and 6 h after allergen provocation, representing the control, early and late phases, respectively. Symptom and rhinoscopic scores were registered on the same occasions. Inflammatory cells were determined in the nasal fluid.

    RESULTS: The early phase was characterized by increased symptom scores, rhinoscopic signs of oedema and secretion and neutrophilia. In the late phase, symptom scores had diminished, but the signs of ongoing secretion remained. Both the total nasal symptom score and the secretion score correlated with the number of neutrophils in lavage fluids at 1 h. The eosinophil count did not increase during the early or late phases.

    CONCLUSION: A single allergen provocation induces an early-phase response dominated by neutrophils, with secretion being the only clinical sign remaining during the late phase. The increase in neutrophil numbers correlated with the registration of secretory symptoms. The presented data indicate a role for neutrophils in intermittent allergic rhinitis and their relation with secretory parameters makes it intriguing to speculate that neutrophils may function as promoters of nasal secretion.

  • 52.
    Gawel, Danuta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    James, A. Rani
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Liljenstrom, R.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Muraro, A.
    Padua University Hospital, Italy .
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    The Allergic Airway Inflammation Repository - a user-friendly, curated resource of mRNA expression levels in studies of allergic airways2014Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, nr 8, s. 1115-1117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Public microarray databases allow analysis of expression levels of candidate genes in different contexts. However, finding relevant microarray data is complicated by the large number of available studies. We have compiled a user-friendly, open-access database of mRNA microarray experiments relevant to allergic airway inflammation, the Allergic Airway Inflammation Repository (AAIR, http://aair.cimed.ike.liu.se/). The aim is to allow allergy researchers to determine the expression profile of their genes of interest in multiple clinical data sets and several experimental systems quickly and intuitively. AAIR also provides quick links to other relevant information such as experimental protocols, related literature and raw data files.

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  • 53.
    Guillot, Gilles
    et al.
    INRA, Applied Mathematics Department, Paris, France / Stochastic Centre, Chalmers University of Technology, Sweden.
    Olsson, Maja
    The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Benson, Mikael
    The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Rudemo, Mats
    Department of Mathematical Statistics, Chalmers and Göteborg University, Gothenburg, Sweden.
    Discrimination and scoring using small sets of genes for two-sample microarray data2007Ingår i: Mathematical Biosciences, ISSN 0025-5564, E-ISSN 1879-3134, Vol. 205, nr 2, s. 195-203Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Comparison of gene expression for two groups of individuals form an important subclass of microarray experiments. We study multivariate procedures, in particular use of Hotelling's T2 for discrimination between the groups with a special emphasis on methods based on few genes only. We apply the methods to data from an experiment with a group of atopic dermatitis patients compared with a control group. We also compare our methodology to other recently proposed methods on publicly available datasets. It is found that (i) use of several genes gives a much improved discrimination of the groups as compared to one gene only, (ii) the genes that play the most important role in the multivariate analysis are not necessarily those that rank first in univariate comparisons of the groups, (iii) Linear Discriminant Analysis carried out with sets of 2-5 genes selected according to their Hotelling T2 give results comparable to state-of-the-art methods using many more genes, a feature of our method which might be crucial in clinical applications. Finding groups of genes that together give optimal multivariate discrimination (given the size of the group) can identify crucial pathways and networks of genes responsible for a disease. The computer code that we developed to make computations is available as an R package.

  • 54.
    Gustafsson, Mika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Edström, Måns
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Gawel, Danuta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Barrenäs, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Tojo, James
    Karolinska Institute, Sweden Centre Molecular Med, Sweden .
    Kockum, Ingrid
    Karolinska Institute, Sweden Centre Molecular Med, Sweden .
    Olsson, Tomas
    Karolinska Institute, Sweden Centre Molecular Med, Sweden .
    Serra-Musach, Jordi
    IDIBELL, Spain .
    Bonifaci, Nuria
    IDIBELL, Spain .
    Angel Pujana, Miguel
    IDIBELL, Spain .
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment2014Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 6, nr 17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.

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  • 55.
    Gustafsson, Mika
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Gawel, Danuta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Alfredsson, Lars
    Karolinska Institute, Sweden.
    Baranzini, Sergio
    University of Calif San Francisco, CA, USA.
    Bjorkander, Janne
    County Council Jonköping, Sweden.
    Blomgran, Robert
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Hellberg, Sandra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Eklund, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Kockum, Ingrid
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden.
    Konstantinell, Aelita
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Arctic University of Norway, Norway.
    Lahesmaa, Riita
    University of Turku, Finland; Abo Akad University, Finland.
    Lentini, Antonio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Liljenström, H. Robert I.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Mattson, Lina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Matussek, Andreas
    County Council Jonköping, Sweden.
    Mellergård, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Mendez, Melissa
    University of Peruana Cayetano Heredia, Peru.
    Olsson, Tomas
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden.
    Pujana, Miguel A.
    Catalan Institute Oncol, Spain.
    Rasool, Omid
    University of Turku, Finland; Abo Akad University, Finland.
    Serra-Musach, Jordi
    Catalan Institute Oncol, Spain.
    Stenmarker, Margaretha
    County Council Jonköping, Sweden.
    Tripathi, Subhash
    University of Turku, Finland; Abo Akad University, Finland.
    Viitala, Miro
    University of Turku, Finland; Abo Akad University, Finland.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Allergicentrum US.
    A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases2015Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, nr 313, artikel-id 313ra178Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

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  • 56.
    Gustafsson, Mika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Barabasi, Albert-Laszlo
    Northeastern University, MA 02115 USA.
    Baranzini, Sergio
    University of Calif San Francisco, CA 94143 USA.
    Brunak, Soeren
    Technical University of Denmark, Denmark; University of Copenhagen, Denmark.
    Fan Chung, Kian
    University of London Imperial Coll Science Technology and Med, England.
    Federoff, Howard J.
    Georgetown University, DC 20057 USA.
    Gavin, Anne-Claude
    European Molecular Biol Lab, Germany.
    Meehan, Richard R.
    University of Edinburgh, Scotland.
    Picotti, Paola
    University of Zurich, Switzerland.
    Angel Pujana, Miguel
    Bellvitge Biomed Research Institute IDIBELL, Spain.
    Rajewsky, Nikolaus
    Max Delbruck Centre Molecular Med, Germany.
    Smith, Kenneth G. C.
    University of Cambridge, England; University of Cambridge, England.
    Sterk, Peter J.
    University of Amsterdam, Netherlands.
    Villoslada, Pablo
    Hospital Clin Barcelona, Spain; Hospital Clin Barcelona, Spain.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Modules, networks and systems medicine for understanding disease and aiding diagnosis2014Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 6, nr 82Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Many common diseases, such as asthma, diabetes or obesity, involve altered interactions between thousands of genes. High-throughput techniques (omics) allow identification of such genes and their products, but functional understanding is a formidable challenge. Network-based analyses of omics data have identified modules of disease-associated genes that have been used to obtain both a systems level and a molecular understanding of disease mechanisms. For example, in allergy a module was used to find a novel candidate gene that was validated by functional and clinical studies. Such analyses play important roles in systems medicine. This is an emerging discipline that aims to gain a translational understanding of the complex mechanisms underlying common diseases. In this review, we will explain and provide examples of how network-based analyses of omics data, in combination with functional and clinical studies, are aiding our understanding of disease, as well as helping to prioritize diagnostic markers or therapeutic candidate genes. Such analyses involve significant problems and limitations, which will be discussed. We also highlight the steps needed for clinical implementation.

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  • 57.
    Jay, Jeremy J.
    et al.
    Jackson Lab, USA .
    Eblen, John D.
    Oak Ridge National Lab, USA .
    Zhang, Yun
    Pioneer HiBred Int Inc, USA .
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Perkins, Andy D.
    Mississippi State University, USA .
    Saxton, Arnold M.
    University of Tennessee, USA .
    Voy, Brynn H.
    University of Tennessee, USA .
    Chesler, Elissa J.
    Jackson Lab, USA .
    Langston, Michael A.
    University of Tennessee, USA .
    A systematic comparison of genome-scale clustering algorithms2012Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A wealth of clustering algorithms has been applied to gene co-expression experiments. These algorithms cover a broad range of approaches, from conventional techniques such as k-means and hierarchical clustering, to graphical approaches such as k-clique communities, weighted gene co-expression networks (WGCNA) and paraclique. Comparison of these methods to evaluate their relative effectiveness provides guidance to algorithm selection, development and implementation. Most prior work on comparative clustering evaluation has focused on parametric methods. Graph theoretical methods are recent additions to the tool set for the global analysis and decomposition of microarray co-expression matrices that have not generally been included in earlier methodological comparisons. In the present study, a variety of parametric and graph theoretical clustering algorithms are compared using well-characterized transcriptomic data at a genome scale from Saccharomyces cerevisiae. Methods: For each clustering method under study, a variety of parameters were tested. Jaccard similarity was used to measure each clusters agreement with every GO and KEGG annotation set, and the highest Jaccard score was assigned to the cluster. Clusters were grouped into small, medium, and large bins, and the Jaccard score of the top five scoring clusters in each bin were averaged and reported as the best average top 5 (BAT5) score for the particular method. Results: Clusters produced by each method were evaluated based upon the positive match to known pathways. This produces a readily interpretable ranking of the relative effectiveness of clustering on the genes. Methods were also tested to determine whether they were able to identify clusters consistent with those identified by other clustering methods. Conclusions: Validation of clusters against known gene classifications demonstrate that for this data, graph-based techniques outperform conventional clustering approaches, suggesting that further development and application of combinatorial strategies is warranted.

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  • 58.
    Johansson, S.
    et al.
    Department of Pediatrics, Göteborg University, Queen Silvia Children's Hospital, Sweden.
    Keen, C.
    Department of Pediatrics, Göteborg University, Queen Silvia Children's Hospital, Sweden.
    Ståhl, A.
    , Göteborg University, Sahlgrenska Hospital, Göteborg, Sweden.
    Wennergren, G.
    Department of Pediatrics, Göteborg University, Queen Silvia Children's Hospital, Sweden.
    Benson, Mikael
    Department of Pediatrics, Göteborg University, Queen Silvia Children's Hospital, Sweden.
    Low levels of CC16 in nasal fluid of children with birch pollen-induced rhinitis2005Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 60, nr 5, s. 638-642Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:  Clara cell protein 16 (CC16; secretoglobin 1A1) is an anti-inflammatory protein mainly expressed in the epithelial cells in the airways.

    Objective:  To compare the levels of CC16 in nasal lavage (NAL) from children with intermittent allergic rhinitis and healthy controls and to study the effect of a local steroid.

    Methods:  Thirty schoolchildren with birch pollen allergy and 30 healthy controls from the same schools were included in the study. The NAL fluid was collected before the season, during the birch pollen season and, for the patients, after 1 week of treatment with a local steroid. Symptom scores were obtained on every occasion. CC16 and eosinophil cationic protein (ECP) were analyzed with enzyme-linked immunosorbent assay.

    Results:  The nasal fluid levels of CC16 were significantly lower in patients than in controls, before and during pollen season. Before the season, the median CC16 concentrations were 9.1 (range 1.1–117) μg/l in patients and 25.7 (6.1–110.2) μg/l in controls. During the season, the median CC16 concentrations in nasal fluid were 12.9 (2.3–89.7) μg/l in the allergic children and 22.0 (9.5–90.1) μg/l in the healthy controls (P = 0.0005). Symptom scores, nasal fluid eosinophils and ECP were higher in patients during the season. Treatment with a local steroid did not change the CC16 levels.

    Conclusions:  Nasal fluid CC16 levels were lower in children with birch pollen-induced allergic rhinitis than in healthy controls both before and during the pollen season. We speculate that reduction in anti-inflammatory activity by CC16 may contribute to the pathogenesis of allergic rhinitis.

  • 59.
    Keen, Christina
    et al.
    Department of Pediatrics, Göteborg University, Göteborg, Sweden.
    Johansson, Sofi
    Department of Pediatrics, Göteborg University, Göteborg, Sweden.
    Reinholdt, Jesper
    Department of Oral Biology, Royal Dental College, Aarhus, Denmark.
    Benson, Mikael
    Department of Pediatrics, Göteborg University, Göteborg, Sweden.
    Wennergren, Göran
    Department of Pediatrics, Göteborg University, Göteborg, Sweden.
    Bet v 1-specific IgA increases during the pollen season but not after a single allergen challenge in children with birch pollen-induced intermittent allergic rhinitis2005Ingår i: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 16, nr 3, s. 209-216Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Allergen-specific immunoglobulins of the Immunoglobulin A (IgA) type have been found in the nasal fluid of patients with allergic rhinitis. IgA may play a protective role, but there are also data which show that allergen-specific IgA can induce eosinophil degranulation. The aim of this study was to quantitate Bet v 1-specific IgA in relation to total IgA in the nasal fluid of children with birch pollen-induced intermittent allergic rhinitis and healthy controls, after allergen challenge and during the natural pollen season. Eosinophil cationic protein (ECP), Bet v 1-specific IgA and total IgA were analyzed in nasal fluids from 30 children with birch pollen-induced intermittent allergic rhinitis and 30 healthy controls. Samples were taken before the pollen season, after challenge with birch pollen and during the pollen season, before and after treatment with nasal steroids. During the pollen season, but not after nasal allergen challenge, Bet v 1-specific IgA increased in relation to total IgA in children with allergic rhinitis. No change was found in the healthy controls. The ratio of Bet v 1-specific IgA to total IgA increased from 0.1 x 10(-3) (median) to 0.5 x 10(-3) in the allergic children, p < 0.001. No change was seen after treatment with nasal steroids, although symptoms, ECP and eosinophils were reduced. In conclusion, allergen-specific IgA in relation to total IgA increases in nasal fluids during the pollen season in allergic children but not in healthy controls. These findings are compatible with the hypothesis that allergen-specific IgA plays a role in the allergic inflammation and further studies are needed to clarify the functional role of these allergen-specific antibodies.

  • 60.
    Kinhult, J
    et al.
    Malmö University Hospital, Sweden.
    Egesten, A
    Malmö University Hospital, Sweden.
    Benson, Mikael
    Malmö University Hospital, Sweden.
    Uddman, R
    Malmö University Hospital, Sweden.
    Cardell, L O
    Malmö University Hospital, Sweden.
    Increased expression of surface activation markers on neutrophils following migration into the nasal lumen2003Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 33, nr 8, s. 1141-1146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The sequence of events following the recruitment of a free-flowing neutrophil in the peripheral circulation, via adhesion, migration and release of mediators, to a neutrophil on the surface of the nasal epithelium is a co-ordinated process. Little is known about the state of neutrophil activation following this course of events.

    OBJECTIVES: To investigate the expression of surface activation markers on neutrophils, reflecting activation during their recruitment to the nose, and to see whether the inflammatory process during allergic rhinitis influences this process.

    METHOD: Nine healthy controls and 12 patients with grass pollen-induced intermittent allergic rhinitis were investigated during the peak of the pollen season. The expression of CD11b, CD66b and CD63 on the neutrophil cell surface, as a reflection of activation, was analysed using flow cytometry. Neutrophils were derived from peripheral blood and nasal lavage fluid. In addition, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) as well as L-, P- and E-selectins in the nasal lavage fluid were analysed using RIA and ELISA, respectively.

    RESULTS: A marked increase in the expression of all three CD markers on the neutrophil cell surface was noticed following migration from the bloodstream to the surface of the nasal mucosa. At the peak of the grass pollen season, the MPO levels increased, reflecting an increase in the total number of nasal fluid neutrophils. In parallel, the expression of CD11b was further augmented. The expression of the CDb11b was reduced on neutrophils remaining in the circulation. In addition, the level of L-selectin was reduced on neutrophils derived from the blood during allergic inflammation.

    CONCLUSION: Neutrophils might become activated during their transfer from the blood to the surface of the nasal mucosa, but these changes may also be due to depletion of activated neutrophils in the blood via activated endothelial/epithelial adhesion and chemoattractant measures. The increased expression of surface activation markers during allergic rhinitis suggests roles for neutrophils in the inflammatory process.

  • 61.
    Mansson Kvarnhammar, Anne
    et al.
    Karolinska Institute.
    Rydberg, Camilla
    Karolinska Institute.
    Jarnkrants, Malin
    Karolinska Institute.
    Eriksson, Mia
    Karolinska Institute.
    Uddman, Rolf
    Skåne University Hospital.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Cardell, Lars-Olaf
    Karolinska Institute.
    Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines2012Ingår i: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 13, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: S100A7 is an antimicrobial peptide involved in several inflammatory diseases. The aim of the present study was to explore the expression and regulation of S100A7 in seasonal allergic rhinitis (SAR). less thanbrgreater than less thanbrgreater thanMethods: Nasal lavage (NAL) fluid was obtained from healthy controls before and after lipopolysaccharide (LPS) provocation, from SAR patients before and after allergen challenge, and from SAR patients having completed allergen-specific immunotherapy (ASIT). Nasal biopsies, nasal epithelial cells and blood were acquired from healthy donors. The airway epithelial cell line FaDu was used for in vitro experiments. Real-time RT-PCR and immunohistochemistry were used to determine S100A7 expression in nasal tissue and cells. Release of S100A7 in NAL and culture supernatants was measured by ELISA. The function of recombinant S100A7 was explored in epithelial cells, neutrophils and peripheral blood mononuclear cells (PBMC). less thanbrgreater than less thanbrgreater thanResults: Nasal administration of LPS induced S100A7 release in healthy non-allergic subjects. The level of S100A7 was lower in NAL from SAR patients than from healthy controls, and it was further reduced in the SAR group 6 h post allergen provocation. In contrast, ASIT patients displayed higher levels after completed treatment. S100A7 was expressed in the nasal epithelium and in glands, and it was secreted by cultured epithelial cells. Stimulation with IL-4 and histamine repressed the epithelial S100A7 release. Further, recombinant S100A7 induced activation of neutrophils and PBMC. less thanbrgreater than less thanbrgreater thanConclusions: The present study shows an epithelial expression and excretion of S100A7 in the nose after microbial stimulation. The levels are diminished in rhinitis patients and in the presence of an allergic cytokine milieu, suggesting that the antimicrobial defense is compromised in patients with SAR.

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  • 62.
    Menditto, E.
    et al.
    CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; University of Naples Federico II, Naples, Italy.
    Costa, E.
    UCIBIO, REQUIMTE, Faculty of Pharmacy, and Competence Center on Active and Healthy Ageing of University of Porto (Porto4Ageing), University of Porto, Porto, Portugal.
    Midão, L.
    UCIBIO, REQUIMTE, Faculty of Pharmacy, and Competence Center on Active and Healthy Ageing of University of Porto (Porto4Ageing), University of Porto, Porto, Portugal.
    Bosnic-Anticevich, S.
    Woolcock Institute of Medical Research, University of Sydney Woolcock Emphysema Centre and Sydney Local Health District, Glebe, NSW, Australia.
    Novellino, E.
    University of Naples Federico II, Naples, Italy.
    Bialek, S.
    Department of Biochemistry and Clinical Chemistry, Faculty of Pharmacy with the Division of Laboratory Medicine, Warsaw Medical University, Warsaw, Poland.
    Briedis, V.
    Lithuanian University of Health Sciences, Kaunas, Lithuania.
    Mair, A.
    DG for Health and Social Care, Scottish Government, Edinburgh, United Kingdom.
    Rajabian-Soderlund, R.
    Department of Nephrology and Endocrinology, Karolinska University Hospital, Stockholm, Sweden.
    Arnavielhe, S.
    KYomed INNOV, Montpellier, France.
    Bedbrook, A.
    MACVIA-France, Fondation partenariale FMC VIA-LR, Montpellier, France.
    Czarlewski, W.
    Medical Consulting Czarlewski, Levallois, France.
    Annesi-Maesano, I.
    Epidemiology of Allergic and Respiratory Diseases, Department Institute Pierre Louis of Epidemiology and Public Health, INSERM and Sorbonne Université, Medical School Saint Antoine, Paris, France.
    Anto, J.M.
    ISGlobAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; IMIM (Hospital del Mar Research Institute), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
    Devillier, P.
    Laboratoire de Pharmacologie Respiratoire UPRES EA220, Hôpital Foch, Suresnes, France; Université Versailles Saint-Quentin, Université Paris Saclay, Paris Saclay, France.
    De, Vries G.
    Peercode BV, Geldermalsen, Netherlands.
    Keil, T.
    Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany; Institute for Clinical Epidemiology and Biometry, University of Wuerzburg, Wuerzburg, Germany.
    Sheikh, A.
    The Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, United Kingdom.
    Orlando, V.
    CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; University of Naples Federico II, Naples, Italy.
    Larenas-Linnemann, D.
    Center of Excellence in Asthma and Allergy, Médica Sur Clinical Foundation and Hospital, México City, Mexico.
    Cecchi, L.
    SOS Allergology and Clinical Immunology, USL Toscana Centro, Prato, Italy.
    De, Feo G.
    Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy.
    Illario, M.
    Division for Health Innovation, Campania Region and Federico II University Hospital Naples (RandD and DISMET), Naples, Italy.
    Stellato, C.
    Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy.
    Fonseca, J.
    CINTESIS, Center for Research in Health Technologies and Information Systems, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; MEDIDA, Lda, Porto, Portugal.
    Malva, J.
    Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, Coimbra, Portugal; Ageing@Coimbra EIP-AHA Reference Site, Coimbra, Portugal.
    Morais-Almeida, M.
    Allergy Center, CUF Descobertas Hospital, Lisbon, Portugal.
    Pereira, A.M.
    Allergy Unit, CUF-Porto Hospital and Institute, Porto, Portugal; Center for Research in Health Technologies and Information Systems CINTESIS, Universidade do Porto, Porto, Portugal.
    Todo-Bom, A.M.
    Imunoalergologia, Centro Hospitalar Universitário de Coimbra and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
    Kvedariene, V.
    Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
    Valiulis, A.
    Department of Public Health, Clinic of Childrens Diseases, and Institute of Health Sciences, Vilnius University Institute of Clinical Medicine, Vilnius, Lithuania; European Academy of Paediatrics (EAP/UEMS-SP), Brussels, Belgium.
    Bergmann, K.C.
    Charité – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Department of Dermatology and Allergy, Comprehensive Allergy Center, Berlin Institute of Health, Berlin, Germany.
    Klimek, L.
    Euforea, Brussels, Belgium.
    Mösges, R.
    Medical Faculty, Institute of Medical Statistics, and Computational Biology, University of Cologne, Cologne, Germany; CRI-Clinical Research International-Ltd, Hamburg, Germany.
    Pfaar, O.
    Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Phillipps-Universität Marburg, Germany.
    Zuberbier, T.
    Charité – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Department of Dermatology and Allergy, Comprehensive Allergy Center, Berlin Institute of Health, Berlin, Germany.
    Cardona, V.
    Allergy Section, Department of Internal Medicine, Hospital Vall dHebron, and ARADyAL Spanish Research Network, Barcelona, Spain.
    Mullol, J.
    Rhinology Unit and Smell Clinic, ENT Department, Hospital Clínic, Barcelona, Spain; Clinical and Experimental Respiratory Immunoallergy, IDIBAPS, CIBERES, University of Barcelona, Barcelona, Spain.
    Papadopoulos, N.G.
    Division of Infection, Immunityand Respiratory Medicine, Royal Manchester Childrens Hospital, University of Manchester, Manchester, United Kingdom; Allergy Department, 2nd Pediatric Clinic, Athens General Childrens Hospital “PandA Kyriakou”, University of Athens, Athens, Greece.
    Prokopakis, E.P.
    Department of Otorhinolaryngology, University of Crete School of Medicine, Heraklion, Greece.
    Bewick, M.
    iQ4U Consultants Ltd, London, United Kingdom.
    Ryan, D.
    Allergy and Respiratory Research Group, The University of Edinburgh, Edinburgh, United Kingdom.
    Roller-Wirnsberger, R.E.
    Department of Internal Medicine, Medical University of Graz, Graz, Austria.
    Tomazic, P.V.
    Department of ENT, Medical University of Graz, Graz, Austria.
    Cruz, A.A.
    ProAR – Nucleo de Excelencia em Asma, Federal University of Bahia, Salvador, Brazil; WHO GARD Planning Group, Salvador, Brazil.
    Kuna, P.
    Division of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland.
    Samolinski, B.
    Department of Prevention of Envinronmental Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland.
    Fokkens, W.J.
    Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, Netherlands.
    Reitsma, S.
    Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, Netherlands.
    Bosse, I.
    Allergist, La Rochelle, France.
    Fontaine, J.-F.
    Allergist, Reims, France.
    Laune, D.
    KYomed INNOV, Montpellier, France.
    Haahtela, T.
    Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Toppila-Salmi, S.
    Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Bachert, C.
    Upper Airways Research Laboratory, ENT Department, Ghent University Hospital, Ghent, Belgium.
    Hellings, P.W.
    Euforea, Brussels, Belgium.
    Melén, E.
    Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wickman, M.
    Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden.
    Bindslev-Jensen, C.
    Department of Dermatology and Allergy Centre, Odense University Hospital, Odense Research Center for Anaphylaxis (ORCA), Odense, Denmark.
    Eller, E.
    Department of Dermatology and Allergy Centre, Odense University Hospital, Odense Research Center for Anaphylaxis (ORCA), Odense, Denmark.
    OHehir, R.E.
    Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC, Australia; Department of Immunology, Monash University, Melbourne, VIC, Australia.
    Cingi, C.
    ENT Department, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey.
    Gemicioglu, B.
    Department of Pulmonary Diseases, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
    Kalayci, O.
    Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, Ankara, Turkey.
    Ivancevich, J.C.
    Servicio de Alergia e Immunologia, Clinica Santa Isabel, Buenos Aires, Argentina.
    Bousquet, J.
    Euforea, Brussels, Belgium.
    the, MASK group
    Adherence to treatment in allergic rhinitis using mobile technology. The MASK Study2019Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, nr 4, s. 442-460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Mobile technology may help to better understand the adherence to treatment. MASK‐rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient‐centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries.

    Objectives

    To assess the adherence to treatment in allergic rhinitis patients using the Allergy DiaryApp.

    Methods

    An observational cross‐sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach.

    Results

    A total of 12 143 users were registered. A total of 6 949 users reported at least one VAS data recording. Among them, 1 887 users reported ≥7 VAS data. About 1 195 subjects were included in the analysis of adherence. One hundred and thirty‐six (11.28%) users were adherent (MPR ≥70% and PDC ≤1.25), 51 (4.23%) were partly adherent (MPR ≥70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non‐adherent to medications (MPR <70%). Of those, the largest group was non‐adherent to medications and the time interval was increased in 442 (36.68%) users.

    Conclusion and clinical relevance

    Adherence to treatment is low. The relative efficacy of continuous vs on‐demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication‐taking behaviour in a real‐world setting.

  • 63.
    Mobini, Reza
    et al.
    Unit for Clinical Systems Biology, Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Bengt A.
    Department of Immunology, Sahlgrenska Academy, Gothenburg, Sweden.
    Erjefält, Jonas
    Department of Experimental Medicine, Lund University, Lund, Sweden.
    Hahn-Zoric, Mirjana
    Department of Immunology, Sahlgrenska Academy, Gothenburg, Sweden.
    Langston, Michael A.
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, TN, USA.
    Perkins, Andy D.
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, TN, USA.
    Cardell, Lars Olaf
    Department of Oto-rhino-largyngeology, Karolinska Institute, Stockholm, Sweden.
    Benson, Mikael
    Unit for Clinical Systems Biology, Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden.
    A module-based analytical strategy to identify novel disease-associated genes shows an inhibitory role for interleukin 7 Receptor in allergic inflammation2009Ingår i: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 3, nr 19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The identification of novel genes by high-throughput studies of complex diseases is complicated by the large number of potential genes. However, since disease-associated genes tend to interact, one solution is to arrange them in modules based on co-expression data and known gene interactions. The hypothesis of this study was that such a module could be a) found and validated in allergic disease and b) used to find and validate one ore more novel disease-associated genes.

    RESULTS: To test these hypotheses integrated analysis of a large number of gene expression microarray experiments from different forms of allergy was performed. This led to the identification of an experimentally validated reference gene that was used to construct a module of co-expressed and interacting genes. This module was validated in an independent material, by replicating the expression changes in allergen-challenged CD4+ cells. Moreover, the changes were reversed following treatment with corticosteroids. The module contained several novel disease-associated genes, of which the one with the highest number of interactions with known disease genes, IL7R, was selected for further validation. The expression levels of IL7R in allergen challenged CD4+ cells decreased following challenge but increased after treatment. This suggested an inhibitory role, which was confirmed by functional studies.

    CONCLUSION: We propose that a module-based analytical strategy is generally applicable to find novel genes in complex diseases.

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  • 64.
    Månsson, Anne
    et al.
    Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Fransson, Mattias
    Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Adner, Mikael
    Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Benson, Mikael
    Department of Pediatrics, Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Uddman, Rolf
    Laboratory of Clinical and Experimental Allergy Research, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Björnsson, Sven
    Department of Clinical Chemistry, Malmö University Hospital, Lund University, Malmö, Sweden.
    Cardell, Lars-Olaf
    Division of ENT Diseases Huddinge, Karolinska Institutet, Stockholm, Sweden .
    TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis2010Ingår i: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 151, nr 2, s. 118-128Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND/AIM: Viral respiratory infections are increasingly implicated in allergic exacerbations. Virus-induced activation of eosinophils through Toll-like receptors (TLRs) could be involved. The present study was designed to examine TLR3 expression in eosinophils from bone marrow (BM) and peripheral blood (PB) during symptomatic allergic rhinitis, and to evaluate the functional responsiveness of TLR3 in purified eosinophils.

    METHODS: BM and PB samples were obtained from healthy volunteers and patients with seasonal allergic rhinitis outside and during the pollen season. Eosinophils were analyzed for TLR3 expression by flow cytometry. Polyinosinic:polycytidylic acid [poly(I:C)], an agonist for TLR3, was used to assess its functional role in purified eosinophils and the intracellular signaling pathways involved.

    RESULTS: TLR3 expression was demonstrated in BM and PB eosinophils. It was higher in BM-derived than in circulating cells and it was downregulated in both compartments during symptomatic allergic rhinitis. TLR3 expression was also downregulated in the presence of interleukin (IL)-4 and IL- 5. Stimulation with poly(I:C) increased the percentage of CD11b+ cells and enhanced the secretion of IL-8, effects mediated via the p38 mitogen-activated protein kinases and nuclear factor-kappaB signaling pathways. Moreover, pretreatment with IL-5 augmented the poly(I:C)-induced IL-8 release.

    CONCLUSIONS: Eosinophils activated via TLR3 might be more able to home and recruit leukocytes to sites of inflammation. The decreased TLR3 expression during symptomatic allergic rhinitis and in the presence of Th2 cytokines indicates a role in allergic airway inflammation. Thus, eosinophils might function as a link between viral infections and exacerbations of allergic disease.

  • 65.
    Nestor, Colm
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Barrenäs, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Lentini, Antonio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Bruhn, Sören
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Jornsten, Rebecka
    University of Gothenburg, Sweden .
    Langston, Michael A.
    University of Tennessee, TN USA .
    Rogers, Gary
    University of Tennessee, TN USA .
    Gustafsson, Mika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4(+) T-Cell Population Structure2014Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 1, s. e1004059-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Altered DNA methylation patterns in CD4(+) T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its welldefined phenotype and etiology. We generated genome-wide DNA methylation (N-patients = 8, N-controls = 8) and gene expression (N-patients = 9, N-controls = 10) profiles of CD4(+) T-cells from SAR patients and healthy controls using Illuminas HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (N-patients = 12, N-controls = 12), but not by gene expression (N-patients = 21, N-controls = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (N-patients = 35) and controls (N-controls = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4(+) T cells.

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  • 66.
    Nestor, Colm E
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Dadfa, Elham
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Björkander, Jan Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Sublingual immunotherapy alters expression of IL-4 and its soluble and membrane-bound receptors2014Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, nr 11, s. 1564-1566Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Seasonal allergic rhinitis (SAR) is a disease of increasing prevalence, which results from an inappropriate T-helper cell, type 2 (Th2) response to pollen. Specific immunotherapy (SIT) involves repeated treatment with small doses of pollen and can result in complete and lasting reversal of SAR. Here, we assayed the key Th2 cytokine, IL-4, and its soluble and membrane-bound receptor in SAR patients before and after SIT. Using allergen-challenge assays, we found that SIT treatment decreased IL-4 cytokine levels, as previously reported. We also observed a significant decrease in the IL-4 membrane-bound receptor (mIL4R) at both the level of mRNA and protein. SIT treatment resulted in a significant increase in the inhibitory soluble IL-4 receptor (sIL4R). Reciprocal changes in mIL4R and sIL4R were also observed in patient serum. Altered mIL4R and sIL4R is a novel explanation for the positive effects of immunotherapy with potential basic and clinical research implications.

  • 67.
    Nestor, Colm E
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Ottaviano, Raffaele
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Reinhardt, Diana
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Cruickshanks, Hazel A
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    Mjoseng, Heidi K
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
    McPherson, Rhoanne C
    MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
    Lentini, Antonio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Thomson, John P
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK .
    Dunican, Donncha S
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK .
    Pennings, Sari
    Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
    Anderton, Stephen M
    MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Hjärt- och Medicincentrum, Allergicentrum US.
    Meehan, Richard R
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK .
    Rapid reprogramming of epigenetic and transcriptional profiles in mammalian culture systems.2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, s. 11-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundThe DNA methylation profile of mammalian cell lines differs from the primary tissue from which they were derived, exhibiting increasing divergence from the in vivo methylation profile with extended time in culture. Few studies have directly examined the initial epigenetic and transcriptional consequences of adaptation of primary mammalian cells to culture, and the potential mechanisms through which this epigenetic dysregulation occurs is unknown.ResultsWe demonstrate that adaptation of mouse embryonic fibroblast, MEFS, to cell culture results in a rapid reprogramming of epigenetic and transcriptional states. We observed global 5-hydroxymethylcytosine (5hmC) erasure within three days of culture initiation. Loss of genic 5hmC was independent of global 5-methylcytosine (5mC) levels and could be partially rescued by addition of Vitamin C. Significantly, 5hmC loss was not linked to concomitant changes in transcription. Discrete promoter-specific gains of 5mC were also observed within seven days of culture initiation. Against this background of global 5hmC loss we identified a handful of developmentally important genes that maintained their 5hmC profile in culture, including the imprinted loci Gnas and H19. Similar outcomes were identified in the adaption of CD4+ T-cells to culture.ConclusionsWe report a dramatic and novel consequence of adaptation of mammalian cells to culture in which global loss of 5hmC occurs; suggesting rapid concomitant loss of methylcytosine dioxygenase activity. The observed epigenetic and transcriptional re-programming occurs much earlier than previously assumed, and has significant implications for the use of cell lines as faithful mimics of in vivo epigenetic and physiological processes.

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  • 68.
    Nestor, Colm E
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting. MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Reddington, James P
    MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Meehan, Richard R
    MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Investigating 5-hydroxymethylcytosine (5hmC): the state of the art2014Ingår i: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1094, s. 243-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The discovery of 5-hydroxymethylcytosine (5hmC) as an abundant base in mammalian genomes has excited the field of epigenetics, and stimulated an intense period of research activity aimed at decoding its biological significance. However, initial research efforts were hampered by a lack of assays capable of specifically detecting 5hmC. Consequently, the last 3 years have seen the development of a plethora of new techniques designed to detect both global levels and locus-specific profiles of 5hmC in mammalian genomes. This research effort has culminated in the recent publication of two complementary techniques for quantitative, base-resolution mapping of 5hmC in mammalian genomes, the first true mammalian hydroxymethylomes. Here, we review the techniques currently available to researchers studying 5hmC, discuss their advantages and disadvantages, and explore the technical hurdles which remain to be overcome.

  • 69.
    Olsson, M.
    et al.
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Broberg, A.
    Department of Dermatology, Sahlgrenska Academy, Gothenburg, Sweden.
    Jernås, M.
    Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Gothenburg, Sweden.
    Carlsson, L.
    Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Gothenburg, Sweden.
    Rudemo, M.
    Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Suurküla, M.
    Department of Pathology, Sahlgrenska Academy, Gothenburg, Sweden.
    Svensson, P-A
    Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Gothenburg, Sweden.
    Benson, Mikael
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Increased expression of aquaporin 3 in atopic eczema2006Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 61, nr 9, s. 1132-1137Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Dry skin in atopic eczema depends on increased water loss. The mechanisms behind this are poorly understood. The aim of this work was to identify genes that may contribute to water loss in eczema.

    METHODS: Affymetrix DNA microarrays U133A were used to analyse gene expression in skin biopsies from 10 patients with atopic eczema and 10 healthy controls.

    RESULTS: DNA microarray analysis showed up-regulation of 262 genes and down-regulation of 129 genes in atopic eczema. The known functions of these genes were analysed using Gene Ontology to identify genes that could contribute to increased water loss. This led to identification of aquaporin 3 (AQP3), which has a key role in hydrating healthy epidermis. Increased expression of AQP3 was found in eczema compared with healthy skin. This was confirmed with real-time polymerase chain reaction (P<0.001). In healthy skin, epidermal AQP3 immunoreactivity was weak and mainly found in the stratum basale. A gradient was formed with decreasing AQP3 staining in the lower layers of the stratum spinosum. By contrast, in acute and chronic atopic eczema strong AQP3 staining was found in both the stratum basale and the stratum spinosum.

    CONCLUSIONS: Aquaporin 3 is the predominant aquaporin in human skin. Increased expression and altered cellular distribution of AQP3 is found in eczema and this may contribute to water loss.

  • 70.
    Pedicini, Marco
    et al.
    Istituto per le Applicazioni del Calcolo “Mauro Picone”, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy.
    Barrenäs, Fredrik
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Clancy, Trevor
    Department of Tumor Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo, Norway.
    Castiglione, Filippo
    Istituto per le Applicazioni del Calcolo “Mauro Picone”, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy.
    Hovig, Eivind
    Department of Tumor Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo, Norway / The Institute for Medical Informatics, Rikshospitalet, Oslo University Hospital, Oslo, Norway / Department of Informatics, University of Oslo, Oslo, Norway.
    Kanduri, Kartiek
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Santoni, Daniele
    Istituto per le Applicazioni del Calcolo “Mauro Picone”, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy / Barcelona Institute for Research in Biomedicine (IRB), Barcelona Science Park, Barcelona, Spain.
    Benson, Mikael
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden / Unit for Pediatric Allergology, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation2010Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 6, nr 12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.

  • 71.
    Schoenrock, Andrew
    et al.
    Carleton University, Ottawa, Canada.
    Samanfar, Bahram
    Carleton University, Ottawa, Canada.
    Pitre, Sylvain
    Carleton University, Ottawa, Canada.
    Hooshyar, Mohsen
    Carleton University, Ottawa, Canada.
    Jin, Ke
    University of Toronto, Toronto, Canada.
    Phillips, Charles A
    University of Tennessee, Knoxville, Tennessee, USA.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Gothenburg University, Gothenburg, Sweden.
    Phanse, Sadhna
    University of Toronto, Toronto, Canada.
    Omidi, Katayoun
    University of Toronto, Toronto, Canada.
    Gui, Yuan
    University of Toronto, Toronto, Canada.
    Alamgir, Md
    University of Toronto, Toronto, Canada.
    Wong, Alex
    University of Toronto, Toronto, Canada.
    Barrenäs, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Gothenburg University, Gothenburg, Sweden.
    Babu, Mohan
    University of Regina, Regina, Saskatchewan, Canada.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping. Gothenburg University, Gothenburg, Sweden.
    Langston, Michael A
    Carleton University, Ottawa, Canada.
    Green, James R
    Carleton University, Ottawa, Canada.
    Dehne, Frank
    Carleton University, Ottawa, Canada.
    Golshani, Ashkan
    Carleton University, Ottawa, Canada.
    Efficient prediction of human protein-protein interactions at a global scale2014Ingår i: BMC bioinformatics, ISSN 1471-2105, Vol. 15, nr 1, s. 383-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundOur knowledge of global protein-protein interaction (PPI) networks in complex organisms such as humans is hindered by technical limitations of current methods.ResultsOn the basis of short co-occurring polypeptide regions, we developed a tool called MP-PIPE capable of predicting a global human PPI network within 3 months. With a recall of 23% at a precision of 82.1%, we predicted 172,132 putative PPIs. We demonstrate the usefulness of these predictions through a range of experiments.ConclusionsThe speed and accuracy associated with MP-PIPE can make this a potential tool to study individual human PPI networks (from genomic sequences alone) for personalized medicine.

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  • 72.
    Sjogren, A-K M
    et al.
    University of Gothenburg.
    Barrenäs, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Muraro, A
    Padua Gen University Hospital.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Saetrom, P
    University of Gothenburg.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Monozygotic twins discordant for intermittent allergic rhinitis differ in mRNA and protein levels2012Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 67, nr 6, s. 831-833Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Monozygotic (MZ) twins discordant for complex diseases may help to find disease mechanisms that are not due to genetic variants. Intermittent allergic rhinitis (IAR) is an optimal disease model because it occurs at defined time points each year, owing to known external antigens. We hypothesized that MZ twins discordant for IAR could help to find gene expression differences that are not dependent on genetic variants. We collected blood outside of the season from MZ twins discordant for IAR, challenged their peripheral blood mononuclear cells (PBMC) with pollen allergen in vitro, collected supernatants and isolated CD4+ T cells. We identified disease-relevant mRNAs and proteins that differed between the discordant MZ twins. By contrast, no differences in microRNA expression were found. Our results indicate that MZ twins discordant for IAR is an optimal model to identify disease mechanisms that are not due to genetic variants.

  • 73.
    Skogberg, Gabriel
    et al.
    University of Gothenburg, Sweden.
    Gudmundsdottir, Judith
    University of Gothenburg, Sweden.
    van der Post, Sjoerd
    University of Gothenburg, Sweden.
    Sandstrom, Kerstin
    University of Gothenburg, Sweden.
    Bruhn, Sören
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Mincheva-Nilsson, Lucia
    Umeå University, Sweden.
    Baranov, Vladimir
    Umeå University, Sweden.
    Telemo, Esbjorn
    University of Gothenburg, Sweden.
    Ekwall, Olov
    University of Gothenburg, Sweden.
    Characterization of Human Thymic Exosomes2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exosomes are nanosized membrane-bound vesicles that are released by various cell types and are capable of carrying proteins, lipids and RNAs which can be delivered to recipient cells. Exosomes play a role in intercellular communication and have been described to mediate immunologic information. In this article we report the first isolation and characterization of exosomes from human thymic tissue. Using electron microscopy, particle size determination, density gradient measurement, flow cytometry, proteomic analysis and microRNA profiling we describe the morphology, size, density, protein composition and microRNA content of human thymic exosomes. The thymic exosomes share characteristics with previously described exosomes such as antigen presentation molecules, but they also exhibit thymus specific features regarding surface markers, protein content and microRNA profile. Interestingly, thymic exosomes carry proteins that have a tissue restricted expression in the periphery which may suggest a role in T cell selection and the induction of central tolerance. We speculate that thymic exosomes may provide the means for intercellular information exchange necessary for negative selection and regulatory T cell formation of the developing thymocytes within the human thymic medulla.

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  • 74.
    Wang, H.
    et al.
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Mobini, R.
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Fang, Y.
    Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Immunology, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
    Barrenäs, F.
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Zhang, H.
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden / Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
    Xiang, Z.
    Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Benson, Mikael
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden / The Pediatric Allergy Unit, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Allergen challenge of peripheral blood mononuclear cells from patients with seasonal allergic rhinitis increases IL-17RB, which regulates basophil apoptosis and degranulation2010Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 40, nr 8, s. 1194-1202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Previously, expression profiling has been used to analyse allergen-challenged T-helper type 2 cells, nasal biopsies and nasal fluid cells from patients with seasonal allergic rhinitis (SAR). Allergen-challenged peripheral blood mononuclear cells (PBMCs) provide a human in vitro model of how antigen-presenting cells, CD4+ T cells and effector cells such as basophils interact in allergic inflammation.

    OBJECTIVE: To identify novel genes and pathways in allergen-challenged PBMCs from patients with SAR using gene expression profiling and functional studies.

    METHODS: PBMCs from 11 patients with SAR and 23 healthy controls were analysed with gene expression profiling. mRNA expression of IL17RB in basophils was evaluated using quantitative real-time PCR. Membrane protein expression and apoptosis of basophils were examined by flow cytometry. Degranulation of basophils was assessed by measuring beta-hexosaminidase release. Cytokine release was measured using ELISA.

    RESULTS: Gene expression microarray analysis of allergen-challenged PBMCs showed that 209 out of 44000 genes were differentially expressed in patients compared with controls. IL17RB was the gene whose expression increased most in patients (P<0.0001). FACS analysis of PBMCs showed, for the first time, that basophils express IL-17RB. Following allergen challenge, IL-17RB protein increased significantly on basophils from patients compared with controls (P<0.05). IL-3 significantly increased both mRNA and protein expressions of IL17RB. Activation of IL-17RB by its ligand, IL-25, inhibited apoptosis of basophils. Moreover, IgE-mediated degranulation was enhanced by IL-25.

    CONCLUSION: Increased expression of IL-17RB on allergen-challenged basophil is regulated by IL-3, inhibits apoptosis and promotes IgE-mediated degranulation of basophils.

  • 75.
    Wang, Hui
    et al.
    Unit for Clinical Systems Biology, Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden.
    Barrenäs, Fredrik
    Unit for Clinical Systems Biology, Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden.
    Bruhn, Sören
    Unit for Clinical Systems Biology, Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden.
    Mobini, Reza
    Unit for Clinical Systems Biology, Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden.
    Benson, Mikael
    Unit for Clinical Systems Biology, Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden.
    Increased IFN-gamma activity in seasonal allergic rhinitis is decreased by corticosteroid treatment2009Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 124, nr 6, s. 1360-1362Artikel i tidskrift (Refereegranskat)
  • 76.
    Wang, Hui
    et al.
    University of Gothenburg, Sweden.
    Chavali, S.
    University of Gothenburg, Sweden.
    Mobini, R.
    University of Gothenburg, Sweden.
    Muraro, A.
    University of Padua, Italy.
    Barbon, F.
    University of Padua, Italy.
    Boldrin, D.
    University of Padua, Italy.
    Aberg, N.
    The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Benson, Mikael
    The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    A pathway-based approach to find novel markers of local glucocorticoid treatment in intermittent allergic rhinitis2011Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 66, nr 1, s. 132-140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Glucocorticoids (GCs) may affect the expression of hundreds of genes in different cells and tissues from patients with intermittent allergic rhinitis (IAR). It is a formidable challenge to understand these complex changes by studying individual genes. In this study, we aimed to identify (i) pathways affected by local GC treatment and (ii) examine if those pathways could be used to find novel markers of local GC treatment in nasal fluids from patients with IAR. METHODS: Gene expression microarray- and iTRAQ-based proteomic analyses of nasal fluids, nasal fluid cells and nasal mucosa from patients with IAR were performed to find pathways enriched for differentially expressed genes and proteins. Proteins representing those pathways were analyzed with ELISA in an independent material of nasal fluids from 23 patients with IAR before and after treatment with a local GC. RESULTS: Transcriptomal and proteomic high-throughput analyses of nasal fluids, nasal fluid cells and nasal mucosal showed that local GC treatment affected a wide variety of pathways in IAR such as the glucocorticoid receptor pathway and the acute phase response pathway. Extracellular proteins encoded by genes in those pathways were analyzed in an independent material of nasal fluids from patients. Proteins that changed significantly in expression included known biomarkers such as eosinophil cationic protein but also proteins that had not been previously described in IAR, namely CCL2, M-CSF, CXCL6 and apoH. CONCLUSION: Pathway-based analyses of genomic and proteomic high-throughput data can be used as a complementary approach to identify novel potential markers of GC treatment in IAR.

  • 77.
    Wang, Hui
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Gottfries, Johan
    University of Gothenburg.
    Barrenäs, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Identification of Novel Biomarkers in Seasonal Allergic Rhinitis by Combining Proteomic, Multivariate and Pathway Analysis2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 8, s. e23563-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Glucocorticoids (GCs) play a key role in the treatment of seasonal allergic rhinitis (SAR). However, some patients show a low response to GC treatment. We hypothesized that proteins that correlated to discrimination between symptomatic high and low responders (HR and LR) to GC treatment might be regulated by GCs and therefore suitable as biomarkers for GC treatment.

    Methodology/Principal Findings: We identified 953 nasal fluid proteins in symptomatic HR and LR with a LC MS/MS based-quantitative proteomics analysis and performed multivariate analysis to identify a combination of proteins that best separated symptomatic HR and LR. Pathway analysis showed that those proteins were most enriched in the acute phase response pathway. We prioritized candidate biomarkers for GC treatment based on the multivariate and pathway analysis. Next, we tested if those candidate biomarkers differed before and after GC treatment in nasal fluids from 40 patients with SAR using ELISA. Several proteins including ORM (P<0.0001), APOH (P<0.0001), FGA (P<0.01), CTSD (P<0.05) and SERPINB3 (P<0.05) differed significantly before and after GC treatment. Particularly, ORM (P<0.01), FGA (P<0.05) and APOH (P<0.01) that belonged to the acute phase response pathway decreased significantly in HR but not LR before and after GC treatment.

    Conclusions/Significance: We identified several novel biomarkers for GC treatment response in SAR with combined proteomics, multivariate and pathway analysis. The analytical principles may be generally applicable to identify biomarkers in clinical studies of complex diseases.

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  • 78.
    Wang, Kai
    et al.
    University of Tennessee, Knoxville, USA.
    Phillips, Charles A
    University of Tennessee, Knoxville, USA.
    Rogers, Gary L
    National Institute for Computational Sciences, Oak Ridge, Tennessee, USA.
    Barrenäs, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Langston, Michael A
    University of Tennessee, Knoxville, USA.
    Differential Shannon entropy and differential coefficient of variation: alternatives and augmentations to differential expression in the search for disease-related genes2014Ingår i: International journal of computational biology and drug design, ISSN 1756-0756, Vol. 7, nr 2-3, s. 183-94Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Differential expression has been a standard tool for analysing case-control transcriptomic data since the advent of microarray technology. It has proved invaluable in characterising the molecular mechanisms of disease. Nevertheless, the expression profile of a gene across samples can be perturbed in ways that leave the expression level unaltered, while a biological effect is nonetheless present. This paper describes and analyses differential Shannon entropy and differential coefficient of variation, two alternate techniques for identifying genes of interest. Ontological analysis across 16 human disease datasets demonstrates that these alternatives are effective at identifying disease-related genes not found by mere differential expression alone. Because the two alternate techniques are based on somewhat different mathematical formulations, they tend to produce somewhat different gene lists. Moreover, each may pinpoint genes completely overlooked by the other. Thus, measures of entropy and variation can be used to replace or better yet augment standard differential expression computations.

  • 79.
    Zhang, Huan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Cardell, Lars Olaf
    Division of ENT diseases Huddinge, CLINTEC, Karolinska Institute, Stockholm, Sweden.
    Björkander, Janne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Comprehensive Profiling of Peripheral Immune Cells and Subsets in Patients with Intermittent Allergic Rhinitis Compared to Healthy Controls and After Treatment with Glucocorticoids2013Ingår i: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 36, nr 4, s. 821-829Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intermittent allergic rhinitis (IAR) is a common allergic disease, which is associated with local infiltration of T cells, eosinophils, and basophils. However, changes of circulating inflammatory cells may reflect local and systemic allergic inflammation and potentially, also the response to treatment with glucocorticoids (GCs). In this study, we comprehensively profiled peripheral blood immune cells and subsets from 12 patients with IAR during the birch pollen season before and after GC treatment and nine healthy controls by flow cytometry. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified that peripheral immune cells and subsets markedly separated symptomatic patients and controls. Eosinophils, basophils, and Th2 cells contributed most to the separation. However, there was no good separation between patients before and after GC treatment. Local allergic inflammation in the nasal mucosa is associated with increased circulating Th2 cells, eosinophils, and basophils. Local GC treatment has limited effects on circulating immune cells.

  • 80.
    Zhang, Huan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Nestor, Colm E
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Chung, Kian Fan
    Experimental Studies, National Heart and Lung Institute, Imperial College London, London, UK / NIHR Respiratory Biomedical Research Unit at the Royal Brompton NHS Foundation Trust and Imperial College London, London, UK; Royal Brompton NHS Fdn Trust, NIHR Resp Biomed Res Unit, London, England.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Targeted omics and systems medicine: personalising care2014Ingår i: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 2, nr 10, s. 785-787Artikel i tidskrift (Övrigt vetenskapligt)
  • 81.
    Zhang, Huan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Zhao, Shuli
    Nanjing Medical University, Nanjing, China.
    Lentini, Antonio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bohle, Barbara
    Medical University of Vienna, Austria.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Profiling of human CD4+ T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS12013Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 132, nr 4, s. 1005-1008Artikel i tidskrift (Övrigt vetenskapligt)
  • 82.
    Zhao, Yelin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Muraro, Antonella
    University of Padua, Italy .
    Bruhn, Sören
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Combined Multivariate and Pathway Analyses Show That Allergen-Induced Gene Expression Changes in CD4(+) T Cells Are Reversed by Glucocorticoids2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Glucocorticoids (GCs) play a key role in the treatment of allergy. However, the genome-wide effects of GCs on gene expression in allergen-challenged CD4(+) T cells have not been described. The aim of this study was to perform a genome-wide analysis to investigate whether allergen-induced gene expression changes in CD4(+) T cells could be reversed by GCs. Methodology/Principal Findings: Gene expression microarray analysis was performed to profile gene expression in diluent( D), allergen- (A), and allergen + hydrocortisone- (T) challenged CD4(+) T cells from patients with seasonal allergic rhinitis. Principal component analysis (PCA) showed good separation of the three groups. To identify the correlation between changes in gene expression in allergen-challenged CD4(+) T cells before and after GC treatment, we performed orthogonal partial least squares discriminant analysis (OPLS-DA) followed by Pearson correlation analysis. This revealed that allergen-induced genes were widely reversed by GC treatment (r = -0.77, Pless than0.0001). We extracted 547 genes reversed by GC treatment from OPLS-DA models based on their high contribution to the discrimination and found that those genes belonged to several different inflammatory pathways including TNFR2 Signalling, Interferon Signalling, Glucocorticoid Receptor Signalling and T Helper Cell Differentiation. The results were supported by gene expression microarray analyses of two independent materials. Conclusions/Significance: Allergen-induced gene expression changes in CD4(+) T cells were reversed by treatment with glucocorticoids. The top allergen-induced genes that reversed by GC treatment belonged to several inflammatory pathways and genes of known or potential relevance for allergy.

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  • 83.
    Zhou, Yuan
    et al.
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Wang, Cong
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Qiu, Xuefeng
    Nanjing University, Peoples R China.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Allergicentrum US.
    Yin, Xiaoqin
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Xiang, Zou
    University of Gothenburg, Sweden.
    Li, Dongmei
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Han, Xiaodong
    Nanjing University, Peoples R China; Nanjing University, Peoples R China; Nanjing University, Peoples R China.
    Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity2015Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 287, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microcystin (MC)-LR, a cyclic heptapeptide, is a potent reproductive system toxin. To understand the molecular mechanisms of MC-induced reproductive system cytotoxicity, we evaluated global changes of miRNA and mRNA expression in mouse Sertoli cells following MC-LR treatment. Our results revealed that the exposure to MC-LR resulted in an altered miRNA expression profile that might be responsible for the modulation of mRNA expression. Bio-functional analysis indicated that the altered genes were involved in specific cellular processes, including cell death and proliferation. Target gene analysis suggested that junction injury in Sertoli cells exposed to MC-LR might be mediated by miRNAs through the regulation of the Sertoli cell-Sertoli cell pathway. Collectively, these findings may enhance our understanding on the modes of action of MC-LR on mouse Sertoli cells as well as the molecular mechanisms underlying the toxicity of MC-LR on the male reproductive system.

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