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  • 1. Abu-Elyazeed, R R
    et al.
    Heineman, T
    Dubin, G
    Fourneau, M
    Leroux-Roels, I
    Leroux-Roels, G
    Richardus, J H
    Ostergaard, L
    Diez-Domingo, J
    Poder, A
    Van Damme, P
    Romanowski, B
    Blatter, M
    Silfverdal, Sven Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, J
    Josefsson, A
    Cunningham, A L
    Flodmark, C E
    Tragiannidis, A
    Dobson, S
    Olafsson, J
    Puig-Barbera, J
    Mendez, M
    Barton, S
    Bernstein, D
    Mares, J
    Ratner, P
    Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age: results from a randomised, controlled, double-blind trial2013In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 31, no 51, p. 6136-6143Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed.

    METHODS: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus.

    RESULTS: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants.

    CONCLUSION: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.

  • 2. Anantharajah, Ahalieyah
    et al.
    Faure, Emmanuel
    Buyck, Julien M.
    Sundin, Charlotta
    Creative Antibiotics, Umeå, Sweden .
    Lindmark, Tuulikki
    Mecsas, Joan
    Yahr, Timothy L.
    Tulkens, Paul M.
    Mingeot-Leclercq, Marie-Paule
    Guery, Benoît
    Van Bambeke, Françoise
    Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation2016In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 7, p. 1105-1116Article in journal (Refereed)
    Abstract [en]

    With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are 2 virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces interleukin 1 beta (IL-1 beta) release and reduces interleukin 17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis. Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination and IL-1 beta secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality, as evidenced by a reduction in secretory activity and flagellar motility and an increase in adenosine triphosphate levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising therapeutic approach.

  • 3.
    Anderl, Ines
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere, Tampere, Finland.
    Vesala, Laura
    Ihalainen, Teemu O.
    Vanha-aho, Leena-Maija
    Andó, István
    Rämet, Mika
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere, Tampere, Finland.
    Transdifferentiation and Proliferation in Two Distinct Hemocyte Lineages in Drosophila melanogaster Larvae after Wasp Infection2016In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, no 7, article id e1005746Article in journal (Refereed)
    Abstract [en]

    Cellular immune responses require the generation and recruitment of diverse blood cell types that recognize and kill pathogens. In Drosophila melanogaster larvae, immune-inducible lamellocytes participate in recognizing and killing parasitoid wasp eggs. However, the sequence of events required for lamellocyte generation remains controversial. To study the cellular immune system, we developed a flow cytometry approach using in vivo reporters for lamellocytes as well as for plasmatocytes, the main hemocyte type in healthy larvae. We found that two different blood cell lineages, the plasmatocyte and lamellocyte lineages, contribute to the generation of lamellocytes in a demand-adapted hematopoietic process. Plasmatocytes transdifferentiate into lamellocyte-like cells in situ directly on the wasp egg. In parallel, a novel population of infection-induced cells, which we named lamelloblasts, appears in the circulation. Lamelloblasts proliferate vigorously and develop into the major class of circulating lamellocytes. Our data indicate that lamellocyte differentiation upon wasp parasitism is a plastic and dynamic process. Flow cytometry with in vivo hemocyte reporters can be used to study this phenomenon in detail.

  • 4.
    Andersen, Grethe
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hägglund, M
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Petrovska, R
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J E S
    Quantitative measurement of the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin peptide gene expression in subsets of human peripheral blood leucocytes2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 3, p. 279-284Article in journal (Refereed)
    Abstract [en]

    Levels of the melanocortin receptor (MCR) 1, 2, 3 and 5 subtypes and pro-opio-melanocortin (POMC) protein mRNA were measured by the real-time quantitative reverse transcriptase polymerase chain reaction method in CD4+ T helper (Th) cells, CD8+ T cytotoxic cells, CD19+ B cells, CD56+ natural killer (NK) cells, CD14+ monocytes and CD15+ granulocytes from healthy donors. We found high levels of all of the MC1, 2, 3 and 5R subtype mRNA in Th cells and moderate levels in NK cells, monocytes and granulocytes. POMC peptide mRNA was found in all examined leucocyte subsets, but only low levels were present in granulocytes. Our findings suggest a co-ordinating role for MCR subtypes and their naturally occurring ligands in the co-operation between innate and adaptive immunity. Moreover, our findings are compatible with earlier finding of MCR-mediated tolerance induction in Th cells.

  • 5. Andersen, M.
    et al.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Meyer, M. K.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Andersen, G. N.
    Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8(+) T Cytotoxic Lymphocytes and CD19(+) B Lymphocytes in Rheumatoid Arthritis Responding to TNF- Inhibition2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 1, p. 31-39Article in journal (Refereed)
    Abstract [en]

    Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF- inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4(+) T helper (h) lymphocytes (ly), CD8(+) T cytotoxic (c) ly, CD19(+) B ly and CD14(+) monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8(+) Tc and CD19(+) B ly was significant. Fold change in MC1-5R and IFN gene expressions correlated significantly in CD8(+) Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1 gene expressions correlated significantly in CD4(+) Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8(+) Tc ly and CD19(+) B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8(+) Tc ly and CD4(+) Th ly point at a central immune modulating function of the melanocortin system in RA.

  • 6. Andersen, M.
    et al.
    Olesen, M. K.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Andersen, G. N.
    Vendsyssel Hosp, Clin Res Ctr, Rheumatol Unit, Hjorring, Denmark.
    Adalimumab (Humira (R)) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+leucocyte subsets in rheumatoid arthritis2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no Suppl. 127, p. 25-26 Meeting Abstr. PP119Article in journal (Other academic)
  • 7.
    Andersson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Bjerg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lundbäck, Bo
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    The clinical expression of asthma in schoolchildren has changed between 1996 and 20062010In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 21, no 5, p. 859-866Article in journal (Refereed)
    Abstract [en]

    Several studies have reported diverging trends in the prevalence of asthma and wheeze. The aim of this study was to investigate the clinical expression of childhood asthma in 1996 and 2006 by studying asthma morbidity, treatment, and environmental exposures in school children with physician-diagnosed asthma and wheeze, respectively. All children enrolled in first or second grade (7-8 yr-old) in three municipalities in northern Sweden were invited to a questionnaire study in 1996 and 2006, respectively. In 1996, 3430 (97%) participated; and in 2006, 2585 (96%) participated. The same parental completed questionnaire, including the ISAAC questions, was used in both surveys. Physician-diagnosed asthma was reported at 5.7% in 1996 and 7.4% in 2006. A significantly greater proportion of children with asthma were using inhaled corticosteroids (ICS) in 2006, 67% vs. 55% in 1996. This increase was parallel to a major decrease in severe asthma symptoms such as disturbed sleep because of wheeze (49% vs. 38%) and troublesome asthma (21% vs. 11%). The prevalence of current wheeze among the asthmatics decreased significantly; however, this was seen only among children not using ICS. Parental smoking decreased significantly as did the proportion living in damp buildings. In conclusion, although asthma remains a major public health issue in school age children, children with asthma had less respiratory symptoms and a better asthma control in 2006 compared to 1996. This parallels with an increase in treatment with ICS, more beneficial environmental conditions, and an increased diagnostic intensity resulting in a larger proportion of children with mild symptoms being diagnosed as having asthma.

  • 8.
    Andersson, Yvonne
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lönnerdal, Bo
    Department of Nutrition, University of California, Davis, CA 95616.
    Graverholt, Gitte
    Arla Foods Ingredients, Aarhus, Denmark.
    Fält, Helen
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Formula feeding skews immune cell composition toward adaptive immunity compared to breastfeeding2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 7, p. 4322-4328Article in journal (Refereed)
    Abstract [en]

    The ontogeny of the immune system and the effect thereon by type of infant feeding is incompletely understood. We analyzed frequencies and composition of immune cells in blood of breastfed (BF) and formula-fed (FF) infants at 1.5, 4, and 6 mo of age. Three formulas with the same protein concentration but with varying levels of alpha-lactalbumin and caseinoglycomacropeptide were compared. Twenty-nine exclusively BF infants served as reference, and 17 infants in each formula group completed the study. Whole blood and PBMCs were analyzed by flow cytometry and immunoflow cytometry, respectively. Leukocyte count of BF infants increased with time due to increased frequency of neutrophils. Lymphocyte count was high at 1.5 mo and was unchanged over time, as were the relative proportions of CD4+ alphabetaT cells, CD8+ alphabetaT cells, B cells, NK cells, and gammadeltaT cells. Most CD45R0+CD3+ cells were HLA-DR- and hence memory cells. Compared with breastfeeding, formula feeding resulted in a significant decrease in proportion of NK cells, but a significant increase in naive CD4+ alphabetaT cells and an elevated CD4-to-CD8 ratio, that is, 3.3 in the combined FF groups compared with 2.6 in the BF group. No significant differences were found between the three groups of FF infants. In conclusion, blood cells of lymphoid lineage did not change significantly in frequencies or composition from 1.5 to 6 mo of age in BF infants. In contrast, FF infants displayed an ongoing maturation of adaptive immunity cells and a delayed recruitment of innate immunity cells as compared with BF infants.

  • 9. Apcher, Sebastien
    et al.
    Martins, Rodrigo Prado
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Equipe Labellisée la Ligue Contre le Cancer, Inserm UMR1162, Université Paris, France ; RECAMO, Masaryk Memorial Cancer Institute, Czech Republic.
    The source of MHC class I presented peptides and its implications2016In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 40, p. 117-122Article, review/survey (Refereed)
    Abstract [en]

    The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-todate account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.

  • 10. Arnheim, L
    et al.
    Dillner, Joakim
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden.
    Sanjeevi, CB
    A population-based cohort study of KIR genes and genotypes in relation to cervical intraepithelial neoplasia2005In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 65, no 3, p. 252-259Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are involved both in control of virus infections and in elimination of tumor cells. Killer immunoglobulin-like receptors (KIRs) either activate or inhibit NK cell-mediated cytolysis, protecting healthy cells from destruction while enabling killing of abnormal cells. To investigate whether KIR genes or genotypes are associated with cervical carcinogenesis, a nested case-control study of 65 case women with cervical intraepithelial neoplasia (CIN) diagnosed during a 6-year follow-up of 15,234 women and 150 control women from the same cohort that remained healthy was performed. More than 70 different genotypes were observed, and 33 of which had not been described previously. An A-genotype including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, and KIR2DS4 was associated with increased risk of CIN (OR 6.7; 95% CI 1.7-26.3), and KIR2DL5B*002 appeared to have an inverse association with disease (OR 0.5; 95% CI 0.5-2.9). There was no association of CIN with the number of activating KIR genes. There was also no association between KIR genes and type of human papilloma virus or with other CIN-related immune response genes. It was concluded that certain KIR genes and genotypes may associate with cervical neoplasia.

  • 11.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ska obeprövade metoder få användas i svensk sjukvård?2017In: PIObladet, ISSN 1103-6249, no 2, p. 10-11Article in journal (Other academic)
  • 12. Baharom, Faezzah
    et al.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smed-Sorensen, Anna
    Human Lung Mononuclear Phagocytes in Health and Disease2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 499Article, review/survey (Refereed)
    Abstract [en]

    The lungs are vulnerable to attack by respiratory insults such as toxins, allergens, and pathogens, given their continuous exposure to the air we breathe. Our immune system has evolved to provide protection against an array of potential threats without causing collateral damage to the lung tissue. In order to swiftly detect invading pathogens, monocytes, macrophages, and dendritic cells (DCs)-together termed mononuclear phagocytes (MNPs)-line the respiratory tract with the key task of surveying the lung microenvironment in order to discriminate between harmless and harmful antigens and initiate immune responses when necessary. Each cell type excels at specific tasks: monocytes produce large amounts of cytokines, macrophages are highly phagocytic, whereas DCs excel at activating naive T cells. Extensive studies in murine models have established a division of labor between the different populations of MNPs at steady state and during infection or inflammation. However, a translation of important findings in mice is only beginning to be explored in humans, given the challenge of working with rare cells in inaccessible human tissues. Important progress has been made in recent years on the phenotype and function of human lung MNPs. In addition to a substantial population of alveolar macrophages, three subsets of DCs have been identified in the human airways at steady state. More recently, monocyte-derived cells have also been described in healthy human lungs. Depending on the source of samples, such as lung tissue resections or bronchoalveolar lavage, the specific subsets of MNPs recovered may differ. This review provides an update on existing studies investigating human respiratory MNP populations during health and disease. Often, inflammatory MNPs are found to accumulate in the lungs of patients with pulmonary conditions. In respiratory infections or inflammatory diseases, this may contribute to disease severity, but in cancer patients this may improve clinical outcomes. By expanding on this knowledge, specific lung MNPs may be targeted or modulated in order to attain favorable responses that can improve preventive or treatment strategies against respiratory infections, lung cancer, or lung inflammatory diseases.

  • 13.
    Bailey, Leslie
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Chlamydia pneumoniae infection results in generalized bone loss in mice2008In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 10-11, p. 1175-1181Article in journal (Refereed)
  • 14.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse2017In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 6, p. 363-369Article in journal (Refereed)
    Abstract [en]

    The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.

  • 15.
    Bas, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Extrathymic T cell receptor gene rearrangement in human alimentary tract2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    T lymphocytes regulate the initiation, duration, and magnitude of adaptive immune responses and function as effector cells in cell mediated immunity. To become immunologically competent they must generate functional antigen receptors. This process takes place in the thymus and requires somatic recombination of T cell receptor (TCR) genes. It is mediated by the endonucleases recombination activating gene-1 (RAG1) and RAG2. Although the thymus regresses at puberty, T cells are present throughout life implying that other tissues must provide the proper milieu for T cell development. This thesis describes extrathymic T cell maturation in man. RAG1, RAG2, and the preTα-chain (pTα), which is exclusively utilized in developing T cells, were used as markers for TCR gene rearrangement. Two new exons (1A and 1B) encoding sequences in the 5’ untranslated region (5’UTR) of mRNA were discovered in the human RAG1 gene. The previously described 5’UTR exon (renamed 1C) was located between the new exons and exon 2, the latter containing the entire coding sequence. We found that small intestinal lymphocytes of the T cell lineage expressed the new exons in three different splice forms. RAG1 mRNA containing the 1C exon was not expressed in small intestinal lymphocytes. In contrast, splice forms containing the 1A exon were not expressed in thymocytes. RAG1 and pTα mRNA expressing lymphocytes were seen both within the epithelium and in lamina propria. Thymocyte-like CD2+CD7+CD3-, CD4+CD8+, CD1a+, and IL7-R+ lymphocytes were identified in the small intestinal mucosa. CD2+CD7+CD3- cells had the highest expression levels of mRNA for RAG1 and pTα, suggesting that the small intestinal mucosa is indeed a site for T cell maturation. Small intestinal T lymphocytes were also shown to kill via the Fas/FasL pathway in a TCR/CD3 independent manner and via the perforin/granzyme pathway in a TCR/CD3 dependent manner. The Fas/FasL-mediated cytotoxicity may reflect an ongoing selection process of extrathymically maturated T cells.

    The nasopharyngeal tonsil is the major inductive site for immune reactions against inhaled antigens. Previous demonstration of RAG1 expression in tonsillar B cells was interpreted as antigen driven receptor revision. The present study confirms the expression of RAG1 in B cells. We also found that RAG1, RAG2, and pTa mRNAs were expressed in lymphocytes of the T cell lineage. A small population of cells with the immature phenotype CD2+CD7+CD3- was demonstrated. This population had the highest expression levels of mRNA for RAG1, RAG2, pTα and terminal deoxynucleotidyl transferase. All four splice-forms of RAG1 mRNA were expressed. RAG1 and pTα mRNA expressing cells were mainly located in the proximity of the surface epithelium and in the outer rim of the follicles. These results suggest that the nasopharyngeal tonsil is a site where extrathymic T cell development and antigen driven TCR revision are occurring in parallel.

    Celiac disease (CD) is a small intestinal enteropathy characterized by permanent intolerance to gluten. Gluten reactive intestinal T cells are central in the pathogenesis and CD can be regarded as a failure to maintain tolerance to this food antigen. Expression of the RAG1 1A/2 splice form was significantly decreased in small intestinal T cell subsets of CD patients suggesting that impaired TCR gene rearrangement could contribute to failure of maintain tolerance in CD.

    Together, these findings show that both small intestinal and nasopharyngeal tonsillar lymphocytes of T cell lineage have the molecular machinery for antigen receptor rearrangement and that thymocyte-like lymphocytes are present in both tissues. Thus these organs are likely sites of T lymphocyte ontogeny as well as for secondary T cell receptor rearrangement in man.

  • 16.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology. Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Cilio, Corrado M
    Umeå University, Faculty of Medicine, Molecular Biology. Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Endocrine Research Unit, Wallenberg Laboratory, Malmö University Hospital MAS, University of Lund, 205 02 Malmö Sweden.
    Penha-Gonçalves, Carlos
    Umeå University, Faculty of Medicine, Molecular Biology. Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Lamhamedi-Cherradi, Salah-Eddine
    INSERM U25, Hopital Necker, Paris, France.
    Löfgren, Anna
    Umeå University, Faculty of Medicine, Molecular Biology.
    Colucci, Francesco
    Umeå University, Faculty of Medicine, Molecular Biology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Molecular Biology.
    Garchon, Henri-Jean
    INSERM U25, Hopital Necker, Paris, France.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Molecular Biology. Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 2, p. 105-113Article in journal (Refereed)
    Abstract [en]

    The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

  • 17.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Campino, Susana
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Penha-Gonçalves, Carlos
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains2003In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, no 7, p. 1677-1682Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.

  • 18.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Penha-Gonçalves, Carlos
    Gulbenkian Institute for Science, Oeiras, Portugal, PT.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Molecular Biology.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Molecular Biology.
    Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 8, p. 1054-1061Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. This mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development.

    Methods: We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes.

    Results: Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C57Bl/6 mice. This aberrant proliferation was most pronounced in CD4 /loCD8+ cells differentiating from the CD4CD8 to the CD4+CD8+ stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is linked to the insulin-dependent diabetes susceptibility locus Idd6.

    Conclusion/interpretation: Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.

  • 19. Berthold, Malin
    et al.
    Bjerg, Anders
    Winberg, Anna
    Mattsson, Lars
    Borres, Magnus
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Obstructive Lung Disease in Northern Sweden (OLIN) studies, Norrbotten county council, Luleå, Sweden.
    Association of Sensitization to Specific Pet Allergen Components with Asthma Symptoms in School Children2015In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 135, no 2, p. AB22-AB22Article in journal (Other academic)
    Abstract [en]

    Animal sensitization is a known determinant of asthma in children. The objective was to study the association of asthma with sensitization to pet allergen components in schoolchildren. Methods: A random sample of 696 children (11-12 y) from a Swedish population-based cohort was analyzed for sensitization (≥0.1 kUA/L) to cat, dog and horse dander extracts using ImmunoCAP. Sensitized children were further analyzed for IgE antibodies to animal allergen components using ImmunoCAP ISAC112. An expanded ISAAC questionnaire was completed by the parents. Results: Of 259 animal-sensitized children (37%) the majority (75%) were sensitized to more than one species. Among the 11 % (n=77) with current asthma 69 % were sensitized to at least one animal extract, as compared to one third of children without current asthma (p<0.001). Current asthma and asthma symptoms upon contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. Already at moderate levels of IgE antibodies to Fel d 4 (1-15 ISU), at which level most children were sensitized also to Fel d 1, the prevalence of asthma symptoms upon contact with cats was significantly increased. Dog-sensitized children were commonly sensitized to several dog components, and the greatest risk for asthma was seen in children co-sensitized to Can f 5 and Can f 1/f 2. Conclusions: Among Northern Swedish schoolchildren furry animals were the main perennial sensitizers. Asthma symptoms were associated with sensitizations to multiple components within an animal species. In particular, cat Fel d 4 sensitization was strongly related to asthma symptoms.

  • 20. Bielig, H
    et al.
    Rompikuntal, Pramod Kumar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Mitesh, Dongre
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Zurek, B
    Lindmark, B
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ramstedt, Madeleine
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kufer, T A
    University of Cologne.
    NOD-like receptor activation by outer-membrane vesicles (OMVs) from non-O1 non-O139 Vibrio cholerae is modulated by the quorum sensing regulator HapR2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 4, p. 1418-1427Article in journal (Refereed)
    Abstract [en]

    Vibrio cholerae is an inhabitant of aquatic systems and one of the causative agents of severe dehydrating diarrhea in humans. It has also emerged as an important cause of different kinds of inflammatory responses and in particular, V. cholerae strains of the non-O1 non-O139 serogroups (NOVC) have been associated with such infections in human. We analyzed the potential of outer membrane vesicles (OMVs) derived from the NOVC strain V:5/04 to induce inflammatory responses in human host cells. V:5/04 OMVs were taken up by human epithelial cells and induced inflammatory responses. siRNA-mediated gene knock-down revealed that the inflammatory potential of NOVC OMVs was partially mediated by the nucleotide-binding domain, leucine rich repeat containing family member NOD1. Physiochemical analysis of the content of these OMVs, in conjunction with NOD1 and NOD2 reporter assays in HEK293T cells, confirmed the presence of both NOD1 and NOD2 active peptidoglycan in the OMVs. Furthermore, we show that deletion of the quorum sensing regulator HapR which mimics an infective life style, specifically reduced the inflammatory potential of the V:5/04 OMVs and their ability to activate NOD1 and NOD2. In conclusion, our study shows that NOVC OMVs elicit immune responses mediated by NOD1 and NOD2 in mammalian host cells. Moreover, we provide evidence that the quorum sensing machinery plays an important regulatory role in this process by attenuating the inflammatory potential of OMVs in infective conditions. This work thus identified a new facet of how Vibrio affects host immune responses and defines a role for the quorum sensing machinery in this process.

  • 21.
    Bitar, Aziz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Vibrio cholerae modulates the immune defense of human gut mucosa2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The key function of innate immunity is to sense danger signals and initiate effective responses as a defense mechanism against pathogens. Simultaneously, effector responses must be regulated to avoid excessive inflammation with resulting tissue damage. microRNAs (miRNAs), are small endogenous molecules, that has recently gained attention as important regulatory elements in the human inflammation cascade. The control over host miRNA expression may represent a previously uncharacterized molecular strategy exploited by pathogens to mitigate innate host cell responses.

    Vibrio cholerae is a Gram-negative bacterium that colonizes the human small intestine and causes life-threatening secretory diarrhea, essentially mediated by cholera toxin (CT). It is considered a non-invasive pathogen and does not cause clinical inflammation. Still, cholera is associated with inflammatory changes of the small intestine. Furthermore, CT-negative strains of V. cholerae cause gastroenteritis and are associated with extra-intestinal manifestations, suggesting that other virulence factors than CT are also involved in the pathogenesis.

    The innate immune response to V. cholerae is poorly investigated and the potential role of miRNA in cholera had not been studied before. Therefore, this thesis explores the role of intestinal epithelial cells in response to V. cholerae infection with a focus on regulatory miRNA as a potential contributor to the pathogenesis. The in vivo material was small intestinal biopsies from patients suffering from V. cholerae infection. As an in vitro model for V. cholerae attack on intestinal epithelium, we used tight monolayers of T84 cells infected with V. cholerae and their released factors. We analyzed changes in levels of cytokines, immunomodulatory microRNA and their target genes.

    We showed that miRNA-146a and miRNA-155 reached significantly elevated levels in the intestinal mucosa at acute stages of disease in V. cholerae infected patients and declined to normal levels at the convalescent stage. Low-grade inflammation was identified at the acute stage of V. cholerae infection, which correlated with elevated levels of regulatory miRNA. Furthermore, outer membrane vesicles (OMVs) released by the bacteria were shown to induce miR-146a and live bacteria induced miR-155 in intestinal epithelial cells. In addition, OMVs decreased epithelial permeability and caused mRNA suppression of pro-inflammatory cytokines, including immune cell attractant IL-8 and CLL20, and the inflammasome markers IL-1b and IL-18. These results propose that V. cholerae regulates the host expression of miRNA during infection and may set the threshold for activation of the intestinal epithelium.

    Moreover, we showed that V. cholerae also harbors inflammatory-inducing capabilities, by secreting a pore-forming toxin, Vibrio cholerae cytolysin (VCC). By using genetically modified strains as well as soluble protein challenge experiments, VCC was found solely responsible for the increased epithelial permeability and induction of several pro-inflammatory cytokines in intestinal epithelial cells. In contrast to OMVs, VCC displayed strong upregulation of the pro-inflammatory cytokines IL-8, TNF-a, CCL20 and IL-1b and IRAK2, a key signaling molecule in the IL-1 inflammasome pathway. This suggest that VCC is an important virulence factor in the V. cholerae pathogenesis, particularly in CT-negative strains. Furthermore, we showed that the bacterium could control the inflammatory actions of VCC by secreting the PrtV protease, which degraded VCC and consequently abolished inflammation.  

    In summary, we showed that V. cholerae harbors immunomodulating capabilities, both at the gene level, through induction of host regulatory miRNA, and at the protein level, through secretion of VCC and PrtV. These strategies may be relevant for V. cholerae to promote survival in the gut and cause successful infections in the human host.

  • 22.
    Bitar, Aziz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kyaw, Min Aung
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Marie-Louise, Hammarström
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Wai, Sun Nynt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vibrio cholerae derived outer membrane vesicles modulate the inflammatory response ofhuman intestinal epithelial cells by inducing microRNA-146aIn: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed)
    Abstract [en]

    The small intestinal epithelium of Vibrio cholerae infected patients expresses the immunomodulatory microRNAs miR-146a and miR-155 at acute stage of disease. V. cholerae release outer membrane vesicles (OMVs) that serve as vehicles for translocation of virulencefactors including V. cholerae cytolysin (VCC). The aim was to investigate whether OMVs, with and/or without VCC-cargo could be responsible for induction of microRNAs in intestinal epithelial cells and thereby contribute to immunomodulation. Polarized tight monolayers of T84 cells were challenged with OMVs of wild-type and a VCC deletion mutant of the non-O1/non-O139 (NOVC) V. cholerae strain V:5/04 and with soluble VCC. OMVs, with and without VCC-cargo, caused significantly increased levels of miR-146a. Challenge with soluble VCC caused significant increases in interleukin-8 (IL-8), tumour necrosis factor-α(TNF-α), CCL20, IL-1β, and IRAK2 mRNA levels while challenge with OMVs did not causeany changes. Notably, OMVs from the VCC deficient mutant caused significant decreases in CCL20 and IL-18 mRNA levels. These results suggest that V. cholerae bacteria release OMVs that induce miR-146a in order to pave the way for colonization by reducing thestrength of an epithelial innate immune defence reaction and also preventing inflammation inthe mucosa that factors like VCC can evoke.

  • 23. Bjerg, Anders
    et al.
    Ekerljung, Linda
    Eriksson, Jonas
    Näslund, Jonas
    Sjölander, Sigrid
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Gothenburg University, Göteborg.
    Dahl, Åslög
    Holmberg, Kenneth
    Wennergren, Göran
    Torén, Kjell
    Borres, Magnus P
    Lötvall, Jan
    Lundbäck, Bo
    Increase in pollen sensitization in Swedish adults and protective effect of keeping animals in childhood2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 10, p. 1328-1336Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To date, most studies of the "allergy epidemic" have been based on self-reported data. There is still limited knowledge on time trends in allergic sensitization, especially among adults.

    OBJECTIVE: To study allergic sensitization, its risk factors, and time trends in prevalence.

    METHODS: Within West Sweden Asthma Study (WSAS) a population-based sample of 788 adults (17-60y) underwent skin prick tests (SPT) for 11 aeroallergens 2009-2012. Specific IgE was analyzed in 750 of the participants. Those aged 20-46y (n=379) were compared with the European Community Respiratory Health Survey sample aged 20-46y from the same area (n=591) in 1991-1992.

    RESULTS: Among those aged 20-46y the prevalence of positive SPT to pollen increased; timothy from 17.1% to 29.0% (p<0.001) and birch from 15.6% to 23.7% (p=0.002) between 1991-1992 and 2009-2012. Measurements of specific IgE confirmed these increases. Prevalence of sensitization to all other tested allergens was unchanged. In the full WSAS sample aged 17-60y any positive SPT was seen in 41.9%, and the dominating sensitizers were pollen (34.3%), animals (22.8%) and mites (12.6%). Pollen sensitization was strongly associated with rhinitis, whereas indoor allergens were more associated with asthma. Growing up with livestock or furred pets decreased the risk of sensitization, adjusted odds ratio 0.53 (0.28-0.995) and 0.68 (0.47-0.98) respectively.

    CONCLUSION: Pollen sensitization has increased in Swedish adults since the early 1990's, while the prevalence of sensitization to other allergens has remained unchanged. This is one plausible explanation for the increase in rhinitis 1990-2008 in Swedish adults, during which time the prevalence of asthma, which is more associated with perennial allergens, was stable. Contact with animals in childhood seems to reduce the risk of sensitization well into adulthood. One major factor contributing to the rise in pollen allergy is a significant increase in levels of birch and grass pollen over the past three decades.

  • 24.
    Bjerg, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Göteborg, Sweden.
    Winberg, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berthold, Malin
    Mattsson, Lars
    Borres, Magnus P
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Göteborg, Sweden.
    A population-based study of animal component sensitization, asthma, and rhinitis in schoolchildren2015In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 6, p. 557-563Article in journal (Refereed)
    Abstract [en]

    Background: Animal sensitization is a major determinant of asthma in children. Component-resolved studies of unselected pediatric populations are lacking. The aim was to describe sensitization to animal components and the association with asthma and rhinitis in animal-sensitized schoolchildren. Methods: A random sample of 696 children (11-12years) from a Swedish population-based cohort was tested for sensitization to cat, dog, and horse dander using ImmunoCAP. Sera from animal-sensitized children were further analyzed by microarray including three allergen components from cat, four from dog, and two from horse. The parents completed an expanded ISAAC questionnaire. Results: Of 259 animal-sensitized children (0.1 kU(A)/l), 51% were sensitized to all three, 23% to two, and 25% to one species. Current asthma and asthma symptoms following contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. This association was seen already at moderate-level sensitization (1-15 ISU) to Fel d 4, at which level most children were sensitized to Fel d 1, as well. In dog-sensitized children, the majority was sensitized to more than one dog component, and co-sensitization to Can f 5 and Can f 1/f 2 conferred the greatest risk for asthma. Sensitization to the highly cross-reactive serum albumins was uncommon and not associated with asthma. Conclusions: Among schoolchildren in northern Sweden, where mite allergy is uncommon, furry animals were the primary perennial sensitizers. Asthma was associated with higher levels of component sensitization, and sensitization to more than one component from the same animal conferred the greatest risk.

  • 25. Bjornsdottir, Halla
    et al.
    Christenson, Karin
    Forsman, Huamei
    Stylianou, Marios
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Urban, Constantin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Dahlgren, Claes
    Karlsson, Anna
    Bylund, Johan
    Cytotoxic Peptides from S. aureus Cause Neutrophil Cell Death with NET-like Features2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 432-432Article in journal (Other academic)
  • 26.
    Blomberg, Jeanette
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Höglund, Andreas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Jacobsson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line2011In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 16, no 8, p. 783-794Article in journal (Refereed)
    Abstract [en]

    Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.

  • 27.
    Boman, Jens
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindqvist, Helena
    Forsberg, Lars
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brief manual-based single-session Motivational Interviewing for reducing high-risk sexual behaviour in women: an evaluation2018In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 29, no 4, p. 396-403Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to develop and evaluate brief Motivational Interviewing (MI) to facilitate behaviour change in women at high risk of contracting sexually transmitted infections (STIs). One hundred and seventy-three women (mean age 24.7) at high risk of contracting STIs were randomized to a brief risk-reducing MI counselling intervention (n = 74) or assigned to the control group (n = 99). MI skill was assessed using the Motivational Interviewing Treatment Integrity (MITI) Coding System. Seventeen of 74 (23%) women tested for Chlamydia trachomatis (CT) in the MI intervention group and 22 of 99 (22%) in the control group had a genital CT infection 0-24 months before baseline. All additional CT testing was monitored up to 24 months for all 173 women in the study. None of the 49 CT-retested women in the MI group was CT infected, as compared to 3 of 72 (4%) women in the control group. A generalized estimating equations model with sexual high-risk behaviour measured at baseline and at six-month follow-up produced an adjusted estimated odds ratio of 0.38 (95% confidence interval = 0.158, 0.909), indicating efficacy. Brief manual-based single-session MI counselling seems to be effective in reducing high-risk sexual behaviour in women at high risk of acquiring STIs.

  • 28. Brenner, David
    et al.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Univ Ulm, Dept Neurol, Ulm, Germany.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice"2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 2, p. 530-Article in journal (Refereed)
  • 29. Browall, Sarah
    et al.
    Norman, Martin
    Tångrot, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Bioinformatics Infrastructure for Life Sciences, Computational Life Science Cluster.
    Galanis, Ilias
    Sjöstrom, Karin
    Dagerhamn, Jessica
    Hellberg, Christel
    Pathak, Anuj
    Spadafina, Tiziana
    Sandgren, Andreas
    Bättig, Patrick
    Franzén, Oscar
    Andersson, Björn
    Örtqvist, Åke
    Normark, Staffan
    Henriques-Normark, Birgitta
    Intraclonal Variations Among Streptococcus pneumoniae Isolates Influence the Likelihood of Invasive Disease in Children2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 3, p. 377-388Article in journal (Refereed)
    Abstract [en]

    Background. Pneumococcal serotypes are represented by a varying number of clonal lineages with different genetic contents, potentially affecting invasiveness. However, genetic variation within the same genetic lineage may be larger than anticipated. Methods. A total of 715 invasive and carriage isolates from children in the same region and during the same period were compared using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Bacterial genome sequencing, functional assays, and in vivo virulence mice studies were performed. Results. Clonal types of the same serotype but also intraclonal variants within clonal complexes (CCs) showed differences in invasive-disease potential. CC138, a common CC, was divided into several PFGE patterns, partly explained by number, location, and type of temperate bacteriophages. Whole-genome sequencing of 4 CC138 isolates representing PFGE clones with different invasive-disease potentials revealed intraclonal sequence variations of the virulence-associated proteins pneumococcal surface protein A (PspA) and pneumococcal choline-binding protein C (PspC). A carrier isolate lacking PcpA exhibited decreased virulence in mice, and there was a differential binding of human factor H, depending on invasiveness. Conclusions. Pneumococcal clonal types but also intraclonal variants exhibited different invasive-disease potentials in children. Intraclonal variants, reflecting different prophage contents, showed differences in major surface antigens. This suggests ongoing immune selection, such as that due to PspC-mediated complement resistance through varied human factor H binding, that may affect invasiveness in children.

  • 30.
    Bråbäck, Lennart
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Department of Research and Development, Västernorrland County Council and Sundsvalls sjukhus, Sundsvall.
    Ekéus, Cecilia
    Lowe, Adrian J
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Murdoch Childrens Research Institute and Centre for MEGA Epidemiology , School of Population Health, The University of Melbourne, Melbourne, Australia.
    Hjern, Anders
    Confounding with familial determinants affects the association between mode of delivery and childhood asthma medication: a national cohort study2013In: Allergy, Asthma & Clinical Immunology, ISSN 1710-1484, E-ISSN 1710-1492, Vol. 9, no 1, p. 14-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mode of delivery may affect the risk of asthma but the findings have not been consistent and factors shared by siblings may confound the associations in previous studies. METHODS: The association between mode of delivery and dispensed inhaled corticosteroid (ICS) (a marker of asthma) was examined in a register based national cohort (n=199 837). A cohort analysis of all first born children aged 2-5 and 6-9 years was performed. An age-matched sibling-pair analysis was also performed to account for shared genetic and environmental risk factors. RESULTS: Analyses of first-borns demonstrated that elective caesarean section was associated with an increased risk of dispensed ICS in both 2-5 (adjusted odds ratio (aOR)=1.19, 95% confidence interval (CI) 1.09-1.29) and 6-9 (aOR=1.21, 1.09-1.34) age groups. In the sibling-pair analysis, the increased risk associated with elective caesarean section was confirmed in 2-5 year olds (aOR=1.22, 1.05-1.43) but not in 6-9 year olds (aOR=1.06, 0.78-1.44). Emergency caesarean section and vacuum extraction had some association with dispensed ICS in the analyses of first-borns but these associations were not confirmed in the sibling-pair analyses. CONCLUSIONS: Confounding by familial factors affects the association between mode of delivery and dispensed ICS. Despite this confounding, there was some evidence that elective caesarean section contributed to a modestly increased risk of dispensed ICS but only up to five years of age.

  • 31.
    Bröms, Jeanette E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    IglG and IglI of the Francisella pathogenicity island are important virulence determinants of Francisella tularensis LVS2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 9, p. 3683-3696Article in journal (Refereed)
    Abstract [en]

    The Gram-negative bacterium Francisella tularensis is the causative agent of tularemia, a disease intimately associated with the multiplication of the bacterium within host macrophages. This in turn requires the expression of Francisella pathogenicity island (FPI) genes, believed to encode a type VI secretion system. While the exact functions of many of the components have yet to be revealed, some have been found to contribute to the ability of Francisella to cause systemic infection in mice as well as to prevent phagolysosomal fusion and facilitate escape into the host cytosol. Upon reaching this compartment, the bacterium rapidly multiplies, inhibits activation of the inflammasome, and ultimately causes apoptosis of the host cell. In this study, we analyzed the contribution of the FPI-encoded proteins IglG, IglI, and PdpE to the aforementioned processes in F. tularensis LVS. The ΔpdpE mutant behaved similarly to the parental strain in all investigated assays. In contrast, ΔiglG and ΔiglI mutants, although they were efficiently replicating in J774A.1 cells, both exhibited delayed phagosomal escape, conferred a delayed activation of the inflammasome, and exhibited reduced cytopathogenicity as well as marked attenuation in the mouse model. Thus, IglG and IglI play key roles for modulation of the intracellular host response and also for the virulence of F. tularensis.

  • 32.
    Carré, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindström, Richard
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lundqvist, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Asking about condom use: a key to individualized care when screening for chlamydia2011In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 22, no 8, p. 436-441Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis (CT) infection has been a target for both selective and national screening programmes, and Sweden has an opportunistic approach. A national plan of action states that risk groups should be identified and offered risk reduction counselling. Patients attending a drop-in sexually transmitted infection (STI) clinic reception at the University Hospital, Umeå, Sweden, were invited to complete a questionnaire regarding sociodemographic characteristics, symptoms and sexual risk behaviour; all had a CT test taken. A total of 1305 patients were included, 58% men, mean age 27.8 years. CT prevalence was 11%; 51% of those with CT were ≥ 25 years old. Only 5% used a condom during the entire sexual intercourse with their last new/temporary partner. Sexually active inconsistent condom users comprised 62% of the study population and contributed to 81% of the chlamydia infections. Asking whether a condom was used could quickly triage patients into groups with a 'higher risk' (none or inconsistent use of condoms and at least one new/temporary partners), and 'lower risk' (with more consistent condom use, although not always accurate) allowing for individualized care and counselling when screening for chlamydia. Evaluating whether a condom was used throughout the sexual intercourse did not add any useful information.

  • 33. Cerveny, Lukas
    et al.
    Straskova, Adela
    Dankova, Vera
    Hartlova, Anetta
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ceckova, Martina
    Staud, Frantisek
    Stulik, Jiri
    Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms2013In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 3, p. 629-635Article, review/survey (Refereed)
    Abstract [en]

    The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while high-lighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of Yersinia, Pseudomonas, and Shigella.

  • 34. Clendenen, Tess V
    et al.
    Koenig, Karen L
    Arslan, Alan A
    Lukanova, Annekatrin
    Berrino, Franco
    Gu, Yian
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Krogh, Vittorio
    Lokshin, Anna E
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Muti, Paola
    Marrangoni, Adele
    Nolen, Brian M
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Shore, Roy E
    Sieri, Sabina
    Zeleniuch-Jacquotte, Anne
    Factors associated with inflammation markers, a cross-sectional analysis2011In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 56, no 3, p. 769-778Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have reported associations between circulating inflammation markers and risk of chronic diseases. It is of interest to examine whether risk factors for these diseases are associated with inflammation. We conducted a cross-sectional analysis to evaluate whether reproductive and lifestyle factors and circulating vitamin D were associated with inflammation markers, including C-reactive protein, cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFα), and cytokine modulators (IL-1RA, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1/R2), among 616 healthy women. We confirmed associations of several inflammation markers with age and BMI. We also observed significantly higher levels of certain inflammation markers in postmenopausal vs. premenopausal women (TNFα, sIL-1RII, sIL-2Ra), with increasing parity (IL-12p40), and with higher circulating 25(OH) vitamin D (IL-13) and lower levels among current users of non-steroidal anti-inflammatory drugs (NSAIDs) (IL-1β, IL-2, IL-10, IL-12p70, and IL-12p40), current smokers (IL-4, IL-13, IL-12p40), and women with a family history of breast or ovarian cancer (IL-4, IL-10, IL-13). Our findings suggest that risk factors for chronic diseases (age, BMI, menopausal status, parity, NSAID use, family history of breast and ovarian cancer, and smoking) are associated with inflammation markers in healthy women.

  • 35. Codemo, Mario
    et al.
    Muschiol, Sandra
    Iovino, Federico
    Nannapaneni, Priyanka
    Plant, Laura
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriques-Normark, Birgitta
    Immunomodulatory Effects of Pneumococcal Extracellular Vesicles on Cellular and Humoral Host Defenses2018In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, no 2, article id e00559-18Article in journal (Refereed)
    Abstract [en]

    Gram-positive bacteria, including the major respiratory pathogen Streptococcus pneumoniae, were recently shown to produce extracellular vesicles (EVs) that likely originate from the plasma membrane and are released into the extracellular environment. EVs may function as cargo for many bacterial proteins, however, their involvement in cellular processes and their interactions with the innate immune system are poorly understood. Here, EVs from pneumococci were characterized and their immunomodulatory effects investigated. Pneumococcal EVs were protruding from the bacterial surface and released into the medium as 25 to 250 nm lipid stained vesicles containing a large number of cytosolic, membrane, and surface-associated proteins. The cytosolic pore-forming toxin pneumolysin was significantly enriched in EVs compared to a total bacterial lysate but was not required for EV formation. Pneumococcal EVs were internalized into A549 lung epithelial cells and human monocyte-derived dendritic cells and induced proinflammatory cytokine responses irrespective of pneumolysin content. EVs from encapsulated pneumococci were recognized by serum proteins, resulting in C3b deposition and formation of C5b-9 membrane attack complexes as well as factor H recruitment, depending on the presence of the choline binding protein PspC. Addition of EVs to human serum decreased opsonophagocytic killing of encapsulated pneumococci. Our data suggest that EVs may act in an immunomodulatory manner by allowing delivery of vesicle-associated proteins and other macromolecules into host cells. In addition, EVs expose targets for complement factors in serum, promoting pneumococcal evasion of humoral host defense.

    Importance: Streptococcus pneumoniae is a major contributor to morbidity and mortality worldwide, being the major cause of milder respiratory tract infections such as otitis and sinusitis and of severe infections such as community-acquired pneumonia, with or without septicemia, and meningitis. More knowledge is needed on how pneumococci interact with the host, deliver virulence factors, and activate immune defenses. Here we show that pneumococci form extracellular vesicles that emanate from the plasma membrane and contain virulence properties, including enrichment of pneumolysin. We found that pneumococcal vesicles can be internalized into epithelial and dendritic cells and bind complement proteins, thereby promoting pneumococcal evasion of complement-mediated opsonophagocytosis. They also induce pneumolysin-independent proinflammatory responses. We suggest that these vesicles can function as a mechanism for delivery of pneumococcal proteins and other immunomodulatory components into host cells and help pneumococci to avoid complement deposition and phagocytosis-mediated killing, thereby possibly contributing to the symptoms found in pneumococcal infections.

  • 36. Cohen, Cheryl
    et al.
    Walaza, Sibongile
    Moyes, Jocelyn
    Groome, Michelle
    Tempia, Stefano
    Pretorius, Marthi
    Hellferscee, Orienka
    Dawood, Halima
    Chhagan, Meera
    Naby, Fathima
    Haffejee, Summaya
    Variava, Ebrahim
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nzenze, Susan
    Tshangela, Akhona
    von Gottberg, Anne
    Wolter, Nicole
    Cohen, Adam L.
    Kgokong, Babatyi
    Venter, Marietjie
    Madhi, Shabir A.
    Epidemiology of Viral-associated Acute Lower Respiratory Tract Infection Among Children < 5 Years of Age in a High HIV Prevalence Setting, South Africa, 2009-20122015In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 34, no 1, p. 66-72Article in journal (Refereed)
    Abstract [en]

    Background: Data on the epidemiology of viral-associated acute lower respiratory tract infection (LRTI) from high HIV prevalence settings are limited. We aimed to describe LRTI hospitalizations among South African children aged < 5 years. Methods: We prospectively enrolled hospitalized children with physician-diagnosed LRTI from 5 sites in 4 provinces from 2009 to 2012. Using polymerase chain reaction (PCR), nasopharyngeal aspirates were tested for 10 viruses and blood for pneumococcal DNA. Incidence was estimated at 1 site with available population denominators. Results: We enrolled 8723 children aged < 5 years with LRTI, including 64% < 12 months. The case-fatality ratio was 2% (150/8512). HIV prevalence among tested children was 12% (705/5964). The overall prevalence of respiratory viruses identified was 78% (6517/8393), including 37% rhinovirus, 26% respiratory syncytial virus (RSV), 7% influenza and 5% human metapneumovirus. Four percent (253/6612) tested positive for pneumococcus. The annual incidence of LRTI hospitalization ranged from 2530 to 3173/100,000 population and was highest in infants (8446-10532/100,000). LRTI incidence was 1.1 to 3.0-fold greater in HIV-infected than HIV-uninfected children. In multivariable analysis, compared to HIV-uninfected children, HIV-infected children were more likely to require supplemental-oxygen [odds ratio (OR): 1.3, 95% confidence interval (CI): 1.1-1.7)], be hospitalized > 7 days (OR: 3.8, 95% CI: 2.8-5.0) and had a higher case-fatality ratio (OR: 4.2, 95% CI: 2.6-6.8). In multivariable analysis, HIV-infection (OR: 3.7, 95% CI: 2.2-6.1), pneumococcal coinfection (OR: 2.4, 95% CI: 1.1-5.6), mechanical ventilation (OR: 6.9, 95% CI: 2.7-17.6) and receipt of supplemental-oxygen (OR: 27.3, 95% CI: 13.2-55.9) were associated with death. Conclusions: HIV-infection was associated with an increased risk of LRTI hospitalization and death. A viral pathogen, commonly RSV, was identified in a high proportion of LRTI cases.

  • 37. Cohen, Cheryl
    et al.
    Walaza, Sibongile
    Moyes, Jocelyn
    Groome, Michelle
    Tempia, Stefano
    Pretorius, Marthi
    Hellferscee, Orienka
    Dawood, Halima
    Haffejee, Summaya
    Variava, Ebrahim
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tshangela, Akhona
    von Gottberg, Anne
    Wolter, Nicole
    Cohen, Adam L.
    Kgokong, Babatyi
    Venter, Marietjie
    Madhi, Shabir A.
    Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged >= 5 Years in a High HIV-Prevalence Setting, 2009-20122015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, article id e0117716Article in journal (Refereed)
    Abstract [en]

    Objective There are few published studies describing severe acute respiratory illness ( SARI) epidemiology amongst older children and adults from high HIV-prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged >= 5 years in South Africa. Methods We conducted prospective surveillance for individuals with SARI from 2009-2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators. Findings We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9%(600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13-19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR): 1.7; 95% CI:1.1-2.7), have pneumococcal infection (OR 2.4; 95% CI: 1.7-3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95% CI: 1.2-2.2) and had a higher case-fatality ratio (8% vs 5%; OR1.7; 95% CI: 1.2-2.3), but were less likely to be infected with influenza (OR 0.6; 95% CI: 0.5-0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8; 95% CI: 1.3-2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95% CI: 1.3-32.0) and supplemental-oxygen therapy (OR 2.6; 95% CI: 2.1-3.2). Conclusion The burden of hospitalized SARI amongst individuals aged >= 5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting.

  • 38. Commins, Scott P.
    et al.
    James, Hayley R.
    Kelly, Libby A.
    Pochan, Shawna L.
    Workman, Lisa J.
    Perzanowski, Matthew S.
    Kocan, Katherine M.
    Fahy, John V.
    Nganga, Lucy W.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Cooper, Philip J.
    Platts-Mills, Thomas A. E.
    The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose2011In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 127, no 5, p. 1286-1293.e6Article in journal (Refereed)
    Abstract [en]

    Background: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives: We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur.

    Methods: Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.

    Results: Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (chi(2) = 26.8, P < .001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A americanum (r(s) = 0.75, P < .001).

    Conclusion: The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.

  • 39.
    Conlan, J Wayne
    et al.
    NRC, Kanada.
    Shen, Hua
    Golovliov, Igor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Oyston, Petra CF
    Chen, Wangxue
    House, Robert V
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Differential ability of novel attenuated targeted deletion mutants of Francisella tularensis subspecies tularensis strain SCHU S4 to protect mice against aerosol challenge with virulent bacteria: effects of host background and route of immunization2010In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 7, p. 1824-1831Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis subspecies tularensis is a highly virulent facultative intracellular pathogen of humans and a potential biological weapon. A live vaccine strain, F. tularensis LVS, was developed more than 50 years ago by pragmatic attenuation of a strain of the less virulent holarctica subspecies. LVS was demonstrated to be highly effective in human volunteers who were exposed to intradermal challenge with fully virulent subsp. tularensis, but was less effective against aerosol exposure. LVS faces regulatory hurdles that to date have prevented its licensure for general use. Therefore, a better defined and more effective vaccine is being sought. To this end we have created gene deletion mutants in the virulent subsp. tularensis strain and tested them for their ability to elicit a protective immune response against systemic or aerosol challenge with the highly virulent wild-type subsp. tularensis strain, SCHU S4. Both oral and intradermal (ID) primary vaccination routes were assessed in BALB/c and C3H/HeN mice as was oral boosting. One SCHU S4 mutant missing the heat shock gene, clpB, was significantly more attenuated than LVS whereas a double deletion mutant missing genes FTT0918 and capB was as attenuated as LVS. In general mice immunized with SCHU S4DeltaclpB were significantly better protected against aerosol challenge than mice immunized with LVS. A single ID immunization of BALB/c mice with SCHU S4DeltaclpB was at least as effective as any other regimen examined. Mice immunized with SCHU S4Delta0918DeltacapB were generally protected to a similar degree as mice immunized with LVS. A preliminary examination of immune responses to vaccination with LVS, SCHU S4DeltaclpB, or SCHU S4Delta0918DeltacapB provided no obvious correlate to their relative efficacies.

  • 40. Coppi, Alida
    et al.
    Natarajan, Ramya
    Pradel, Gabriele
    Bennett, Brandy L.
    James, Eric R.
    Roggero, Mario A.
    Corradin, Giampietro
    Persson, Cathrine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tewari, Rita
    Sinnis, Photini
    The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host2011In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 2, p. 341-356Article in journal (Refereed)
    Abstract [en]

    Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite's major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure-function information relevant to malaria vaccine development.

  • 41.
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Serotonin stimulates survival and proliferation of B-cell lymphomas: Effect on proliferation and expression of oncogenes upon inhibition of serotonin signaling in B-cell lymphoma cell lines2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 42. Dinarello, Charles
    et al.
    Arend, William
    Sims, John
    Smith, Dirk
    Blumberg, Hal
    O'Neill, Luke
    Goldbach-Mansky, Raphaela
    Pizarro, Theresa
    Hoffman, H.
    Bufler, Philip
    Nold, Marcel
    Ghezzi, Pietro
    Mantovani, Alberto
    Garlanda, Cecilia
    Boraschi, Diana
    Rubartelli, Anna
    Netea, Mihai
    van der Meer, Jos
    Joosten, Leo
    Mandrup-Poulsen, Tom
    Donath, Marc
    Lewis, Eli
    Pfeilschifter, Josef
    Martin, Michael
    Kracht, Michael
    Muehl, H
    Novick, Daniela
    Lukic, Miodrag
    Conti, Bruno
    Solinger, Alan
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    van de Veerdonk, Frank
    Gabel, Chiristopher
    IL-1 family nomenclature2010In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 11, no 11, p. 973-973Article in journal (Refereed)
  • 43. Dreborg, S
    et al.
    Holgersson, M
    Basomba, A
    Löfkvist, T
    Möller, Christian
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Evaluation of skin reactivity during (immuno) therapy validation of methods for estimation of changes in skin reactivity and correlation to shock organ sensitivity. Proposal of two simple methods2014In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, p. 613-613Article in journal (Other academic)
  • 44.
    Drobni, Mirva
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Li, Tong
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Krüger, Karina
    Loimaranta, Vuokko
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Kilian, Mogens
    Hammarström, Lennart
    Jörnvall, Hans
    Bergman, Tomas
    Strömberg, Nicklas
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    A host-derived pentapeptide enhancing host-bacteria commensalisms and communication2006In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 74, no 11, p. 6293-6299Article in journal (Refereed)
    Abstract [en]

    Salivary proline-rich proteins (PRPs) attach commensal Actinomyces and Streptococcus species to teeth. Here, gel filtration, mass spectrometry and Edman degradation were applied to show the release of a pentapeptide, RGRPQ, from PRP-1 upon proteolysis by Streptococcus gordond. Moreover, synthetic RGRPQ and derivatives were used to investigate associated innate properties and responsible motifs. The RGRPQ peptide increased 2.5-fold the growth rate of S. gordonii via a Q-dependent sequence motif and selectively stimulated oral colonization of this organism in a rat model in vivo. In contrast, the growth of Streptococcus mutans, implicated in caries, was not affected. While the entire RGRPQ sequence was required to block sucrose-induced pH-decrease by S. gordonii and S. mutans, the N-terminal Arg residue mediated the pH increase (i.e., ammonia production) by S. gordonii alone (which exhibits Arg catabolism to ammonia). Strains of commensal viridans streptococci exhibited PR-P degradation and Arg catabolism, whereas cariogenic species did not. The RGRPQ peptide mediated via a differential Q-dependent sequence motif, adhesion inhibition, and desorption of PRP-1-binding strains of A. naeslundii genospecies 2 (5 of 10 strains) but not of S. gordonii (n = 5). The inhibitable A. naeslundii strains alone displayed the same binding profile as S. gordond to hybrid peptides terminating in RGRPQ or GQSPQ, derived from the middle or C-terminal segments of PRP-1. The present findings indicate the presence of a host-bacterium interaction in which a host peptide released by bacterial proteolysis affects key properties in biofilm formation.

  • 45.
    Duarte, Nádia
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Molecular and cellular mechanisms contributing to the pathogenesis of autoimmune diabetes2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes is an autoimmune disorder determined both by genetic and environmental factors. The Non-obese diabetic (NOD) mouse is one of the best animal models of this disease. It spontaneously develops diabetes through a process resembling the human pathogenesis. The strong association of NOD Type 1 diabetes to the MHC region and the existence of other diabetes susceptibility loci are also in parallel with the human disease. The identity of the genetic factors and biological function mediated by these loci remain, however, largely unknown. Like in other autoimmune diseases, defects in tolerance mechanisms are thought to be at the origin of type 1 diabetes. Accordingly, defects in both central and peripheral tolerance mechanisms have been reported in the NOD mouse model.

    Using a subphenotype approach that aimed to dissect the disease into more simple phenotypes, we have addressed this issue. In paper I, we analyzed resistance to dexamethasone-induced apoptosis in NOD immature thymocytes previously mapped to the Idd6 locus. Using a set of congenic mice carrying B6-derived Idd6 regions on a NOD background and vice-versa we could restrict the Idd6 locus to an 8cM region on the telomeric end of chromosome 6 and the control of apoptosis resistance to a 3cM region within this area. In paper II, further analysis of diabetes incidence in these congenic mice separated the genes controlling these two traits, excluding the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. These results also allowed us to further restrict the Idd6 locus to a 3Mb region. Expression analysis of genes in this chromosomal region highlighted the Lrmp/Jaw1 gene as a prime candidate for Idd6. Lrmp encodes an endoplasmatic reticulum resident protein.

    Papers III and IV relate to peripheral tolerance mechanisms. Several T cell populations with regulatory functions have been implicated in type 1 diabetes. In paper III, we analyzed NOD transgenic mice carrying a diverse CD1d-restricted TCR αVa3.2b9), named 24abNOD mice. The number of nonclassical NKT cells was found to be increased in these mice and almost complete protection from diabetes was observed. These results indicate a role for nonclassical NKT cells in the regulation of autoimmune diabetes. In paper IV, we studied the effects of introducing the diverse CD1d-restricted TCR (Va3.2b9) in immunodeficient NOD Rag-/- mice (24abNODRag-/- mice). This resulted in a surprising phenotype with inflammation of the ears and augmented presence of mast cells as well as spleenomegaly and hepatomegaly associated with extended fibrosis and increased numbers of mast cells and eosinophils in the tissues. These observations supported the notion that NKT cells constitute an “intermediary” cell type, not only able to elicit the innate immune system to mount an inflammatory response, but also able to interact with the adaptive immune system affecting the action of effector T cells in an autoimmune situation. In this context the 24abNODRag-/- mice provide an appropriate animal model for studying the interaction of NKT cells with both innate and adaptive components of the immune systemα.

  • 46. Dörr, Tobias
    et al.
    Möll, Andrea
    Chao, Michael C.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lam, Hubert
    Davis, Brigid M.
    Waldor, Matthew K.
    Differential Requirement for PBP1a and PBP1b in In Vivo and In Vitro Fitness of Vibrio cholerae2014In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, no 5, p. 2115-2124Article in journal (Refereed)
    Abstract [en]

    We investigated the roles of the Vibrio cholerae high-molecular-weight bifunctional penicillin binding proteins, PBP1a and PBP1b, in the fitness of this enteric pathogen. Using a screen for synthetic lethality, we found that the V. cholerae PBP1a and PBP1b proteins, like their Escherichia coli homologues, are each essential in the absence of the other and in the absence of the other's putative activator, the outer membrane lipoproteins LpoA and LpoB, respectively. Comparative analyses of V. cholerae mutants suggest that PBP1a/LpoA of V. cholerae play a more prominent role in generating and/or maintaining the pathogen's cell wall than PBP1b/LpoB.V. cholerae lacking PBP1b or LpoB exhibited wild-type growth under all conditions tested. In contrast, V. cholerae lacking PBP1a or LpoA exhibited growth deficiencies in minimal medium, in the presence of deoxycholate and bile, and in competition assays with wild-type cells both in vitro and in the infant mouse small intestine. PBP1a pathway mutants are particularly impaired in stationary phase, which renders them sensitive to a product(s) present in supernatants from stationary-phase wild-type cells. The marked competitive defect of the PBP1a pathway mutants in vivo was largely absent when exponential-phase cells rather than stationary-phase cells were used to inoculate suckling mice. Thus, at least for V. cholerae PBP1a pathway mutants, the growth phase of the inoculum is a key modulator of infectivity.

  • 47. Ek, A.
    et al.
    Middelveld, R. J. M.
    Bertilsson, Helen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Bjerg, A.
    Ekerljung, L.
    Malinovschi, A.
    Stjarne, P.
    Larsson, K.
    Dahlen, S. -E
    Janson, C.
    Chronic rhinosinusitis in asthma is a negative predictor of quality of life: results from the Swedish GA(2)LEN survey2013In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no 10, p. 1314-1321Article in journal (Refereed)
    Abstract [en]

    BackgroundAsthma and chronic rhinosinusitis (CRS) both impair quality of life, but the quality-of-life impact of comorbid asthma and CRS is poorly known. The aim of this study was to evaluate the impact of CRS and other relevant factors on quality of life in asthmatic subjects. MethodsThis Swedish cohort (age 17-76years) consists of 605 well-characterized asthmatics with and without CRS, 110 individuals with CRS only, and 226 controls and is part of the Global Allergy and Asthma European Network (GA(2)LEN) survey. The Mini Asthma Quality of Life Questionnaire (mAQLQ), the Euro Quality of Life (EQ-5D) health questionnaire, spirometry, skin prick test (SPT), exhaled nitric oxide (FeNO), smell test, and peak nasal inspiratory flow were used. ResultsSubjects having both asthma and CRS have lower mAQLQ scores in all domains (P<0.001) and a lower EQ-5D index value and EQ-5D VAS value (P<0.001) compared to those with asthma only. Asthmatics with CRS have significantly lower FEV1%pred and FVC%pred (88.4 [85.1-91.7] and 99.9 [96.7-103.0], respectively) compared with asthma only (91.9 [90.3-93.4] and 104.0 [102.5-105.5], respectively P<0.05). Multiple regression analysis shows that low asthma quality of life is associated with having CRS (P<0.0001), lower lung function (P=0.008), current smoking (P=0.01), BMI>30kg/m(2) (P=0.04), high age (P=0.03), and a negative SPT (P=0.04). ConclusionsComorbid CRS was a significant and independent negative predictor of quality of life in asthmatics. Other negative factors were lower lung function, current smoking, obesity, advanced age, and having nonatopic asthma.

  • 48.
    Ekici, Rifat
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B cells in Type 1 diabetes: studies on cell surface antibody binding2010Licentiate thesis, monograph (Other academic)
  • 49.
    Ekici, Rifat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thay, Bernard
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Enhanced capture of extramembranous IgM and IgG on B cells in the NOD mouse: implications for immune complex trapping2009In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 21, no 5, p. 533-541Article in journal (Refereed)
    Abstract [en]

    Binding of various antibody isotypes to B cells through either FcgammaRs or complement receptors has been attributed to play several roles, e.g. in immune complex (IC) transportation and regulation of B cell receptor signaling. We have revealed a novel B cell intrinsic receptor for IgM and IgG which is present in C57BL/6 (B6) mice and is more abundant in non-obese diabetic (NOD) mice. As a consequence, the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared with B6 mice. The effect of this aberration was that all B cells in peripheral blood of (NOD.IgH(a) x B6(IgH(b)))F(1) mice carried both IgM allotypes on their surface. In addition, analysis of IC binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with B6. We hypothesize that this novel Ig-binding receptor is part of the normal immune system function. The aberrant function in the NOD mouse could contribute to the development of Type 1 diabetes by altering normal B cell functions such as activation, IC transportation and B cell homeostasis.

  • 50. Elmwall, Jonas
    et al.
    Kwiecinski, Jakub
    Na, Manli
    Ali, Abukar Ahmed
    Osla, Veronica
    Shaw, Lindsey N.
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Sävman, Karin
    Josefsson, Elisabet
    Bylund, Johan
    Jin, Tao
    Welin, Amanda
    Karlsson, Anna
    Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus2017In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 85, no 7, article id e00177-17Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a beta-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of S. aureus caused galectin-3 degradation. Similar proteolytic capacities were found in Staphylococcus epidermidis isolates but not in Staphylococcus saprophyticus. Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on S. aureus virulence was studied in a murine skin infection model. In galectin-3 (+)/(+) mice, SspB-expressing S. aureus caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3 (+)/(+) mice, which overall showed smaller lesion sizes than the galectin-3 (+)/(+) animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.

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